Advancing In Vitro Dosimetry Methods and Reporting Standards for Air-Liquid Interface Exposures
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Inhalation is one of the three primary modes of chemical exposure, but it is particularly challenging to screen inhalable substances with in vitro methods. Air-liquid interface (ALI) exposure systems allow direct cell-toxicant interactions and can be applied for a broader variety of inhalable chemicals than direct liquid application, but it is often difficult to achieve reproducible results and quantify cell delivery when using these systems. Physicochemical properties of the inhaled substance must be carefully considered when selecting an ALI exposure system, optimizing its use, and developing methods to characterize exposure conditions. This presentation will provide an overview of commonly utilized in vitro exposure methods and will synthesize how to apply dosimetry modeling results into practical in vitro study design. Best methods to quantify exposure conditions for vapors, reactive gases, and aerosols will be shared along with a case study that highlights differences between volatile organic compound (VOC) and aerosol delivery within an ALI exposure system. Soluble fluorescent tracers can be aerosolized as a tool to evaluate exposure systems and quantify particle deposition and cellular uptake in ALI cell models. We have characterized multiple commercial and in-house ALI exposure systems with aerosolized sodium fluorescein and rhodamine 6G and have found that particle deposition is highly variable within and across exposure systems. These data highlight the need to report deposition and uptake values rather than exposure concentrations for accurate in vitro to in vivo extrapolation (IVIVE). We also observed differences in internal dose rates across ALI vs direct liquid application exposures which is critical to consider when designing in vitro exposure studies. Overall, our results highlight opportunities to better characterize dosimetry for in vitro exposures and improve IVIVE.