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Assessment of the Acute Inhalation Toxicity of Airborne Particles by Exposing Cultivated Human Lung Cells at the Air-Liquid Interface
Published on: February 23, 2020
Inhalation toxicity assessment of imidazolium ionic liquids by a physiology-based high-throughput lung-burden
Wanjun Zhang1, Yizhe Wu2, Jiayin Sun3
1Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China; Department of Occupational and Environmental Health, School of Public Health, Qingdao University, Qingdao 266071, China; CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, University of Chinese Academy of Sciences, Beijing 100190, China.
Abstract:
High-throughput inhalation toxicity assessment remains challenging for structurally diverse organic chemicals such as imidazolium-based ionic liquids (ILs), where lung-selective retention may drive hazard. We developed a physiology-based computational framework (burden-based pulmonary tissue kinetics, BB-PTK) to simulate time-resolved lung burden following single intratracheal instillation, incorporating passive diffusion, electro-migration, pH-pKa ionization equilibrium, and lipid-water partitioning. Model predictions were compared against time-course measurements for four representative compounds (bleomycin, [HOEMIM]Cl, [C₂M₂IM]I, BMIM[BF₄]) in mice, demonstrating reasonable early-to-intermediate concordance between simulated and observed pulmonary burden trajectories. Independent literature analysis (n = 22 chemicals) demonstrated that compounds associated with pulmonary toxicity exhibited significantly longer lung half-lives (median 22.00 h vs. 3.32 h; p = 0.005), together with concordant increases in pulmonary retention across complementary metrics, including measured %original(max) and reconstructed peak lung burden, although statistical significance for these latter comparisons was limited by small sample size. Predicted 7-day integrated lung burden (AUB) showed a positive compound-level association with acute lung injury scores at Day 7, suggesting that potential utility of 7-day AUB for identifying compounds with higher pulmonary toxicity potential. Structure-dosimetry modeling across 133 chemicals identified lipophilicity (logP), acid dissociation constant (pKa), and continuous charge state at pH 7.4 as dominant determinants of cumulative lung exposure, consistent with the transport mechanisms encoded in the BB-PTK framework. This study provides a scalable, mechanistically interpretable strategy for high-throughput screening of inhalation hazards and safer-by-design prioritization of imidazolium ILs and related organic chemicals.
