title: In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles in rats.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA. dingsli@umich.edu.
authors.forename: Dingsheng
authors.identifier: 0000-0002-8432-4023
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Masako
authors.initials: M
authors.lastname: Morishita
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Wagner
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fatouraie
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wooldridge
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: W Ethan
authors.initials: WE
authors.lastname: Eagle
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: James
authors.initials: J
authors.lastname: Barres
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SE-171 77, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Carlander
authors.affiliation: BioSimulation Consulting Inc., Newark, DE, 19713, USA.
authors.forename: Claude
authors.initials: C
authors.lastname: Emond
authors.affiliation: Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Jolliet
mesh_terms: D000818:Animals; D002563:Cerium / Q000493:pharmacokinetics / Q000633:toxicity*; D019570:Inhalation Exposure; D008297:Male; D053768:Metal Nanoparticles / Q000633:toxicity*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D002563:Cerium; C030583:ceric oxide
keywords: Biodistribution; Cerium oxide nanoparticles; Inhalation; PBPK modeling