Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 505338
Title Predicting points of departure for risk assessment based on in vitro cytotoxicity data and physiologically based kinetic (PBK) modeling : The case of kidney toxicity induced by aristolochic acid I
Author(s) Abdullah, Rozaini; Alhusainy, Wasma; Woutersen, Jasper; Rietjens, Ivonne M.C.M.; Punt, Ans
Source Food and Chemical Toxicology 92 (2016). - ISSN 0278-6915 - p. 104 - 116.
Department(s) Sub-department of Toxicology
RIKILT - BU Toxicology Bioassays & Novel Foods
Publication type Refereed Article in a scientific journal
Publication year 2016
Keyword(s) Aristolochic acid I (AAI) - In vitro-in vivo extrapolation - Kidney toxicity - Physiologically based kinetic (PBK) model - Physiologically based pharmacokinetic (PBPK) model - Risk assessment

Aristolochic acids are naturally occurring nephrotoxins. This study aims to investigate whether physiologically based kinetic (PBK) model-based reverse dosimetry could convert in vitro concentration-response curves of aristolochic acid I (AAI) to in vivo dose response-curves for nephrotoxicity in rat, mouse and human. To achieve this extrapolation, PBK models were developed for AAI in these different species. Subsequently, concentration-response curves obtained from in vitro cytotoxicity models were translated to in vivo dose-response curves using PBK model-based reverse dosimetry. From the predicted in vivo dose-response curves, points of departure (PODs) for risk assessment could be derived. The PBK models elucidated species differences in the kinetics of AAI with the overall catalytic efficiency for metabolic conversion of AAI to aristolochic acid Ia (AAIa) being 2-fold higher for rat and 64-fold higher for mouse than human. Results show that the predicted PODs generally fall within the range of PODs derived from the available in vivo studies. This study provides proof of principle for a new method to predict a POD for in vivo nephrotoxicity by integrating in vitro toxicity testing with in silico PBK model-based reverse dosimetry.

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