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In vitro  methods offer opportunities to provide mechanistic insight into bioactivity as well as human-relevant toxicological assessments compared to animal testing. One of the challenges for this task is putting  in vitro  bioactivity data in an  in vivo  exposure context, for which  in vitro  to  in vivo  extrapolation (IVIVE) translates  in vitro  bioactivity to clinically relevant exposure metrics using reverse dosimetry. This study applies an IVIVE approach to the toxicity assessment of ingredients and their mixtures in e-cigarette (EC) aerosols as a case study. Reported  in vitro  cytotoxicity data of EC aerosols, as well as  in vitro  high-throughput screening (HTS) data for individual ingredients in EC liquids (e-liquids) are used. Open-source physiologically based pharmacokinetic (PBPK) models are used to calculate the plasma concentrations of individual ingredients, followed by reverse dosimetry to estimate the human equivalent administered doses (EADs) needed to obtain these plasma concentrations for the total e-liquids. Three approaches (single actor approach, additive effect approach, and outcome-oriented ingredient integration approach) are used to predict EADs of e-liquids considering differential contributions to the bioactivity from the ingredients (humectant carriers [propylene glycol and glycerol], flavors, benzoic acid, and nicotine). The results identified critical factors for the EAD estimation, including the ingredients of the mixture considered to be bioactive,  in vitro  assay selection, and the data integration approach for mixtures. Further, we introduced the outcome-oriented ingredient integration approach to consider e-liquid ingredients that may lead to a common toxicity outcome (e.g., cytotoxicity), facilitating a quantitative evaluation of  in vitro  toxicity data in support of human risk assessment.

Evaluation of Inhalation Exposures and Potential Health Impacts of Ingredient Mixtures Using in vitro to in vivo Extrapolation