Abstract
Air–liquid interface (ALI) systems have been widely used in recent years to investigate the inhalation toxicity of many gaseous compounds, chemicals, and nanomaterials and represent an emerging and promising in vitro method to supplement in vivo studies. ALI exposure reflects the physiological conditions of the deep lung more closely to subacute in vivo inhalation scenarios compared to submerged exposure. The comparability of the toxicological results obtained from in vivo and in vitro inhalation data is still challenging. The robustness of ALI exposure scenarios is not yet well understood, but critical for the potential standardization of these methods. We report a cause-and-effect (C&E) analysis of a flow through ALI exposure system. The influence of five different instrumental and physiological parameters affecting cell viability and exposure parameters of a human lung cell line in vitro (exposure duration, relative humidity, temperature, CO2 concentration and flow rate) was investigated. After exposing lung epithelia cells to a CeO2 nanoparticle (NP) aerosol, intracellular CeO2 concentrations reached values similar to those found in a recent subacute rat inhalation study in vivo. This is the first study showing that the NP concentration reached in vitro using a flow through ALI system were the same as those in an in vivo study.
Highlights
During the last two decades, engineered nanomaterials (ENMs) have received widespread attention due to their broad range of applications including industry, [1,2,3,4,5,6,7] medicine [8,9,10] and consumer products [11,12,13]
The C&E analysis revealed six main branches (Figure 2): cell maintenance and seeding, instrument performance, plate reader, positive control, WST-1 assay, and engineered nanomaterial dispersion and handling. These sources of variability were similar for branch 1, branch 3, branch 4, branch 5 (WST-1 assay) and branch 6 to previous C&E diagrams prepared for the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) nanocytotoxicity assay with A549 cells [50,51,52]
Our results suggest that the relative humidity, lid temperature, flow rate, CO2 concentration and exposure duration are crucial parameters for an air–liquid interface (ALI) flow through exposure system given their impact on the cell viability (Figures 3 and 4)
Summary
During the last two decades, engineered nanomaterials (ENMs) have received widespread attention due to their broad range of applications including industry, [1,2,3,4,5,6,7] medicine [8,9,10] and consumer products [11,12,13]. During the manufacturing process and consumer usage of these products, there is the potential for an increased risk of inhalation exposure [14,15,16,17]. Evaluation of the potential health hazards from inhalation exposure is predominantly conducted using animal models [18,19,20,21,22,23,24]. In vitro nanotoxicological studies are performed under “submerged” conditions where the cells are exposed to particles dispersed in the overlying cell culture medium containing a mixture of proteins and other biological compounds [23,25,26]. After aerosolization and deposition on cells will the NPs come in contact with the cell microenvironment such as mucus or epithelia lining fluid [29]
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