Quantitative Methods in Toxicology for Human Dose-Response Assessment

The process of human risk assessment can be divided into hazard identification, dose-response assessment, exposure assessment and risk characterisation. For human risk assessment quantitative methods and models are applied. Which model should be applied depends on the nature of the question to be answered. A simple model can be applied if a standard has to be established, while a more complex model is required in the case a standard is exceeded and the health impact on a population has to be quantified. In this report an overview is given of important dose-response assessment methods and models as well as their application area. A distinction is made in methods and models for genotoxic compounds and non-genotoxic compounds. The non-genotoxic compounds are assumed to have a threshold below which no effect occurs. Methods to estimate the threshold dose and to derive a human reference dose are presented. Furthermore, extrapolation problems that arise when animal data have to be translated to human data are discussed briefly. PBPK modelling is discussed as a method to improve interspecies extrapolation. For non-genotoxic as well as genotoxic compounds curve-fitting models are described. In addition a biologically based model for genotoxic agents is briefly discussed. Finally methods that are applied and investigated at RIVM are presented and recommendations are given