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Ulrika Carlander,1 Tshepo Paulsen Moto,2 Anteneh Assefa Desalegn,1 Robert A Yokel,3 Gunnar Johanson1 1Unit of Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Solna, Sweden; 2Faculty ofHealth Sciences, School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa; 3Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA Background: Cerium dioxide nanoparticles (nanoceria) are increasingly being used in a variety of products as catalysts, coatings, and polishing agents. Furthermore, their antioxidant properties make nanoceria potential candidates for biomedical applications. To predict and avoid toxicity, information about their biokinetics is essential. A useful tool to explore such associations between exposure and internal target dose is physiologically based pharmacokinetic (PBPK) modeling. The aim of this study was to test the appropriateness of our previously published PBPK model developed for intravenous (IV) administration when applied to various sizes of nanoceria and to exposure routes relevant for humans. Methods: Experimental biokinetic data on nanoceria (obtained from various exposure routes, sizes, coatings, doses, and tissues sampled) in rats were collected from the literature and also obtained from the researchers. The PBPK model was first calibrated and validated against IV data for 30 nm citrate coated ceria and then recalibrated for 5 nm ceria. Finally, the model was modified and tested against inhalation, intratracheal (IT) instillation, and oral nanoceria data.Results: The PBPK model adequately described nanoceria time courses in various tissues for 5 nm ceria given IV. The time courses of 30 nm ceria were reasonably well predicted for liver and spleen, whereas the biokinetics in other tissues were not well captured. For the inhalation, IT instillation, and oral exposure routes, re-optimization was difficult due to low absorption and, hence, low and variable nanoceria tissue levels. Moreover, the nanoceria properties and exposure conditions varied widely among the inhalation, IT instillation, and oral studies, making it difficult to assess the importance of different factors. Conclusion: Overall, our modeling efforts suggest that nanoceria biokinetics depend largely on the exposure route and dose. Keywords: biodistribution, cerium dioxide, inhalation, instillation, intravenous, oral

Ulrika Carlander,1 Dingsheng Li,2 Olivier Jolliet,2 Claude Emond,3,4 Gunnar Johanson1 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA; 3BioSimulation Consulting Inc., Newark, DE, USA; 4Department of Environmental and Occupational Health, School of Public Health, University of Montreal, QC, Canada Abstract: To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. Inaddition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight. Keywords: nondegradable, PBPK, intravenous administration, phagocytosis, rats, nanorods, gold, titanium dioxide, polyacrylamide, polyethylene glycol coating

Background Cerium oxide (CeO2) nanoparticles used as a diesel fuel additive can be emitted into the ambient air leading to human inhalation. Although biological studies have shown CeO2 nanoparticles can cause adverse health effects, the extent of the biodistribution of CeO2 nanoparticles through inhalation has not been well characterized. Furthermore, freshly emitted CeO2 nanoparticles can undergo an aging process by interaction with other ambient airborne pollutants that may influence the biodistribution after inhalation. Therefore, understanding the pharmacokinetic of newly-generated and atmospherically-aged CeO2 nanoparticles is needed to assess the risks to human health. Methods A novel experimental system was designed to integrate the generation, aging, and inhalation exposure of Sprague Dawley rats to combustion-generated CeO2 nanoparticles (25 and 90 nm bimodal distribution). Aging was done in a chamber representing typical ambient urban air conditions with UV lights. Following a single 4-hour nose-only exposure to freshly emitted or aged CeO2 for 15 min, 24 h, and 7 days, ICP-MS detection of Ce in the blood, lungs, gastrointestinal tract, liver, spleen, kidneys, heart, brain, olfactory bulb, urine, and feces were analyzed with a mass balance approach to gain an overarching understanding of the distribution. A physiologically based pharmacokinetic (PBPK) model that includes mucociliary clearance, phagocytosis, and entry into the systemic circulation by alveolar wall penetration was developed to predict the biodistribution kinetic of the inhaled CeO2 nanoparticles. Results Cerium was predominantly recovered in the lungs and feces, with extrapulmonary organs contributing less than 4 % to the recovery rate at 24 h post exposure. No significant differences in biodistribution patterns were found between fresh and aged CeO2 nanoparticles. The PBPK model predicted the biodistribution well and identified phagocytizing cells in the pulmonary region accountable for most of the nanoparticles not eliminated by feces. Conclusions The biodistribution of fresh and aged CeO2 nanoparticles followed the same patterns, with the highest amounts recovered in the feces and lungs. The slow decrease of nanoparticle concentrations in the lungs can be explained by clearance to the gastrointestinal tract and then to the feces. The PBPK model successfully predicted the kinetic of CeO2 nanoparticles in various organs measured in this study and suggested most of the nanoparticles were captured by phagocytizing cells. Electronic supplementary material The online version of this article (doi:10.1186/s12989-016-0156-2) contains supplementary material, which is available to authorized users.