What a Difference the Dose Makes: Translating In Vitro Exposures for Evidence Integration
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New Approach Methods (NAMs) to assess inhalation toxicity often utilize air-liquid interface (ALI) exposure systems which allow direct cell-toxicant interactions and are compatible with a wider range of inhalable chemicals than direct liquid application. However, it is often difficult to quantify cell delivery and achieve reproducible results 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 ALI exposure methods along with critical considerations for their use. 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. Although direct quantification of VOC delivery to cell cultures remains challenging, soluble fluorescent tracers can be aerosolized as a tool to evaluate exposure systems for aerosols by quantifying 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 varies across exposure systems in a chemical-dependent manner. Overall, our results show that physicochemical properties must be considered when designing ALI exposure studies and highlight the need to report deposition and uptake values rather than exposure concentrations for accurate in vitro to in vivo extrapolation (IVIVE). Abstract does not reflect views or policies of the U.S. EPA.