Physiologically based pharmacokinetic modeling of polychlorinated biphenyl-153: cross-species extrapolation and human...

Polychlorinated biphenyl-153 (PCB-153) is a representative organic pollutant that can accumulate in the human body, particularly in adipose tissue, for long periods due to its environmental persistence and high lipid solubility. Existing risk assessments primarily rely on simple extrapolations based on blood concentrations, and a quantitative approach that considers internal exposure at the tissue level is lacking. The main objective of this study was to establish a human physiologically based pharmacokinetic (PBPK) model for PCB-153 and to quantitatively predict tissue accumulation in the human body based on this model, thereby suggesting the possibility of expanding its application as a precise and scientific human risk assessment tool in the future. Based on existing mouse experimental data, a PBPK model was constructed and validated, and a whole-body human PBPK model was established through interspecies extrapolation. Monte Carlo simulations were then performed, considering physiological variations in the adult population, to predict concentration-time curves for major human tissues (fat, liver, brain, skin, and plasma) following a single dose (20 mg/kg) and repeated exposures at the reference dose (RfD) level (5.86 ng/kg/day). The simulation results based on the human PBPK model established in this study showed that adipose tissue showed the highest accumulation pattern with an average partition coefficient (K_p) of 795,725 after a single dose (20 mg/kg), and even under repeated exposure conditions (RfD), the average K_p in adipose tissue was found to be 4961, the highest among all tissues. In addition to adipose tissue, PCB-153 was widely distributed in the brain, skin, liver, etc., and the same pattern was observed in terms of steady-state concentrations upon repeated administration. These results strongly suggest the possibility of PCB-153 accumulation in major organ tissues even at relatively low external exposure doses (RfD), and support the need for a conservative and quantitative risk assessment, especially for the possibility of chronic toxicity due to long-term exposure. The human PBPK model established in this study establishes a foundation for numerically quantifying the tissue-specific accumulation characteristics of PCB-153, suggesting an alternative approach that overcomes the limitations of existing, limited risk assessments. This model can serve as a scientific basis for future human exposure assessments and standardization of highly soluble environmental pollutants.