Inhalability of Particulate Matter in Laboratory Animals
EPA Grant Number:
Inhalability of Particulate Matter in Laboratory Animals
Chemical Industry Institute of Toxicology
EPA Project Officer:
January 17, 2000 through
January 16, 2002
Airborne Particulate Matter Health Effects (1999)
Air Quality and Air Toxics
The overall aim of this study is to develop improved animal dosimetry models
for use in risk assessments of particulate matter (PM). Accurate risk
assessments of PM require a thorough understanding of the relationships between
ambient exposure, dose to the respiratory tract, and responses. A number of
studies have shown that acute exposure to PM is related to increased mortality
and morbidity in humans. Since similar findings have been difficult to observe
in animals, EPA and others have major research initiatives underway, focusing
primarily on compromised animal models. To make the most use of these new data,
quantification or estimation of the particulate dose responsible for given
effects must be determined. Extrapolation of animal deposition study results to
human exposure scenarios requires comparable but not identical exposure
environments. Not all particles in the air are inhalable by rats even though
they may be in the inhalable range for humans. Our primary research objectives
are to (1) develop the necessary body of experimental data on inhalability and
particle deposition in the noses of rats, and (2) use these data to develop and
refine particle dosimetry models. The research proposed here will support the
extrapolation of animal results to humans by providing the necessary correction
factor to adjust for the fact that many of the particles comprising the fine and
coarse modes of urban aerosols are only partially inhalable by animals but are
completely inhalable by humans.
For particles to cause or to exacerbate lower respiratory tract (LRT) injury,
they must first be inhalable; once inhaled, they must be able to penetrate the
nasal region, enter the lungs, and finally deposit on tracheobronchial and
pulmonary surfaces. Thus, a critical aspect of assessing PM toxicity is to
establish functional relationships between inhalability, deposition in various
sites in the respiratory tract, particle size, and breathing conditions.
Inhalability is primarily a function of particle size, outside environmental
conditions, and breathing parameters. To determine the dose in the LRT, one has
to determine the fraction of the particles in the air that is actually inhaled
into the upper respiratory tract (URT) and the effects that the complex geometry
of the nose have on filtering particles so that they do not penetrate to the
LRT. The mechanisms by which the various constituents of PM are deposited in
respiratory tract regions are influenced by particle geometry and density,
airflow patterns, respiratory tract geometry, and the dynamics of breathing.
Losses in the nasal passages and variation in these losses greatly influence the amount that can deposit in lower airways.
Developing realistic PM deposition and clearance models for animals that incorporate physical phenomena is aided by the use of experimental data for model validation. Although the most commonly used laboratory animal is the rat, a set of respiratory tract structural data comprising the entire respiratory tract for any strain of rat is not available. A dosimetry model using structural data from a single rat strain for the entire respiratory tract would be useful for risk assessment purposes. Toward that end, we propose to use Long-Evans rats because of the availability of the anatomical data for the conducting airways and acinar region and because these data set have been used in a mathematical dosimetry model to calculate particle deposition in the rat lung (Anjilvel and Asgharian, 1995; A multiple-path model of particle deposition in the rat lung, Fundam. Appl. Toxicol., 28:41?50). The lung dosimetry model for rats has been extended to humans for a symmetric, dichotomous branching typical-path, 5-lobe symmetric but structurally different, and asymmetric lungs. These various lung geometries have been incorporated into a mathematical model of particle deposition. The deposition model calculates particle deposition in every airway of the LRT from the information on breathing rate, lung parameters, and deposition efficiencies per airway. Site specific, lobar, regional and total deposition fraction are calculated by adding deposition fractions of the individual airways. A software package with a graphical interface has been developed based on the deposition model. The graphical user interface feature of the software enables easy and quick calculations of deposition. The use of the software package allows rapid extrapolation of the rat results to humans since all the information is contained in one package. However, uncertainties regarding comparable exposure scenarios and lack of a more realistic URT deposition model for large particles limit such efforts. Clearly, the above issues need to be addressed and incorporated into the model. We will expose male Long-Evans rats to monodisperse particles in three ways: the exposure atmosphere passing directly through the nose of the animal, nose-only exposure, and whole-body exposure. In Method 1, anesthetized rats will be exposed to particles while their breathing is controlled externally, allowing deposition in the nasal cavity only. The flow is directed through the nose of the animal so that the particle concentration in the exposure air is the same as that entering the nose of the animal. In Methods 2 and 3, rats will be exposed briefly to monodisperse particles via nose-only or whole-body exposures while their breathing parameters are being measured. This procedure will allow deposition in the nasal region and in the LRT under laboratory exposure scenarios. Animals breathe from the air stream so that the inhaled concentration of particles may be different from that in the exposure air.
We expect to publish results in three major areas: 1) Measurement of particle deposition efficiency in the nasal passages. 2) The inhalability factor for particles as a function of particle diameter and breathing rate. 3) Improved dosimetry models for use in PM risk assessments.
Publications and Presentations:
Publications have been submitted on this project: View all 7 publications for this project
Journal Articles have been submitted on this project: View all 4 journal articles for this project
nasal deposition efficiency.
, RFA, Scientific Discipline, Air, particulate matter, Toxicology, Environmental Chemistry, Health Risk Assessment, air toxics, Atmospheric Sciences, ambient aerosol, urban air, inhalability, exposure and effects, dose response, air pollution, chronic health effects, particulate exposure, mortality, lower respiratory tract injury, animal inhalation study, dosimetry
Progress and Final Reports:
2000 Progress Report