title: Efficacy of simple short-term in vitro assays for predicting the potential of metal oxide nanoparticles to cause pulmonary inflammation.
abstract: BACKGROUND
  There has been concern regarding risks from inhalation exposure to nanoparticles (NPs). The large number of particles requiring testing means that alternative approaches to animal testing are needed.
  
  
  OBJECTIVE
  We set out to determine whether short-term in vitro assays that assess intrinsic oxidative stress potential and membrane-damaging potency of a panel of metal oxide NPs can be used to predict their inflammogenic potency.
  
  
  METHODS
  For a panel of metal oxide NPs, we investigated intrinsic free radical generation, oxidative activity in an extracellular environment, cytotoxicity to lung epithelial cells, hemolysis, and inflammation potency in rat lungs. All exposures were carried out at equal surface area doses.
  
  
  RESULTS
  Only nickel oxide (NiO) and alumina 2 caused significant lung inflammation when instilled into rat lungs at equal surface area, suggesting that these two had extra surface reactivity. We observed significant free radical generation with 4 of 13 metal oxides, only one of which was inflammogenic. Only 3 of 13 were significantly hemolytic, two of which were inflammogenic.
  
  
  CONCLUSIONS
  Potency in generating free radicals in vitro did not predict inflammation, whereas alumina 2 had no free radical activity but was inflammogenic. The hemolysis assay was correct in predicting the proinflammatory potential of 12 of 13 of the particles examined. Using a battery of simple in vitro tests, it is possible to predict the inflammogenicity of metal oxide NPs, although some false-positive results are likely. More research using a larger panel is needed to confirm the efficacy and generality of this approach for metal oxide NPs.
authors.affiliation: University of Edinburgh, Edinburgh, UK.
authors.forename: Senlin
authors.initials: S
authors.lastname: Lu
authors.forename: Rodger
authors.initials: R
authors.lastname: Duffin
authors.forename: Craig
authors.initials: C
authors.lastname: Poland
authors.forename: Paul
authors.initials: P
authors.lastname: Daly
authors.forename: Fiona
authors.initials: F
authors.lastname: Murphy
authors.forename: Ellen
authors.initials: E
authors.lastname: Drost
authors.forename: William
authors.initials: W
authors.lastname: Macnee
authors.forename: Vicki
authors.initials: V
authors.lastname: Stone
authors.forename: Ken
authors.initials: K
authors.lastname: Donaldson
mesh_terms: D000537:Aluminum Oxide / Q000633:toxicity; D002460:Cell Line; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*; D009532:Nickel / Q000633:toxicity; D010087:Oxides / Q000633:toxicity*; D011014:Pneumonia / Q000139:chemically induced*
chemical_list: D010087:Oxides; D009532:Nickel; C028007:nickel monoxide; D000537:Aluminum Oxide