Abstract
The present study aimed to establish a physiologically based toxicokinetic (PBTK) model to investigate the absorption, retention, and transport of inhaled nano-sized titanium dioxide (TiO(2)-NPs) particles in rats, thereby providing a basis for understanding the absorption, distribution, and elimination mechanisms of TiO(2)-NPs in various organs. A detailed respiratory module and the Hill coefficient equation were adopted in the PBTK model. Calibration and validation of the model were conducted using the only two available inhalation biodistribution datasets for TiO(2)-NPs found in the literature, encompassing different doses and exposure conditions. The overall fit with both datasets was acceptable with R(2) value of 0.95 in respiratory system and 0.88 in the secondary organs. The sensitivity analysis indicated that the alveolar-interstitial transfer rate (K(alv_inter)) and tissue-blood distribution coefficients (P(lu), P(li), P(ki)) significantly influenced the retention of TiO(2)-NPs in pulmonary regions and distribution to secondary organs, with these parameters exhibiting time-dependent behavior. The PBTK model demonstrates a good predictive performance for TiO(2)-NPs content in all rat organs, with simulated values consistently ranging within 0.5- to 2-fold of the measured data. In last, we developed a PBTK model that can well predict the in vivo distribution of inhaled TiO(2)-NPs and provided a novel computational tool for cross-species extrapolation of human inhalation exposure and subsequent biodistribution.