A Unified Whole Lung PBK Model for Inhalational Uptake of Gases and Aerosols in Men.

Abstract

Assessing the risk or benefit of an inhaled substance is challenging due to the variety of forms it can take (gas, vapor, particle, or droplet) and the complex biological processes involved in its uptake and retention. Physiologically based kinetic (PBK) models offer an alternative to in vivo experiments. However, PBK models for inhalational uptake are to date either designed for gases/vapors or airborne particulates, often with only low regional compartmentalization. The here-presented, newly developed model combines both applications. Its mechanisms are an amalgamation of PBK and non-PBK models integrated into a multicompartmental description of the human lung to include the relevant uptake and clearance processes in the different lung regions, of which macrophage-mediated dissolution is novel to PBK modeling. The model was designed to use a minimal number of substance-specific input parameters, which can be derived from in vitro assays or in silico methods. Model predictions for hypothetical substances with varying physicochemical properties were performed, along with rudimentary sensitivity analyses to identify the most important parameters for gases/vapors and particles. This novel PBK model combines all these aspects and provides in silico predictions of systemic and local lung concentrations, reducing uncertainty in risk assessments and supporting drug development. It serves as a valuable tool to translate nominal ambient air doses into effective localized doses within the lung.