Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish
dc.contributor.author
dc.date.accessioned
2017-05-22T10:58:21Z
dc.date.available
2017-05-22T10:58:21Z
dc.date.issued
2016-02-26
dc.identifier.issn
2045-2322
dc.identifier.uri
dc.description.abstract
The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-specific uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Nature Publishing Group
dc.relation.isformatof
Reproducció digital del document publicat a: http://dx.doi.org/10.1038/srep21978
dc.relation.ispartof
Scientific Reports, núm. 6, art. 21978
dc.relation.ispartofseries
Articles publicats (ICRA)
dc.rights
Attribution 4.0 Spain
dc.rights.uri
dc.subject
dc.title
Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.embargo.terms
Cap
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi