IN VITRO-BASED AND IN VIVO-BASED SIMULATIONS OF BENZENE UPTAKE AND METABOLISM IN RATS

The metabolism of benzene was modelled in the rat by application of a physiologically based pharmacokinetic (PBPK) model. The model paramete rs were set by using reference physiological parameter values and repo rted partition coefficients from in vitro studies. Three sets of V-max and K-m values for benzene, derived from published in vitro studies, were substituted into the model while keeping all other model paramete rs constant. These model simulations were compared with two sets of em pirical data on the metabolism or uptake of benzene after inhalation e xposure. It was observed that the biotransformation parameter sets der ived in vitro predicted all empirical data within a factor of two. In addition, it was observed that simulations across the two sets of empi rical data which used biotransformation parameters obtained by fitting to one set of data to simulate the other set, led to results comparab le to those in the in vitro-based simulations. It is concluded that th e results of in vitro studies can be directly applied in a PBPK model in order to estimate the in vivo uptake and metabolism of benzene on t he basis of previously determined model parameter assumptions. These r esults support earlier studies on the application of in vitro techniqu es for deriving PBPK model parameters. On the basis of other studies o n the simulation of benzene kinetics, it is also concluded that additi onal studies are required to extend the validity of this approach for other compounds.