PNNL-13501 - Pacific Northwest National Laboratory

Development of a Virtual Respiratory System Model for Quantitation of Dosimetry, Clearance
and Biological Response to Particulate Matter in the Mammalian Lung
Richard A. Corley, Charles Timchalk, Harold E. Trease, Joseph S. Oliveira, Kevin R. Minard,
Donald N. Rommereim, Scott H. Elder
Study Control Number: PN00030/1437
Airborne particulate matter has been linked with a variety of adverse human health effects. Those most affected include
the elderly, the young, smokers, and those with preexisting respiratory diseases such as asthma or chronic obstructive
pulmonary disease. Several sources of airborne particulate matter are of concern, including the incomplete combustion of
fossil fuels, and activities associated with the cleanup, demolition, and decommissioning of DOE sites. The development
of accurate models of the dosimetry and clearance of particles from the respiratory tract will significantly improve our
understanding of the health consequences associated with inhaled particulate matter.
Project Description
One of the research priorities recently identified by the
National Academy of Sciences for improving our
understanding of the potential human health impacts of
airborne particulate matter is the need for improved
mathematical models for predicting the regional
dosimetry and clearance of inhaled particulate matter in
the lungs (NRC 1998).
In this project, three-dimensional, biologically based
models of normal and compromised respiratory tracts of
laboratory animals and humans are being developed and
experimentally validated. These models will provide a
quantitative framework for integrating research from
controlled animal studies with potential human variability
and environmental exposure scenarios to facilitate more
informed decisions regarding the potential for human
health risks associated with airborne particulate matter.
A three-dimensional grid structure for the human lung
was developed. This grid structure represents the first
biologically based model to include equations of viscoelasticity
to simulate the expansion and constriction of the
lungs during respiration. The three-dimensional model
was linked to a computational fluid dynamics model for
inhalation, exhalation, and particle movement to complete
the initial virtual lung model. The virtual lung model is
linked to three-dimensional models of the upper
respiratory tract in collaboration with Dr. J. S. Kimbell of
the Chemical Industry Institute of Toxicology. Current,
state-of-the-art particle deposition models were obtained
to benchmark simulations of the regional deposition of
particles predicted by the virtual respiratory tract model.
To experimentally validate the virtual respiratory tract
model, several nuclear magnetic resonance imaging
methods were developed. The NMR successfully
quantitated particles phagocytized by pulmonary
macrophages to determine the kinetics of a key
component in the clearance of particles from the lung.
NMR methods were also refined to improve the imaging
of the pulmonary region in mice in an effort to quantitate
the deposition of particles. If successful, the NMR may
be used to determine the fate of inhaled particles in living
animals over time and thus revolutionize experimental
approaches for validation of the virtual respiratory tract
model. Localized responses of the respiratory tract to
inhaled particles are also known to influence the
deposition and clearance of subsequently inhaled particles
through a cascade of cell signaling pathways. The
activation of several pathways was shown in this project
to be responsive to various particles.
Introduction
Experimental research in particulate matter toxicity is
based upon a variety of in vivo and in vitro animal and
human model systems. Without validated models of lung
dosimetry and biological response, however, controlled
studies with particulate matter toxicity have only limited
utility in predicting human responses. To adequately
define the dose to the specific targets within the
respiratory tract, particulate matter deposition models
must have sufficient species-specific anatomic and
physiologic detail to deliver the material to the
appropriate sites within the respiratory tract. In addition,
these models must include mechanisms of clearance and
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