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    A PBPK-model for B(a)P in the rat relating dose and liver DNA-adduct level

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    Authors
    Zeilmaker MJ
    Eijkeren JCH van
    Olling M
    Series/Report no.
    RIVM Rapport 658603008
    Language
    en
    
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    Title
    A PBPK-model for B(a)P in the rat relating dose and liver DNA-adduct level
    Translated Title
    Een PBPK-model voor B(a)P in de rat: relatie tussen dosis en DNA adduct niveaus in de lever
    Publiekssamenvatting
    In M. Olling et al. (1995) an experiment was reported about the toxicokinetics of Benzo-a-Pyrene B(a)P in rats after repeated daily dosing p.o. From this experiment it appeared that the kinetic parameters AUC, Cmax and tmax varied as a function of time. At the first day of the experiment the values for AUC and Cmax were highest, while the value for tmax was lowest. At day 5 and day 12, i.e. the fifth day of the first and second week, AUC and Cmax were highest and tmax was lowest. However, at day 15, i.e. the first day after the weekend, during which the animals were not dosed, the values were intermediate and almost restored. The observations regarding Cmax can be explained by Ah-receptor dependent autoinduction of B(a)P. In Zeilmaker et al. (1997) a cellular model was reported for Ah-receptor dependent P450 induction. This model was incorporated in a Physiologically Based PharmacoKinetic (PBPK) model of the rat. In this report it is tried to explain the experimental observations of Olling et al. (1995) by the application of the model concepts of Zeilmaker et al. (1997) in a PBPK model for B(a)P in the rat. Based on the calibrated B(a)P model for the rat, the following questions will be raised within the frame of model concept and parametrization, assuming a daily oral dosing regime: - what is the relation between dose level and "steady state"; CB(a)Pmax, daily AUC B(a)P, CMetmax, daily AUCMet (here "Met" stands for metabolized B(a)P) and DNA adducts in the liver
    In Olling et al. (1995) wordt gerapporteerd over een experiment met betrekking tot de toxicokinetiek van Benzo-a-Pyreen (B(a)P) in ratten na herhaalde dagelijkse orale dosering. Uit dit experiment bleek dat de kinetische parameters AUC, Cmax en tmax varieerden als functie van de dag van toediening. Op dag 5 en 12 van het experiment bijvoorbeeld waren AUC en Cmax lager dan op dag 1, terwijl op dag 15, na het weekend gedurende welke geen B(a)P werd toegediend, parameters weer bijna terug op het niveau van dag 1 waren. De waarnemingen aangaande Cmax kunnen verklaard worden door Ah-receptor afhankelijke autoinductie van het metabolisme van B(a)P. In Zeilmaker et al. (1997) wordt een PBPK model gentroduceerd over Ah-receptor afhankelijke inductie van P450-enzymen en het daaruit voortvloeiende B(a)P metabolisme. In dit rapport wordt een gedeelte van de observaties uit Olling et al. verklaard met een PBPK model voor B(a)P in de rat volgens de concepten in Zeilmaker et al. (1997). Met het gecalibreerde model zijn simulaties uitgevoerd die de vraag beantwoorden over de relatie tussen dosisniveau en de interne concentratie van moederstof en metabolieten, en over de relatie tussen dosisniveau en P450-enzym inductiestatus, EROD activiteit en DNA-adduct niveau.
    Publisher
    Rijksinstituut voor Volksgezondheid en Milieu RIVM
    URI
    http://hdl.handle.net/10029/10239
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    RIVM official reports

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