A biomathematical model for rodent and human lung describing exposure, dose, and response to inhaled silica

A physiologically-based mathematical model was constructed with the following features: compartments to describe the retention and clearance of quartz; a threshold burden for initiation of inflammation; and a description of neutrophil (PMN) and alveolar macrophage (AM) recruitment. This is the first model to go beyond the earlier models of retention and clearance of dusts to describe the exposure, dose, and response relationships. Data were available from two recent NIOSH studies of rats exposed by inhalation to respirable quartz. Data from the first study (including lavageable and non-lavageable lung burdens, lymph node burdens, and PMN and AM numbers) were used to estimate the model parameters not obtainable from the earlier studies, using a numerical method combining nonlinear least squares 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- year inhalation experiment with DQ-12 quartz and to derive a no observed adverse effect level for quartz. Finally, the model was extrapolated to humans using appropriate scaling rules. The model was also extended to describe the dose-response relationships, including the oxidant dose, anti-oxidant reaction, transcription factor switching, cell damage, and fibrosis