Estimation of toxicokinetic population parameters in a four-stage hierarchical model

A basic part in the risk assessment of potential carcinogens is the determination of toxicokinetic parameters. The partition of the xenobiotic in the body of experimental animals is a first step of the biochemical pathway of the formation of DNA adducts which might lead to the development of cancer. Fundamental in the extrapolation from one species to another is the characterisation of processes by means of population parameters. Nevertheless, the consideration of individual parameters varying between repeated experiments and different doses is of great importance to obtain a more precise insight into the variability structure of the process so that a valid basis for further research is the final result. Two nonlinear four-stage hierarchical models for a repeated measurement design and for repeated exposures to different doses are presented. The estimation of the individual and population parameters as well as of the covariance matrices is performed by an EM algorithm.