Grantee Research Project Results
2006 Progress Report: Mechanistic Dosimetry Models of Nanomaterial Deposition in the Respiratory Tract
EPA Grant Number: R832531Title: Mechanistic Dosimetry Models of Nanomaterial Deposition in the Respiratory Tract
Investigators: Asgharian, Bahman , Wong, Brian A.
Institution: The Hamner Institutes
EPA Project Officer: Hahn, Intaek
Project Period: November 15, 2005 through November 15, 2007
Project Period Covered by this Report: November 15, 2005 through November 15, 2006
Project Amount: $375,000
RFA: Exploratory Research: Nanotechnology Research Grants Investigating Environmental and Human Health Effects of Manufactured Nanomaterials: A Joint Research Solicitation - EPA, NSF, NIOSH (2005) RFA Text | Recipients Lists
Research Category: Safer Chemicals , Nanotechnology
Objective:
Accurate health risk assessments of inhalation exposure to nanomaterials will require dosimetry models that account for interspecies differences in dose delivered to the respiratory tract. Mechanistic models offer advantage to interspecies extrapolation: physicochemical properties of particles and species differences in ventilation, airway architecture, and physiological parameters can be incorporated into the mechanistic models explicitly to describe inhaled dose. The objective of this research project is to extend existing, verified mechanistic models of particle deposition in the respiratory tract of rats and humans to cover the range of size for nanoparticles and nanotubes. Deposition mechanisms are described based on first principles and are semi-empirical as required. Semi-empirical models of penetration from the upper respiratory tract (URT) can also be used to describe regional deposition fraction in the URT and could be extended to localized modeling. The approach includes model verification with experimental data obtained both in human and rat casts of the upper respiratory tract as well as in vivo studies of respiratory tract deposition.
Progress Summary:
A model of nanoparticle transport by airflow convection and diffusion migration, and deposition by Brownian diffusion was developed in the human lung. The model was based on an existing model for the deposition of various-size particles in the lungs of humans and rats but with full accounts for axial and radial Brownian movement in the airways. The advective-dispersion equation was solved to find particle concentration throughout the lung. A mass balance on the inhaled and exhaled particles moving through each airway of the lung was performed to find local, regional, and total lung deposition during breathing cycles. Because of high deposition of nanoparticles by Brownian diffusion, there was significant particle loss in the upper airways of the lung despite a high convective flow through the airways. As a result, depending on the particle size, very few or no particles reached the deep lung where axial diffusion was significant. Hence, the influence of axial diffusion on particle transport and deposition was limited by the lack of particle availability. This also explained why regional and total deposition of particles was not affected by the addition of transport by axial diffusion in the deposition model. The only significant outcome of including axial diffusion was the increased deposition predictions in the last few airways in which particle concentration had not diminished. Hence, despite the fact that regional and total deposition was unaffected, the distribution of deposited material in lung airways was altered. While existing deposition models can be safely used for prediction of regional deposition of nanoparticles, the proposed model will be useful in site-specific prediction that is more appropriately related to the biological response.
Deposition fractions of particles smaller than 0.1 mm in diameter were measured in nasal casts of humans and rats. Nasal casts of humans were built using stereolithography from digitized cross sectional data of magnetic resonance imaging and computed tomography scans of nasal passages. The rat nasal model was made from a postmortem cast of an F344 rat nose and comprised the nasal passages, nasopharynx, and larynx. Depending on the particle size, two particle generation systems were used. For particles between 5 and 30 nm, an electrospray generator (Model 3480; TSI Inc., St. Paul MN) was used to generate monodisperse nanoparticles. For particles between 30 and 100 nm, an electrostatic classifier (Model 3080; TSI Inc., St. Paul, MN) was used to select a stream of monodisperse particles of pre-selected size from the output of a nebulizer. Generated particles were passed through the nasal molds and particle concentrations prior to entering and immediately after exiting the models were measured using St. Paul, MN). Measurements were taken during a steady flow of air through the molds at different particle size and inhalation flow rates. Deposition of nanosized particles in the nasal passages approached 100% when particle size dropped below 10 nm. As particle size increased, deposition decreased and approached only a few percent for particles around 100 nm. Deposition fraction of nanoparticles appeared to be independent of the inhalation flow rate. Particle losses were higher in rats than in humans.
Future Activities:
A series of approximately15-minute, nose-only exposures will be conducted while the animals’ breathing rates are being measured. Animals will be exposed to different sizes of nanoparticles. Animals will be killed immediately at the end of exposures, and nasal airways and lung lobes will be dissected. The amount of deposition in each region will be measured and combined with breathing rates to compute deposition fractions. Measured regional deposition fractions will be compared against model predictions.
Behavior of nanotubes in the lung airways will be modeled with the presence of Brownian rotation. Brownian rotation is expected to modify the shear-flow induced periodic rotation of nanotubes when fiber dimensions are in sub-micrometer size range. New expressions for deposition efficiency will be developed for nanotubes that include the influence of its orientation on transport and deposition. The deposition efficiency formula will be included in a lung deposition model for fibers to predict deposition of nanotubes in the human lungs.
Journal Articles:
No journal articles submitted with this report: View all 5 publications for this projectSupplemental Keywords:
nanoparticles, lung deposition, nasal cast, deposition fraction,, Health, Scientific Discipline, Health Risk Assessment, Risk Assessments, Biochemistry, fate and transport, toxicology, dosimetry models, animal model, inhalation toxicology, metal oxide nanoscale materials, bioaccumulation, biochemical researchProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.