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Effect of Inter-individual Variability on a Phenotypic Endpoint Assay Battery in an In Vitro Co-culture Model of the Human Bronchus after Exposure to Model Reactive Gas Acrolein
Citation:
Simmons, A., E. Aungst, L. Dailey, N. Mallek, P. Clapp, AND S. McCullough. Effect of Inter-individual Variability on a Phenotypic Endpoint Assay Battery in an In Vitro Co-culture Model of the Human Bronchus after Exposure to Model Reactive Gas Acrolein. American Society for Cellular and Computational Toxicology Annual Meeting, Chapel Hill, NC, October 19 - 21, 2022.
Impact/Purpose:
Present data describing the impact of inter-individual variability in in vitro primary human bronchial epithelial cell models of the human respiratory tract in response to the model reactive gas acrolein.
Description:
The “Toxicology in the 21st Century” program goal is to increase the throughput and human relevance of chemical testing by integrating new approach methodologies (NAMs). The use of primary human cell-based in vitro NAMs for the evaluation of inhaled chemicals on the respiratory tract has posed several challenges. One of these challenges is evaluating the impact of inter-individual variability on primary cell-based in vitro system performance and use in chemical safety evaluation. Here we characterized inter-individual variability across 14 donors using an in vitro co-culture model of the human tracheobronchial respiratory tract and using acrolein as a model reactive gas, a ubiquitous combustion byproduct generated during commonplace indoor activities (e.g., cooking, smoking) and used in large-scale industrial reactions or as industrial or environmental biocide. 1) Donors exhibited variable cytotoxicity after exposure to acrolein between 1 ppm and 4 ppm with some donors displaying resilience against high acrolein concentrations while others were highly responsive. 2) Likewise, ciliary beat frequency shared similar trends. 3) Barrier integrity exhibited high inter-individual variability at baseline, but only 4 ppm acrolein exposure resulted in loss of barrier integrity across all donors. 4) Finally, mucus production remained stable in each donor despite acrolein exposure. These observations are among the first to define the impact of inter-individual variability on primary cell-based in vitro system performance and we posit that exploration into individual endpoint response informs users about system quality, relative assay sensitivity, and informs research infrastructure for the evaluation of inhaled chemicals. Does not reflect EPA policy.