An integrated approach to the prediction of systemic toxicity using computer-based biokinetic models and biological in vitro test methods: Overview of a prevalidation study based on the ECITTS project

Chemical toxicity was estimated by integrating in vitro study results with physiologically-based biokinetic models for eight neurotoxic compounds (ben zene, toluene, lindane, acrylamide, parathion;oxon, caffeine, diazepam and phenytoin), In vitro studies on general and specific neurotoxicity were per formed and biotransformation and tissue-blood distribution studies were use d in modelling the biokinetic behaviour of the compounds. Subsequently, neu rotoxicity was estimated from the integrated in vitro and kinetic studies. These results were compared with in vivo data from the literature on minima l neurotoxicity for these compounds, such as lowest-observed-effect levels (LOELs), The discrepancy between estimated and experimental LOELs ranged fr om 2- to 10-fold. LOEL estimates for compounds with a relatively low toxici ty were more accurate than for compounds with a relatively high toxicity. L OELs for the most active compounds could only be established after consider ation of additional in vitro results from the literature. The present study has generated encouraging results on the risk assessment of chemicals from in vitro studies and computer simulations and has identified some key dire ctions for future research. (C) 1999 Elsevier Science Ltd. Ali rights reser ved.