Support for refining animal usage, evolution of the Centre's website, dissemination of advances in the field and twelve new projects. (360G-Wellcome-086819_Z_08_Z)

"Physiologically based pharmacokinetic (PBPK) modelling has been proposed as having great potential for the reduction and replacement of animals in experimentation. PBPK modelling is a powerful means of simulating the factors that determine tissue dose within an organism. The ability to correlate tissue dose with a response e.g., a health effect, has led to the increased use of PBPK models in chemical risk assessment (RA). They are ideal tools for integrating disparate in vitro and in vivo mechanistic, pharmacokinetic, toxicological and chemical specific information. Consequently, the greater demands of PBPK models for more varied input parameters have led to them being described as 'data hungry' and 'resource intensive'. In order to address the latter and facilitate the more widespread use of PBPK modelling in chemical risk assessment, the Health and Safety Laboratory has developed and merged a model equation generator (MEGEN) and PBPK parameter database, which permit the construction of models in minutes rather than days. The user is engaged in a dialogue relating to the details of the physiology of the system to be modelled, and the biochemistry and physicochemistry of the compound of interest. Model parameters are retrieved from an electronic database, which is interrogated during use of MEGEN. On the basis of this information, a model is produced in the form of an XML document, which provides a format for generic storage of models. The XML model can be exported and transformed to a preferred commercial visualisation script. The ability to integrate in vitro data into PBPK models enhances the value, and facilitates the interpretation of many in vitro techniques proposed as alternatives to the use of animals in toxicological research. It is envisaged that MEGEN will play a major role in shifting the emphasis from the perceived requirement for considerable expertise in mathematics and computer programming to biology. This shift should encourage an increased take-up and use of PBPK modelling in chemical RA and facilitate the inclusion of validated in vitro alternatives in the risk assessment process. Therefore, the greater availability of such a PBPK modelling capability could potentially also lead to a marked reduction in the use of animals."