Prediction of Phthalate Permeation Through Pulmonary Alveoli using a Cultured A549 Cell-based in Vitro Alveolus Model and a Numerical Simulation

Kokoro Iwasawa1, Genya Tanaka1, Takuya Aoyama1, Mohammad Mahfuz Chowdhury1, Kikuo Komori1, Toshiko Tanaka-Kagawa2, Hideto Jinno2, and Yasuyuki Sakai1

1Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
2National Institute of Health Sciences, Tokyo, Japan

AATEX 18(1):19-31, 2013

The animal-free prediction of inhalation toxicities in the lungs is very important concerning various low-volatile organic carbons such as phthalate. Phthalate are contained in plastics as plastisizer, easily released into environment as plastic ages, and ingested through dust. We therefore investigated benzylbutyl phthalate (BBP) permeation using an A549 cell-based lung alveolus model, in which the cell monolayers were formed on semipermeable membranes between two chambers filled with cell culture medium. With kinetic parameters obtained via these experiments, the model largely described the concentration changes in the three compartments (the apical, A549 cell, and basolateral layers) but revealed very high BBP accumulation in the alveolus cell layer at equilibrium, which did not likely reflect the in vivo situation. We therefore changed the parameter of thickness of the cell layer from 10 (cultured A549 cells) to 0.5μm (alveoli) and the parameter of the concentration in basolateral compartment to be always zero because of the continuous perfusion of blood in vivo. After changing these parameters, the accumulation of BBP remarkably decreased, and the total permeated amount significantly increased. These results indicated that various parameters and assumptions should be changed to overcome the limitations and/or properties of existing culture models to improve the predictive accuracy of the system when using in vitro cell-based tissue models and numerical simulations to predict health hazards in humans.

key words: in vitro, phthalate, alveolus, Numerical model


(AATEX: Altern. Animal Test. EXperiment.: Alternatives to Animal Testing and EXperimentation)