title: Informing selection of nanomaterial concentrations for ToxCast in vitro testing based on occupational exposure potential.
abstract: BACKGROUND
  Little justification is generally provided for selection of in vitro assay testing concentrations for engineered nanomaterials (ENMs). Selection of concentration levels for hazard evaluation based on real-world exposure scenarios is desirable.
  
  
  OBJECTIVE
  Our goal was to use estimates of lung deposition after occupational exposure to nanomaterials to recommend in vitro testing concentrations for the U.S. Environmental Protection Agency's ToxCast™ program. Here, we provide testing concentrations for carbon nanotubes (CNTs) and titanium dioxide (TiO2) and silver (Ag) nanoparticles (NPs).
  
  
  METHODS
  We reviewed published ENM concentrations measured in air in manufacturing and R&D (research and development) laboratories to identify input levels for estimating ENM mass retained in the human lung using the multiple-path particle dosimetry (MPPD) model. Model input parameters were individually varied to estimate alveolar mass retained for different particle sizes (5-1,000 nm), aerosol concentrations (0.1 and 1 mg/m3), aspect ratios (2, 4, 10, and 167), and exposure durations (24 hr and a working lifetime). The calculated lung surface concentrations were then converted to in vitro solution concentrations.
  
  
  RESULTS
  Modeled alveolar mass retained after 24 hr is most affected by activity level and aerosol concentration. Alveolar retention for Ag and TiO2 NPs and CNTs for a working-lifetime (45 years) exposure duration is similar to high-end concentrations (~ 30-400 μg/mL) typical of in vitro testing reported in the literature.
  
  
  CONCLUSIONS
  Analyses performed are generally applicable for providing ENM testing concentrations for in vitro hazard screening studies, although further research is needed to improve the approach. Understanding the relationship between potential real-world exposures and in vitro test concentrations will facilitate interpretation of toxicological results.
authors.affiliation: National Center for Computational Toxicology, Offce of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA. gangwal.sumit@epa.gov
authors.forename: Sumit
authors.initials: S
authors.lastname: Gangwal
authors.forename: James S
authors.initials: JS
authors.lastname: Brown
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Elaine A Cohen
authors.initials: EA
authors.lastname: Hubal
mesh_terms: D000336:Aerosols / Q000633:toxicity; D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000818:Animals; D002244:Carbon / Q000633:toxicity; D003198:Computer Simulation; D006801:Humans; D019570:Inhalation Exposure; D008954:Models, Biological; D053758:Nanoparticles / Q000633:toxicity; D043942:Nanotubes; D016273:Occupational Exposure; D011650:Pulmonary Alveoli / Q000187:drug effects*; D012680:Sensitivity and Specificity; D012834:Silver / Q000633:toxicity; D014025:Titanium / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D000336:Aerosols; D000395:Air Pollutants, Occupational; C009495:titanium dioxide; D012834:Silver; D002244:Carbon; D014025:Titanium