Fraunhofer Institute for Toxicology and Experimental MedicineModeling the Inhalation of Gases and Aerosols
Assessing the risks or potential effects of inhaled substances is challenging. The reason: these substances can occur in very different forms – such as gases, vapors, particles, or droplets – and their absorption and retention in the lung are determined by complex biological processes. Physiologically based kinetic (PBK) models provide an important alternative to animal testing or other in vivo experiments.
However, existing PBK models for inhalation are usually designed either for gases and vapors or for airborne particles and only represent the different regions of the lung in a simplified manner. Within the framework of the Cefic-LRI-B21 project (funded by Cefic as part of the Long-Range Research Initiative, LRI) and the EU RISK-HUNT3R project, researchers at Fraunhofer ITEM have developed a new model that, for the first time, combines both approaches in a single framework (published under DOI: 10.1002/psp4.70117).
To achieve this, mechanisms from PBK and non-PBK models were integrated into a detailed, multi-compartmental description of the human lung. This allows the key processes of absorption and elimination in different lung regions to be realistically represented. A novel aspect of this model is the inclusion of macrophage-mediated particle clearance, which has not been incorporated in PBK models before.
The model was designed to require only a few substance-specific input parameters, which can be obtained from in-vitro experiments or via in-silico methods. To evaluate the model, simulations were conducted for hypothetical substances with different physicochemical properties. Simple sensitivity analyses were also performed to identify the main factors affecting gases, vapors, and particles.
Overall, this new PBK model enables in-silico predictions of both systemic exposure and local concentrations in the lung. It can reduce uncertainties in risk assessment and support the development of inhaled drugs. Additionally, the model helps translate nominal environmental exposures into biologically relevant, locally active lung doses.
