Title : Pbpk modelling under the real-life-risk-simulation approach: 3R and conventional in-vivo testing for cumulative risk assessment
Environmental chemicals are currently regulated almost exclusively on a single-chemical exposure basis. In reality, people are exposed to chemical mixtures on a daily basis via many different exposure scenarios. The global scientific community has supported efforts to develop the toxicological evaluation and regulation of chemical mixtures for a considerable number of years. The study of the effects on human and animal health, as well as the environment, from exposure to chemical mixtures requires appropriate fit-for-purpose approaches including New Approach Methodologies (NAM) which endeavour to replace animal studies. For the foreseeable future these approaches will continue to depend on some in vivo testing although they might provide data for the development of animal-free toxicology testing tools.
The Real-Life Risk Simulation (RLRS) approach aims to study long-term-low-dose exposure to chemical mixtures and includes replicating such exposure scenarios in rodents. However, the current accepted paradigm of animal testing, does not provide sufficient information chemical mixtures risk assessment. The in vivo data currently generated could be combined with modelling approaches to: optimise experimental protocols (such as appropriate dose selection for the studied mixtures), study possible interactions (as with comparison of modelling predictions and real experimental in vivo data), and to move towards predictions of toxicity. Having these in mind we consider PBPK modelling as a key future element of the RLRS approach.
In this presentation mixtures toxicology assessment approaches undertaken to date will be summarised, data gaps highlighted, and the potential for PBPK modelling to provide a bridge to the development of animal-free toxicology tools and conventional in vivo testing for cumulative risk assessment following long-term-low-dose exposure to chemical mixtures will be discussed.