A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation

Abstract

The gas 1,3-butadiene (BU) is an important industrial chemical and an environmental air pollutant. BU has been shown to be a weak carcinogen in the rat but a potent carcinogen in the B6C3F1 mouse. This species difference makes risk extrapolation to humans difficult and the underlying mechanism should be clarified before meaningful risk extrapolation to humans can be made. One possible explanation for the species differences in cancer response is that there are quantitative species differences in the formation of genotoxic epoxides. To investigate this possibility a physiologically based pharmacokinetic (pbpk) model for BU together with its first reactive metabolite 1,2-epoxybutene-3 (butadiene monoxide, BMO) was developed. Previously reported values on hepatic glutathione (GSH) turnover, depletion of hepatic GSH in rodents exposed to BU, and in vitro metabolic data of BU and BMO were included in the model, which incorporates intrahepatic first-pass hydrolysis of BMO and the ordered sequential, ping-pong mechanism to describe the enzyme kinetics of BMO-GSH conjugation. In vitro studies were carried out to obtain tissue: air partition coefficients of BU and BMO in rat tissue homogenates. The simulated pharmacokinetics of BU, BMO, and GSH agreed with previously published experimental observations in rat and mouse obtained in closed and open chamber experiments. According to the model, the internal dose of BMO (expressed either as the concentration in mixed venous blood or as the area under the concentration-time curve) is approximately 1.6 times higher in the mouse than in the rat for exposure to BU below 1000 ppm. At higher exposure levels, GSH depletion occurs in the mouse, but not in the rat, after about 6-9 h. This GSH depletion results in up to 2-3 times higher internal doses in the mouse than in the rat. The clear but relatively small species differences in body burdens of BMO indicated from our model can only partly explain the marked species difference in cancer response between mice and rats exposed to BU.

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

“…The diffusional clearance term was estimated by fitting the model to blood SO concentration following inhalation exposure to ST in rodents (Cruzan et al, 1998(Cruzan et al, , 2001 and humans (Johanson et al, 2000). The conjugation of cytosolic SO with GSH is described by an ordered sequential "ping-pong" mechanism between GSH, SO, and GST, consistent with previous model formulations (Johanson & Filser, 1993). Because of its role as a cofactor in the reaction catalyzed by GST, GSH is depleted in liver and lung.…”

“…The kinetics of the biotransformation of ST in the liver and the respiratory tract tissues are modeled according to the previously published works of Johanson and Filser (1993) and Csanady et al (1994). The oxidation of ST by P-450 and the hydrolysis of SO by EH are represented by a saturable process with Michaelis-Menten kinetics.…”

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

“…The Authors declare that no financial or personal conflicts of interest exist with regard to the submission of this manuscript. [27]. b [12].…”

An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

“…The apparent V max , K m and k values were determined by fitting the data to the respective equations using GraphPad Prism (version 5.04, GraphPad Software, Inc. (La Jolla, USA)) except for K m_G , which was set to 100 μM based on literature data obtained with various substrates (Johanson and Filser, 1993;Csanady and Filser, 2007).…”