title: Characterization of a nose-only inhaled phosgene acute lung injury mouse model.
abstract: BACKGROUND
  Phosgene's primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6-24 h post-exposure.
  
  
  OBJECTIVE
  To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures.
  
  
  METHODS
  A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8 ppm) or air (sham). An inhalation lethality study was conducted to determine the 8 ppm median lethal exposure (LCt50) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt50. At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life.
  
  
  CONCLUSIONS
  The 24-hour LCt50 was 226 ppm*min (8 ppm for 28.2 min) and the 48-hour LCt50 was 215 ppm*min (8 ppm for 26.9 min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt50 phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies.
  
  
  CONCLUSIONS
  An 8 ppm phosgene exposure for 34 min (1.2 × LCt50) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant.
authors.affiliation: a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Plahovinsak
authors.affiliation: a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Perry
authors.affiliation: a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Knostman
authors.affiliation: b Discovery Laboratories, Inc , Warrington , PA , USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Segal
authors.affiliation: a Biomedical Research Center, Battelle - LSR , Columbus , OH , USA and.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Babin
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000473:pathology; D000281:Administration, Intranasal; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010705:Phosgene / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D010705:Phosgene
keywords: Inhalation exposure; LCt50; lung injury; model; mouse; pathology; phosgene