Informing Selection of Nanomaterial Concentrations for ToxCast in Vitro Testing Based on Occupational Exposure Potential

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. OBJECTIVES: 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 (TM) program. Here, we provide testing concentrations for carbon nanotubes (CNTs) and titanium dioxide (TiO(2)) 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/m(3)), 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 TiO(2) NPs and CNTs for a working-lifetime (45 years) exposure duration is similar to high-end concentrations (similar to 30- 400 mu g/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.