Toxicodynamic modelling and the interpretation of in vitro toxicity data

The results of in vitro toxicity experiments are not easily extrapolated to 'toxicological risk' for an intact organism. One of the most obvious differences between the situation in vitro and in vivo is the absence of the processes of absorption, distribution, metabolism and excretion that govern the exposure of the target tissues of the organism in vivo. The development of biokinetic models is aimed at estimating the relevant target tissue concentration of a compound. In our study, biokinetic models were constructed, where possible, solely on the basis of in vitro derived parameters for biotransformation as well as on partition coefficients determined or calculated from physicochemical structures. Another requirement is the existence of appropriate in vitro biological systems for the measurement of relevant effects. This requires a thorough knowledge of the possible mechanisms of toxic action, and of the physiology of the target organs. When these prerequisites are met (i.e. when the appropriate parameters can be quantified in a non-animal system), then an estimate of the dynamics in vitro can be made (e.g. as a critical active concentration). This will then result in a model describing a compound's dynamics. Eventually, the result of biokinetic and toxicodynamic models will need to be integrated in a compound's hazard and/or risk evaluation. A study carried out in the ECITTS programme showed promising results for the estimation of the acute and chronic systemic toxicity of a number of neurotoxic compounds.