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 551824
Title Role of toxicokinetics and alternative testing strategies in pyrrolizidine alkaloid toxicity and risk assessment; state-of-the-art and future perspectives
Author(s) Ning, Jia; Chen, Lu; Rietjens, Ivonne M.C.M.
Source Food and Chemical Toxicology 131 (2019). - ISSN 0278-6915
DOI https://doi.org/10.1016/j.fct.2019.110572
Department(s) Toxicology
WIMEK
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2019
Keyword(s) Max 6) toxicokinetics - Physiologically-based kinetic (PBK) models - Pyrrolizidine alkaloids - QIVIVE - Read-across
Abstract

Toxicokinetics influences the toxicity of chemicals. This also holds for 1,2-unsaturated pyrrolizidine alkaloids (PAs), which need bioactivation to become toxic. Given that only for a limited number of 1,2-unsaturated PAs in vivo toxicity data are available, alternative testing strategies including read-across and quantitative in vitro to in vivo extrapolation (QIVIVE) are important. This paper presents how physiologically-based kinetic (PBK) models for the PAs lasiocarpine and riddelliine were developed for rat and human, and used for conversion of in vitro data for toxicity in primary hepatocytes to quantitatively predict in vivo acute liver toxicity for both rat and human. Marked differences in toxicokinetics were observed between the two model PAs influencing the predicted in vivo toxicity. In a next step, in vitro toxicokinetic data that predicted relative bioactivation of the PAs, were shown to provide a possible basis for read-across from the BMDL10 for tumor formation by riddelliine of 237 μg/kg bw per day to other PAs for which tumor data are lacking. It is concluded that when comparing toxicity of different PAs, or when extrapolating in vitro toxicity data for PAs to the in vivo situation, differences in toxicokinetics should be taken into account, while future challenges are also discussed.

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