Fate of inhaled Nano-CeO2 revisited: Predicting the unpredictable

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This paper compares the pulmonary kinetics of inhaled nano-CeO2 from two published repeated inhalation studies of 13-week duration in rats. This database was used to predict the outcome of a 2-year chronic inhalation study with a focus on the no observed adverse effect level (NOAEL) and range of conditions causing kinetic lung overload up to and beyond the maximum tolerated dose (MTD). Modeling identified nano-CeO2 to be typical poorly soluble, low-toxicity particles (PSLTs), although even partial dissolution may lead to interactions with pulmonary surfactant, eventually resulting in pulmonary phospholipidosis and fibrosis. An earlier model published in 2011 to surpass and replace the traditional Morrow approach focused on kinetic lung overload to simulate the pulmonary fate of inhaled micron-sized PSLT in rats. By misunderstanding or inaction, this earlier model was overlooked as a better hypothesis-based model for dosimetry selection of long-term inhalation studies with the aim of reducing study repetition and animal numbers. While it appears that the primary adverse pathway of the earlier model also applies to nano-CeO2, the updated model proposed here also accounts for phospholipid-like additional volume loads. Data from a heralded 2-year inhalation study in rats are not yet available, but the study was traditionally modeled to predict the toxicological NOAEL and MTD hallmarks. When completed, this study's data will clarify whether the advanced 21st century modeling proposed here may be more advantageous for design and execution of inhalation studies, compared to simplistic and outdated gross overload models.HIGHLIGHTSRepeated exposure inhalation studies with poorly soluble particles should be structured by kinetic modeling.The displacement volume of aggregated particles is the key metric for dose-response analyses.The NOAEL and MTD should be expressed relative to the kinetic overload threshold.Pulmonary phospholipidosis may exacerbate overload-dependent etiopathologogies

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