In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles in rats

Abstract

BackgroundCerium 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.MethodsA 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.ResultsCerium 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.ConclusionsThe 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 materialThe online version of this article (doi:10.1186/s12989-016-0156-2) contains supplementary material, which is available to authorized users.

Cerium Oxide Nanoparticles in Lung Acutely Induce Oxidative Stress, Inflammation, and DNA Damage in Various Organs of Mice

“…instillation of CeO 2 NPs. The DNA damage, inflammation, and oxidative stress observed in the brain could at least partly result from the translocation [18, 56] and, hence, the direct effect of these nanoparticles on the brain. Although the mechanism related to nanoparticle translocation into the brain following pulmonary exposure is not fully understood, it has been shown that nanoparticles can reach the central nervous system using sensory nerves present in the upper respiratory tract and tracheobronchial region and some in the alveolar region [57].…”

Physiologically based pharmacokinetic modeling of nanoceria systemic distribution in rats suggests dose- and route-dependent biokinetics

“…In a second attempt, calibrations were performed by adjusting the route-specific parameters only and keeping all other model parameters from the 5 and 30 nm calibrations. With the second approach, the calibration was still unsuccessful for data set 1 from Li et al 49 In spite of differences in size and coatings, the time courses of the ratios after IV administration differed distinctly from the ratios for other exposure routes, illustrated, for example, by the clearly lower blood:liver concentration ratios and the apparently higher spleen:liver concentration ratios ( Figures S13-S15). Noticeably and expected, the concentration in brain was substantially lower than in liver after IV administration (3-5 orders of magnitude) and IT instillation (2-4 orders of magnitude) compared to inhalation exposure (0-2 order of magnitude), suggesting uptake via olfactory nerves ( Figure S15).…”

“…15,[60][61][62][63][64][65][66] Inhalation or IT instillation were addressed in seven publications, which included 14 data sets. 13,14,18,49,53,67,68 Oral uptake was described in six publications, which included 12 data sets. 14,17,53,67,69,70 The experimental studies are summarized in Tables 1-4. Due to the limited and scattered nature of these biodistribution studies, assigning the data to calibration and validation sets could not be randomized.…”

“…70 With few exceptions, poor fits were achieved for the remaining data sets (Figures S17-S23). 17,49,67,69,70…”

Animal simulations facilitate smart drug design through prediction of nanomaterial transport to individual tissue cells

“…In vitro rate constant structure First-order rate constants are variables that describe a proportion (fraction) of drug entering or leaving a specific compartment at any point in time (units of time −1 ). For purposes of this study, in vitro rate constants were scaled according to methods used by Li et al (8,64), where a total maximum first-order uptake rate (hour −1 ) is optimized to animal datasets according to a general equation…”