Predicting the Fate of Particles in the
Respiratory Tract
Perspectives
The retention of inhaled particles in the human lung is an important
determinant of health risk; however, it is not easily estimated. The Multiple
Path Particle Dosimetry (MPPD) model is a useful state-of-the-art tool for
predicting particle dosimetry in the human lung for risk assessments.
Background
Particulate matter (PM) is a constituent of air pollution that is
composed of small solid particles and droplets suspended in the air.
Exposure to elevated levels of PM is associated with increases in
respiratory problems, hospitalizations for lung or heart disease, and
premature death. Of particular concern are fine particles, which are
easily inhaled deep into the lungs.
The size of PM is important to health because it is a major determinant
of which portions of the lung come into contact with PM. The U.S.
Environmental Protection Agency (EPA) recognized this in 1987 when
it changed its National Ambient Air Quality Standards (NAAQS) for PM
from “total suspended particulate” to PM less than 10 micrometers
(µm) in aerodynamic diameter (PM10). This size was chosen to focus
on particles most likely to be inhaled into the lower respiratory tract
(i.e., below the voice box or larynx). As more information became
available on the effects of different size ranges, EPA added another
NAAQS in 1997 for fine PM—particles smaller than 2.5 µm in
diameter or PM2.5—which is more likely to be deposited deep in the
lung where gas exchange occurs (i.e., oxygen for carbon dioxide).
In view of a court ruling, EPA must propose a PM10-2.5 standard if
the Agency wants to regulate large particles. The goal of the NAAQS
is to protect sensitive subpopulations, such as children, the elderly,
and people with pre-existing lung or cardiovascular disease, with an
adequate margin of safety. The extent of the exposed population and
the high costs (in the tens of billions of dollars) of implementation
make accurate risk assessments of PM extremely important.
Under the Clean Air Act, EPA also regulates hazardous air pollutants
(HAPs)—some of which are in particulate form—by setting Maximum
Achievable Control Technology (MACT) standards to control emissions.
Recent MACT standards allow low-risk facilities to qualify for reduced
compliance options (e.g., the industrial, commercial, and institutional
boiler and process heaters MACT). EPA is also evaluating risks—
called “residual risks”—of post-MACT emissions of HAPs to determine
whether additional controls should be required.
August 2005
Extrapolating Laboratory Animal Inhaled Doses
to Humans
There are important differences in how particles are deposited in laboratory
animal lungs compared to human lungs. For example, rat lung structures
differ from humans (see images below, left). Thus, the paths that particles
travel before “landing” on various regions of the lung are different.
CIIT’s lung dosimetry model greatly facilitates dose extrapolations between
animals and humans that are frequently necessary for chemical risk
assessments. Shown below (right) are lung dosimetry plots for rat and
human lungs when both species are exposed for six hours to 100 micrograms of particles (one micron in size) per cubic meter of air (µg/m3).
Lung
Structure
MPPD Model
Deposition Results
Key
Less
deposition
Rat
Greater
deposition
Human
The respiratory tract is both a portal of entry for PM and a potentially
susceptible area of the body for PM-induced effects. A key determinant
of the health risk from exposure to particles is the amount of the
substance retained in the lung after it is inhaled. At a given point
in time, the amount retained is the difference between the amount
deposited and the amount cleared. Several physical and physiological
factors, such as the depth and route of breathing, influence where particles of a given size deposit.
Subsequently, solubility of the particle and lung region-specific clearance mechanisms determine
the amount of material removed.
Researchers at the CIIT Centers for Health Research (CIIT), with funding from the LRI and the Dutch
Ministry of Housing, Spatial Planning, and the Environment, have made significant contributions
to the current understanding of particle dosimetry in the respiratory tract by studying the extent
to which particles are deposited and cleared after they are breathed in. In the research project
described here, CIIT developed a scientifically sophisticated and user-friendly computational model
for estimating laboratory animal and human airway particle dosimetry.
At the gas-exchange
area (the outermost
edges of these
diagrams), the model
predicts that rats
receive a dose per
unit area that is
about five times
higher than humans.
The LongRange
Research
Initiative (LRI),
a program of
the American
Chemistry
Council, sponsors research that increases scientific knowledge of the potential impacts that chemicals
may have on human health, wildlife, and the
environment. See www.USLRI.org.
Approach
Results & Implications
Previous dosimetry models used to predict particle deposition in the lung assumed simple, idealistic lung geometries. The
Multiple Path Particle Dosimetry (MPPD) model was developed to incorporate more realistic asymmetries in the lung branching
structure and calculate deposition at the individual airway level. The MPPD model approach was first used to estimate particle
dosimetry for the laboratory rat using measurements available in the literature.
CIIT extended the model to calculate deposition for a range of particle sizes and breathing rates in the adult human lung. The
researchers developed 10 statistically-based “virtual” lung structure models to examine the randomness and asymmetry of
the airway branching system. This enabled them to gain insights on the effects of lung size and branching pattern on particle
deposition. The researchers found that the MPPD predictions for humans were very close to experimental measurements until
particles were 0.1 µm or less, and then predictions were within 30 percent of the available experimental data.
The MPPD software is available from CIIT free of charge at www.ciit.org/techtransfer/tt_technologies.asp and can be installed
on PC, Macintosh, or Unix platforms. The software has a user-friendly interface and features eight tutorials. The highest priority
for future developments of the MPPD will be lung geometries for children because they are considered to be a potentially sensitive subpopulation for exposures to particles.
The MPPD software enables risk assessors to calculate doses deposited, cleared, and retained in specific parts of the human
lung for a specified exposure scenario and PM concentration. The software allows assessors to test a variety of inputs, such
as lung geometry, breathing parameters, and particle characteristics such as size (from ultrafine (0.01 µm) to coarse (20 µm)),
distribution (monodisperse, polydisperse), and mass density. Also, an assessor can, for example, input the details of a rat inhalation study and calculate the human exposure scenario needed to produce an equivalent dose in humans, thereby substantially
improving the animal-to-human extrapolation.
As required by the Clean Air Act, EPA is currently deciding whether to tighten, loosen, or maintain the current PM standards or to
add new ones. The NAAQS process involves EPA developing an “air quality criteria document” that stipulates the health effects
information that may be used as a foundation for the primary PM standards. In the PM criteria document, EPA used the MPPD
model to characterize differences between human and rat inhaled doses of PM and evaluate whether they were similar.
Use of the MPPD model can also make the risk assessments conducted under MACT regulations more accurate. The model has
become the “gold standard” for calculating dosimetry of particles and will be replacing conservative assumptions in the calculation of EPA inhalation reference concentrations (RfCs) that are used in residual risk assessments.
The MPPD model has been extremely well received by the scientific and regulatory communities. Currently, about 50 organizations, including 15 governmental agencies and 15 chemical industry and pharmaceutical companies, are using it. These uses
include: (1) extrapolating laboratory animal data to humans, (2) comparing different human exposure scenarios (e.g., if the
effects of one exposure are known, what might happen at a different exposure), (3) setting exposure levels for toxicological
studies, and (4) conducting human safety and risk assessments (e.g., cancer and noncancer risk assessments of inhaled particles).
Anjilvel, S. and Asgharian, B. (1995). A multiple-path model of particle deposition in the rat lung.
Fundam Appl Toxicol 28:41-50.
References
Asgharian, B., Hofmann, W., and Bergmann, R. (2001). Particle deposition in a multiple-path
model of the human lung. Aerosol Sci Technol 34:332-339.
Asgharian, B., Hofmann, W., and Miller, F.J. (2001). Mucociliary clearance of insoluble particles
from the tracheobronchial airways of the human lung. J Aerosol Sci 32:817-832.
Asgharian, B., Miller, F.J., and Subramaniam, R.P. (1999). Dosimetry software to predict particle
deposition in humans and rats. CIIT Activities 19(3). March.
Hofmann, W. and Asgharian, B. (2003). The effect of lung structure on mucociliary clearance and
particle retention in human and rat lungs. Toxicol Sci 73:448-456.
Miller, F.J. (2001). Dosimetry of particles: Critical factors having risk assessment implications.
CIIT Activities 21(11-12). March.
USEPA (2004). National Emissions Standards for Hazardous Air Pollutants for Industrial,
Commercial, and Institutional Boilers and Process Heaters, Final Rule. September 13. Federal
Register 69(176):55218-55286.
USEPA (2004). Air Quality Criteria for Particulate Matter. National Center for Environmental
Assessment, Office of Research and Development, Research Triangle Park. EPA/600/P-99/002aF.
Investigators
CIIT Centers for Health Research
Bahman Asgharian, PhD*
Frederick J. Miller, PhD, Fellow ATS
Ravi Subramaniam, PhD
S. Anjilvel, PhD
O.T. Price*
*Currently affiliated with CIIT.