Inhalation exposure and uptake modeling of particle-associated phthalate: from respiratory deposition and clearance to organ toxicokinetics.

This study aimed to develop a novel hybrid computational fluid-particle dynamics (CFPD)-physiologically-based pharmacokinetics (PBPK) model to elucidate the toxicokinetics of particle-associated di(2-Ethylhexyl) phthalate (DEHP) in the human body via inhalation exposure. Initially, a steady mucus flow was simulated with constant rates for the upper and lower respiratory tracts. The desorption, dynamics, and tissue absorption of DEHP were simultaneously described by the Eulerian approach and the mucus-tissue-blood model. Mucociliary clearance effects were examined against the DEHP and its particle carriers using the steady rate constant. Eventually, metabolism and organ distribution were implemented using whole-body PBPK modeling. The model could predict the excretion terms of DEHP metabolites compared to in vivo data. The desorption from particles and absorption of DEHP into deeper tissue layers were governed by the deposition patterns and airway tissue layer thickness. Additionally, mucus clearance was less effective against DEHP than against particulate carriers. Metabolism and distribution across organs emphasize varied instantaneous concentration profiles as a function of biochemical and physiological parameters. In particular, the slow clearance of DEHP has been observed in the brain, muscle, and adipose tissue compared to others. The results confirm that the proposed technique is a reliable tool for exploring the effects of mucus clearance on foreign substances and linking indoor DEHP with its fate in human organs.