title: Comparative iron oxide nanoparticle cellular dosimetry and response in mice by the inhalation and liquid cell culture exposure routes.
abstract: BACKGROUND
  Toxicity testing the rapidly growing number of nanomaterials requires large scale use of in vitro systems under the presumption that these systems are sufficiently predictive or descriptive of responses in in vivo systems for effective use in hazard ranking. We hypothesized that improved relationships between in vitro and in vivo models of experimental toxicology for nanomaterials would result from placing response data in vitro and in vivo on the same dose scale, the amount of material associated with cells.
  
  
  METHODS
  Balb/c mice were exposed nose-only to an aerosol (68.6 nm CMD, 19.9 mg/m(3), 4 hours) generated from of 12.8 nm superparamagnetic iron oxide particles (SPIO). Target cell doses were calculated, histological evaluations conducted, and biomarkers of response were identified by global transcriptomics. Representative murine epithelial and macrophage cell types were exposed in vitro to the same material in liquid suspension for four hours and levels of nanoparticle regulated cytokine transcripts identified in vivo were quantified as a function of measured nanoparticle cellular dose.
  
  
  RESULTS
  Target tissue doses of 0.009-0.4 μg SPIO/cm(2) in lung led to an inflammatory response in the alveolar region characterized by interstitial inflammation and macrophage infiltration. In vitro, higher target tissue doses of ~1.2-4 μg SPIO/ cm(2) of cells were required to induce transcriptional regulation of markers of inflammation, CXCL2 & CCL3, in C10 lung epithelial cells. Estimated in vivo macrophage SPIO nanoparticle doses ranged from 1-100 pg/cell, and induction of inflammatory markers was observed in vitro in macrophages at doses of 8-35 pg/cell.
  
  
  CONCLUSIONS
  Application of target tissue dosimetry revealed good correspondence between target cell doses triggering inflammatory processes in vitro and in vivo in the alveolar macrophage population, but not in the epithelial cells of the alveolar region. These findings demonstrate the potential for target tissue dosimetry to enable the more quantitative comparison of in vitro and in vivo systems and advance their use for hazard assessment and extrapolation to humans. The mildly inflammogentic cellular doses experienced by mice were similar to those calculated for humans exposed to the same material at the existing permissible exposure limit of 10 mg/m(3) iron oxide (as Fe).
authors.forename: Justin G
authors.initials: JG
authors.lastname: Teeguarden
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Mikheev
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Minard
authors.forename: William C
authors.initials: WC
authors.lastname: Forsythe
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.forename: Norman
authors.initials: N
authors.lastname: Karin
authors.forename: Susan C
authors.initials: SC
authors.lastname: Tilton
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.forename: Bahman
authors.initials: B
authors.lastname: Asgharian
authors.forename: Owen R
authors.initials: OR
authors.lastname: Price
authors.forename: Joel G
authors.initials: JG
authors.lastname: Pounds
authors.forename: Brian D
authors.initials: BD
authors.lastname: Thrall
mesh_terms: D000336:Aerosols; D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058185:Magnetite Nanoparticles / Q000633:toxicity*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D013997:Time Factors
chemical_list: D000336:Aerosols; D016207:Cytokines; D018836:Inflammation Mediators; D058185:Magnetite Nanoparticles; D012333:RNA, Messenger