A rat lung model of exposure, dose and response to inhaled silica

The objectives of this study were: (i) to construct a physiologically based mathematical model to describe the retention and clearance of respirable crystalline silica (MIN-U-SIL 5), the inflammatory reaction and the development of fibrosis; (ii) to calibrate/validate the model using animal data from inhalation experiments with MIN-U-SIL 5. A physiologically based mathematical model was constructed with the following features: compartments to describe the retention and clearance of silica, critical lung burdens for initiation of inflammation and fibrosis and recruitment of neutrophils and alveolar macrophages. Data were available from two recent NIOSH studies of rats exposed by inhalation to respirable crystalline silica. Data from the first study were used to estimate the model parameters not obtainable from the earlier studies, using a numerical method combining non-linear least squares analysis and integration of differential equations. The second study was used for model validation by comparing the model predictions with the data. Once validated, the model was used to predict the outcome of a 2 yr inhalation experiment with DQ-12 quartz. Finally, the model was extended to describe the dose–response relationships, including oxidant dose, antioxidant reactions, transcription factor switching, cell damage and fibrosis. A good fit of the model to the data was obtained. The critical doses of MIN-U-SIL 5 were calculated for both inflammation and fibrosis. The model was able to simulate the retention and clearance of DQ-12 quartz. The model was also extended to describe the time course of NF-κB initiation, lipid peroxidation and superoxide dismutase expression. This model has provided a means to relate the inhaled silica dose to inflammation and fibrosis.