Figure 1: The PBPK model structure developed by Nong and coworkers [14] describing tissue manganese kinetics in adult rats. The overall PBPK model structure is shown in (a); an expanded view of the respiratory tract modeling is shown in (b). Inhaled manganese is absorbed through deposition of particles on the nasal and lung epithelium. Most of the manganese deposited in the nasal cavity is absorbed into the systemic blood while a small fraction undergoes direct delivery to the olfactory bulb. Every tissue has a binding capacity, 𝐵 m a x , with affinity defined by association and dissociation rate constants ( 𝑘 𝑎 , 𝑘 𝑑 ). Free manganese moves in the blood throughout the body and is stored in each tissue as bound manganese. Influx and efflux diffusion rate constants ( 𝑘 i n , 𝑘 o u t ) allow for differential increases in manganese levels for different tissues. 𝑄 𝑝 , 𝑄 𝑐 , 𝑄 t i s s u e refer to pulmonary ventilation, cardiac output, and tissue blood flows. Reprinted from [14] (with permission).