Comprehensive integration framework of CFD – Local and whole body hybrid PBPK in indoor chemical exposure modeling: An inhalation exposure study

Di(2-ethylhexyl) phthalate (DEHP) is the most pervasive phthalate in the environment and is identified as an endocrine-disrupting chemical causing dysfunction in multiple organs. This study has employed a novel Computational Fluid Dynamics (CFD)-based pollutant transport analysis and a local-whole-body hybrid physiologically based pharmacokinetics (PBPK) model to elucidate the systematic disposition of DEHP and its metabolites in human organs via inhalation exposure. A local PBPK model was constructed for the respiratory tract, employing the CFD and air-mucus-tissue-blood (AMTB) model to investigate the DEHP transportation and diffusion through the respiratory tissue during breathing activities. This is seamlessly linked with the whole-body PBPK model. As a result, the validation work demonstrates the reliability of the CFD and local whole-body hybrid PBPK model. The absorbed and plasma uptake of DEHP were found to be dependent on the airway tissue thickness and morphometry. Visualization reveals a non-uniform DEHP distribution over the respiratory surface. The whole-body PBPK model tracks DEHP metabolism in the liver and intestine. Cumulative concentration profiles significantly varied across organs as a function of biochemical and physiological parameters. Post-exposure monitoring unveils a slow clearance in the brain, bone, skin, adipose, gonads, and muscle. At the concentration levels covered in this study, a proportional relationship was quantified between the exposure concentration to the cumulative airway tissue concentration and organ concentration. The results consolidate the current technique as a reliable tool to link indoor DEHP exposure to the corresponding adverse effects on human health via inhalation.