Establishment of a Human 3D Tissue-Based Assay for Upper Respiratory Tract Absorption

Abstract

Regulatory human health risk assessment of chemicals ideally requires integration of toxicokinetic absorption, distribution, metabolism, and excretion where the respiratory system is a principal exposure route and threshold site for absorption. This study evaluated the permeability capacity of an in vitro human airway epithelium cell model (MucilAir™). Initially, definition of the in vitro method, including development of standard operating procedure confirmation of transferability and assurance of reproducible performance, was established in a preliminary phase involving two independent laboratories using six chemicals (propranolol, atenolol, nicotine, cadmium dichloride, cobalt chloride, and ammonium hexachloroplatinate). A follow-up investigation of method relevance, measuring relative permeability of 30 chemicals, in 1 laboratory is also reported. Absorption through the lung barrier model was determined as apparent permeability coefficient (Papp) following apical and basolateral exposure to nontoxic concentrations. Papp was calculated from chemical concentrations crossing the cell barrier at appropriate time intervals. Comparative permeability of nasal and bronchial epithelium is also reported. Overall, the results demonstrate that MucilAir is an effective barrier model for assessing the permeability of different classes of compounds across the human airway epithelium. Results indicate a generally higher permeability of the airway epithelium for organic compounds compared to inorganic chemicals, with a low-protein-mediated efflux as permeability mechanism. The in vitro test system provides a robust and transferable method for determination of pulmonary absorption, relevant to toxicokinetic modeling and integration into risk assessment of chemicals.