Kinetic modeling of the retention and fate of inhaled cerium oxide nanoparticles in rats: The cumulative displacement volume of agglomerates determines the outcome

This paper compares the pulmonary kinetics of inhaled nano-CeO2 from published repeated inhalation studies of 1-, 4-, 13-, and 52-week duration using a previously published kinetic model to simulate the pulmonary kinetics of inhaled micron-sized poorly soluble, low toxicity particles (PSPs) in rats. This comparative analysis demonstrates that the kinetic hallmarks characterizing lung overload-related pulmonary inflammation are indistinguishable for PSPs and agglomerated nano-CeO2. Unlike PSPs, nano-CeO2 appears to dissolve within the lung as long as tissue saturation has not been attained. When saturation is reached, the accumulated retained particle displacement volume becomes the prominent unifying factor interrelating the retained volumetric particle dose and pulmonary inflammogenicity observed in inhalation studies of 1- to 52-weeks duration. In summary, the pulmonary kinetics of nano-CeO2 inhaled as micron-sized agglomerates exhibit kinetic and toxicological profiles similar to micron-sized PSPs. The coherence of modeled and empirical outcomes supports the hypothesis that the leading metric of pulmonary toxicity is the displacement volume of accumulated aggregated particles. Whereas agglomerated nano-CeO2 particles follow the typical kinetic of lung overload, evidence of dissolution of nano-CeO2 demonstrates a much shorter elimination half-time of t1/2 = 17 days. Thus, kinetic modeling approaches appear to not only deliver the highest degree of integrated mechanistic information, it also provides a validating feed-back loop to verify/refute the starting hypothesis of inhalation studies.