title: Particle size dependent deposition and pulmonary inflammation after short-term inhalation of silver nanoparticles.
abstract: BACKGROUND
  Although silver nanoparticles are currently used in more than 400 consumer products, it is not clear to what extent they induce adverse effects after inhalation during production and use. In this study, we determined the lung burden, tissue distribution, and the induction and recovery of adverse effects after short-term inhalation exposure to 15 nm and 410 nm silver nanoparticles.
  
  
  METHODS
  Rats were nose-only exposed to clean air, 15 nm silver nanoparticles (179 μg/m³) or 410 nm silver particles (167 μg/m³) 6 hours per day, for four consecutive days. Tissue distribution and the induction of pulmonary toxicity were determined at 24 hours and 7 days after exposure and compared with the internal alveolar dose. Presence of silver nanoparticles in lung cells was visualized by transmission electron microscopy (TEM).
  
  
  RESULTS
  Exposure to 15 nm silver nanoparticles induced moderate pulmonary toxicity compared to the controls, indicated by a 175-fold increased influx of neutrophils in the lungs, a doubling of cellular damage markers in the lungs, a 5-fold increase in pro-inflammatory cytokines, and a 1.5-fold increase in total glutathione at 24 hours after exposure. All the observed effects disappeared at 7 days after exposure. No effects were observed after exposure to 410 nm silver particles. The internal alveolar mass dose of the 15 nm nanoparticles was 3.5 times higher compared to the 410 nm particles, which equals to a 66,000 times higher particle number. TEM analysis revealed 15 nm nanoparticles in vesicles and nuclei of lung cells, which were decreased in size to <5 nm at 24 hours after exposure. This demonstrates substantial dissolution of the silver nanoparticles.
  
  
  CONCLUSIONS
  The results show a clear size-dependent effect after inhalation of similar mass concentrations of 15 nm and 410 nm silver (nano)particles. This can be partially explained by the difference in the internal alveolar dose between the 15 nm and 410 nm silver (nano)particles as well as by a difference in the release rate of silver ions.
authors.affiliation: Department of Toxicogenomics, Maastricht University, PO Box 616, Maastricht, 6200, MD, the Netherlands. hedwig.braakhuis@rivm.nl.|National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. hedwig.braakhuis@rivm.nl.
authors.forename: Hedwig M
authors.initials: HM
authors.lastname: Braakhuis
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. Ilse.gosens@rivm.nl.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gosens
authors.affiliation: Philips Innovation Services, High Tech Campus 11, Eindhoven, 5656, AE, the Netherlands. Petra.krystek@philips.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Krystek
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. John.Boere@rivm.nl.
authors.forename: John A F
authors.initials: JA
authors.lastname: Boere
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. Flemming.cassee@rivm.nl.|Institute of Risk Assessment Sciences, Utrecht University, PO Box 80.163, Utrecht, 3508, TD, the Netherlands. Flemming.cassee@rivm.nl.
authors.forename: Flemming R
authors.initials: FR
authors.lastname: Cassee
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. Paul.Fokkens@rivm.nl.
authors.forename: Paul H B
authors.initials: PH
authors.lastname: Fokkens
authors.affiliation: Cellbiology, Biology Department, Faculty of Science, University of Utrecht, PO box 80.056, Utrecht, 3508, TB, the Netherlands. J.A.Post@uu.nl.
authors.forename: Jan Andries
authors.initials: JA
authors.lastname: Post
authors.affiliation: Department of Toxicogenomics, Maastricht University, PO Box 616, Maastricht, 6200, MD, the Netherlands. Henk.van.loveren@rivm.nl.|National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. Henk.van.loveren@rivm.nl.
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.affiliation: National Institute for Public Health and the Environment (RIVM), PO Box 1, Bilthoven, 3720, BA, the Netherlands. Margriet.park@rivm.nl.
authors.forename: Margriet V D Z
authors.initials: MV
authors.lastname: Park
mesh_terms: D000393:Air Pollutants / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D016207:Cytokines / Q000819:agonists / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000737:chemistry / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D005978:Glutathione / Q000819:agonists / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D008297:Male; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D020556:Neutrophil Infiltration / Q000187:drug effects; D010316:Particle Size; D011014:Pneumonia / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D065589:Respiratory Tract Absorption; D012834:Silver / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000633:toxicity*; D013047:Specific Pathogen-Free Organisms; D014018:Tissue Distribution; D023382:Toxicity Tests, Acute; D066007:Toxicokinetics
chemical_list: D000393:Air Pollutants; D015415:Biomarkers; D016207:Cytokines; D012834:Silver; D005978:Glutathione