PHYSIOLOGICALLY-BASED TOXICOKINETIC MODELING OF 1,3-BUTADIENE LUNG METABOLISM IN MICE BECOMES MORE IMPORTANT AT LOW-DOSES

This paper describes a physiologically based toxicokinetic model for 1 ,3-butadiene uptake, distribution, and metabolic clearance in mice. Mo del parameters for metabolic activity were estimated from the correspo ndence between computer simulation studies and experimental results as published in the literature. The parameterized model was validated wi th independent literature data. With the resulting model, the relative importance of lung metabolism as compared to metabolism in the liver increased with decreasing ambient air concentrations. This was due to saturation of metabolism in the alveolar area of the lung, which occur red in the simulations at ambient air concentrations well below curren t threshold limit values. At higher air concentration, liver metabolis m became relatively more important. The tendency toward increased impo rtance of lung metabolism at low doses indicates the necessity of care ful extrapolation of in vive results to low doses. Moreover, this tren d may also contribute to species difference in susceptibility to the c arcinogenic activity of butadiene.