Abstract
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.
Highlights
Electronic cigarettes (EC) are gaining popularity among adult smokers who are looking for reducedrisk alternatives
With the additive effect approach, the inclusion of PG, VG and BA resulted in an increased to the calculated equivalent administered doses (EADs) (Figure 1) compared to considering just “nicotine + flavor”
This work investigated the application of in vivo extrapolation (IVIVE) as a New approach methodologies (NAMs) to use in vitro data toxicity assessment of EC ingredients separately and as part of total product in the context of human in vivo exposure
Summary
Electronic cigarettes (EC) are gaining popularity among adult smokers who are looking for reducedrisk alternatives. Hundreds of unique flavor ingredients are identified based on reviews of e-liquids on the market (Hua et al, 2019; Krüsemann et al, 2021; Salam et al, 2020), with acids (such as lactic, benzoic, levulinic, salicyclic, malic, and tartaric acids) in some EC products converting nicotine to nicotine salts (Harvanko et al, 2020). The combinations of these ingredients lead to a myriad of e-liquids in the market. In vivo data have inherent uncertainty of the interspecies extrapolation from animal to human
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