Lung dosimetry modelling in nanotoxicology: A critical analysis of the state of the art

Since inhalation is the major route of entry for NMs into the body, it is necessary to assess the deposition of nanomaterials (NMs) in the respiratory system and their subsequent translocation to extra-pulmonary tissues. This is achieved with the aid of lung dosimetry models. The main mechanism responsible for the deposition of NMs in the respiratory tract is diffusion as the NMs collide with air molecules, while other deposition mechanisms, including inertial impaction, gravitational settling, and interception, do not contribute significantly. The significance of each mechanism depends on particle characteristics (such as size, shape and hygroscopicity), location in the lung (trachea, bronchi and alveoli) and ventilation parameters such as breathing rates, tidal volume, breathing frequency. In the end, the toxicology and risk assessment of inhaled NMs will depend on deposition rates in various parts of the lung coupled with clearance/retention rates that may include physical removal by ciliary clearance, macrophage-mediated clearance and lymphatic clearance, as well as dissolution and disintegration. In particular, the rate of dissolution of NMs in the lungs significantly affects the clearance rate, while the distribution of the NMs to other parts of the body largely depends on particle size. A number of models have been designed to estimate the deposition and retention of inhaled particles, ranging from empirical models that do not incorporate lung geometry through stochastic statistical models to mechanistic multiple-path models that are based on actual airway measurements. Various assumptions that are used in these models, including use of a symmetrical or asymmetrical lung, affect the performance of the models. This study presents the state of the art in in vivo dosimetry in nanotoxicology, with a focus on the design of the models and the required input data used, as well as verification and validation status of the model.