title: The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans.
abstract: The role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account that they need to distinguish adverse and adaptive changes in cells. The framework defines the place of in vitro systems in the context of data on exposure, structural and physico-chemical properties, and toxicodynamic and biokinetic modeling. It outlines the determination of a proper point-of-departure (PoD) for in vitro-in vivo extrapolation, allowing implementation in risk assessment procedures. A BoT will need to take into account both the dynamics and the kinetics of the compound in the in vitro systems. For the implementation of the proposed framework it will be necessary to collect and collate data from existing literature and new in vitro test systems, as well as to categorize biomarkers of toxicity and their relation to pathways-of-toxicity. Moreover, data selection and integration need to be driven by their usefulness in a quantitative in vitro-in vivo extrapolation (QIVIVE).
authors.affiliation: Institute for Risk Assessment Sciences, Division of Toxicology, Utrecht University, The Netherlands. b.blaauboer@uu.nl
authors.forename: Bas J
authors.initials: BJ
authors.lastname: Blaauboer
authors.forename: Kim
authors.initials: K
authors.lastname: Boekelheide
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.forename: Mardas
authors.initials: M
authors.lastname: Daneshian
authors.forename: Milou M L
authors.initials: MM
authors.lastname: Dingemans
authors.forename: Alan M
authors.initials: AM
authors.lastname: Goldberg
authors.forename: Marjoke
authors.initials: M
authors.lastname: Heneweer
authors.forename: Joanna
authors.initials: J
authors.lastname: Jaworska
authors.forename: Nynke I
authors.initials: NI
authors.lastname: Kramer
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.forename: Hasso
authors.initials: H
authors.lastname: Seibert
authors.forename: Emanuela
authors.initials: E
authors.lastname: Testai
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vandebriel
authors.forename: James D
authors.initials: JD
authors.lastname: Yager
authors.forename: Joanne
authors.initials: J
authors.lastname: Zurlo
mesh_terms: D000826:Animal Testing Alternatives / Q000379:methods; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards*
chemical_list: D015415:Biomarkers; D015386:Hazardous Substances