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dc.contributor.authorHessel, Ellen V S
dc.contributor.authorStaal, Yvonne C M
dc.contributor.authorPiersma, Aldert H
dc.date.accessioned2018-03-22T11:53:48Z
dc.date.available2018-03-22T11:53:48Z
dc.date.issued2018-03-12
dc.identifier.citationDesign and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing. 2018 Toxicol. Appl. Pharmacol.en
dc.identifier.issn1096-0333
dc.identifier.pmid29544899
dc.identifier.doi10.1016/j.taap.2018.03.013
dc.identifier.urihttp://hdl.handle.net/10029/621677
dc.description.abstractDevelopmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area. Given the impressive progress in mechanistic knowledge of human biology and toxicology, the time is right for a conceptual approach for designing testing strategies that cover the integral mechanistic landscape of developmental neurotoxicity. The ontology approach provides a framework for defining this landscape, upon which an integral in silico model for predicting toxicity can be built. It subsequently directs the selection of in vitro assays for rate-limiting events in the biological network, to feed parameter tuning in the model, leading to prediction of the toxicological outcome. Validation of such models requires primary attention to coverage of the biological domain, rather than classical predictive value of individual tests. Proofs of concept for such an approach are already available. The challenge is in mining modern biology, toxicology and chemical information to feed intelligent designs, which will define testing strategies for neurodevelopmental toxicity testing.
dc.language.isoenen
dc.rightsArchived with thanks to Toxicology and applied pharmacologyen
dc.titleDesign and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing.en
dc.typeArticleen
dc.identifier.journalToxicol Appl Pharmacol 2018; advance online publication (ahead of print)en
html.description.abstractDevelopmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area. Given the impressive progress in mechanistic knowledge of human biology and toxicology, the time is right for a conceptual approach for designing testing strategies that cover the integral mechanistic landscape of developmental neurotoxicity. The ontology approach provides a framework for defining this landscape, upon which an integral in silico model for predicting toxicity can be built. It subsequently directs the selection of in vitro assays for rate-limiting events in the biological network, to feed parameter tuning in the model, leading to prediction of the toxicological outcome. Validation of such models requires primary attention to coverage of the biological domain, rather than classical predictive value of individual tests. Proofs of concept for such an approach are already available. The challenge is in mining modern biology, toxicology and chemical information to feed intelligent designs, which will define testing strategies for neurodevelopmental toxicity testing.


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