A biomathematical model of particle clearance and retention in the lungs of coal miners - II. Evaluation of variability and uncertainty

The objective of this study is to investigate the sources of variability an d uncertainty in a previously developed human lung dosimetry model. That th ree-compartment model describes the retention and clearance kinetics of res pirable particles in the gas-exchange region of the lungs. It was calibrate d using exposure histories and lung dust burden data in U.S. coal miners. A multivariate parameter estimation and optimization method was developed fo r fitting the dosimetry model to these human data. Models with various assu mptions about overloading of alveolar clearance and interstitialization (se questration) of particles were evaluated. Variability in the estimated clea rance rate coefficients was assessed empirically by fitting the model to gr oups' and to each miner's data. Distributions of lung and lymph node partic le burdens were computed at working lifetime exposures, using the variabili ty in the estimated individual clearance rate coefficients. These findings confirm those of the earlier analysis; i.e., the best-fitting exposure-dose model to these data has substantial interstitialization/sequestration of p articles and no dose-dependent decline in alveolar clearance. Among miners with different characteristics for smoking, disease, and race, the group me dian estimated alveolar clearance rate coefficients varied by a factor of a pproximately 4. Adjustment for these group differences provided some improv ement in the dosimetry model fit to all miners (up to 25% reduction in MSE) , although unexplained interindividual differences made up the largest sour ce of variability. The predicted mean lung and lymph node particle burdens at age 75 after exposure to respirable coal mine dust at 2 mg/m(2) for a 45 -year working lifetime were 12 g (5th and 95th percentiles, 3.0-26 g) and 1 .9 g (0.26-5.3), respectively. This study provides quantitative information on variability in particle retention and clearance kinetics in humans. It is useful for risk assessment by providing estimated lung dust burdens asso ciated with occupational exposure to respirable particles. (C) 2001 Academi c Press.