Grantee Research Project Results

Final Report: Mechanistic Dosimetry Models of Nanomaterial Deposition in the Respiratory Tract

EPA Grant Number: R832531
Title: 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 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: Nanotechnology , Safer Chemicals

Objective:

No studies exist on the health impact of inhaled manufactured nanomaterial to aid with human exposure risk assessment. Accurate health risk assessments from exposure to nanomaterial require a thorough understanding of the relationship between dose to the respiratory tract and response. The overall objective of this research was to create the tools and database for the development of a dose-response relationship for nanoparticles. The objective was accomplished by (1) obtaining predictive models of nanosized particle deposition in nasal airways from deposition measurements in nasal replicas, (2) developing deposition models of nanosized particles in human and rat respiratory tract and creating a user-friendly software package based on the developed deposition models, (3) conducting a series of nose-only inhalation exposures in rats to obtain the necessary database on the deposition of nanosized particles in nasal airways and lungs of rats, and (4) validating the models by comparing predictions with deposition measurements for rats and information on humans available in the literature.

Summary/Accomplishments (Outputs/Outcomes):

Deposition efficiencies were measured in the three human nasal replicas at flow rates of 10 and 20 L/min. For particle diameters between 30 and 100 nm, deposition efficiency was generally less than 0.1 at both 10 and 20 L/min steady inspiratory flow. There was no dependence of the deposition on flow rate, within the experimental variability of the data. For particles less than 30 nm, deposition efficiencies in the human replica increased with decreasing diameter from an average of about 0.05 to a maximum of about 0.5 for 5 nm particles. When compared with previous measurements, the data overlaped.

Deposition efficiencies were measured in the rat nasal replicas at flow rates of 200 and 400 mL/min. Measured deposition efficiency of particles in the rat nasal mold increased as particle size decreased. At a particle size of 100 nm deposition efficiency was approximately 0.1. Particle deposition efficiency increased to above 0.9 at approximately 4 nm. These results were similar but slightly lower than reported measurements in the literature. The slight differences in the results may be due to the experimental variability or differences in experimental methods. In addition, the differences may also be due to intersubject variability, as studies were conducted in different nasal molds.

Predictive models of particle deposition efficiencies in human and rat nasal airways were obtained as a function relevant non-dimensional parameters or particle diffusion coefficient and airflow rate. The predictive models were in close agreement with existing models. The semi-empirical models of this study were based on deposition measurements of a wider range of particle sizes including particles as small as 5 nm, and hence, the proposed models will expand the applicability range of existing predictive models in the literature.

A deposition model of nanoparticles from 1 nm to 100 nm was developed for symmetric and asymmetric (stochastic) human and rat lungs. To investigate the penetration depth of different size nanoparticles, the model was employed to calculate concentrations of 2-nm, 5-nm, and 10-nm particles via nasal breathing at the end of inhalation. There was no penetration of 1 nm particles into the lung and no penetration beyond generation 11 for 2-nm particles due to high deposition in the preceding airways. As particle size increased, losses by diffusion in upper airways of the tracheobronchial (TB) airways decreased and as a result, particle penetration into the lung increased. While there was little penetration of 5-nm particles into pulmonary region, a significant portion of 10-nm particles reached the pulmonary region. The inability of nanoparticles less than 5 nm in size to reach the pulmonary airways limited the influence of axial diffusion and dispersion on particle deposition in the deep lung.

Inefficient penetration of nanoparticles into the lung resulted in a very low airway deposition of particles below 5 nm. There was practically no deposition of nanoparticles in the lung for particles below 5nm. Pulmonary deposition for particles larger than 5 nm increased with increasing particle size.

To examine the influence of axial diffusion and dispersion on deposition and its significance on deposition of nanoparticles in particular, the deposition model was utilized to calculate deposition fractions of particles between 1 nm and 100 nm in different regions of the human lung for the cases of particle penetration by convection and convection plus diffusion and dispersion. Diffusive transport of particles through lung airways had no significant effect on particle deposition in the TB region but a small increase was noticed for particles below 10 nm. This was because flow convection was much stronger than axial diffusion for particles larger than 1 nm in TB airways. The most significant but limited effect on deposition by including diffusion and dispersion was observed in the pulmonary region for particles greater than 10 nm. Because of diminishing airflow velocity, convective mixing became negligible in the pulmonary region.

An advantage of stochastically-generated lung geometries is that inter- and intra-subject variability can be examined by calculating deposition of particles in many lung geometries. Deposition fractions in the TB and pulmonary regions of 30 regions of 30 stochastically-generated lung geometries were calculated for particles smaller than 100 nm. Deposition variations in both regions were small near 1 nm and 100 nm size particles. This was because of very high and very low particle deposition of 1 nm and 100 nm particles respectively. The largest variation in deposition was for 10 nm-diameter particles for which the diffusion mechanism was neither overwhelming nor insignificant. By the same argument, a wide range of particle deposition was observed in the PUL region. Because of the differences in TB deposition, the peak pulmonary deposition, which is due to TB filtering effects, was observed at a different particle size for each lung geometry.

However, while the lobar deposition trend between model predictions and the experiment agreed, a significant difference in the abolute values existed. The average ratio for data is 2.48; meaning that there is a 40% discrepancy. One factor that could potentially contribute to this discrepancy is particle clearance. This was thought to be a potential factor particularly because there was approximately 10 minutes between the end of particle exposure and when the animals arrived at necropsy. Additionally, for animals that were dissected last, there was as much as 45 minutes between the end of an exposure and tissue collection, leaving clearance as a distinct possibility. To further examine this, particle clearance calculations were performed. These calculations indicated that in 30 minutes, approximately 21% clearance could be expected, leaving at least a 20% discrepancy to other factors. Such factors might include dissolution due to the hygroscopic nature of the aerosol, and subsequent absorption into the bloodstream. From an experimental standpoint, getting the animals to stay in a given position and breathe normally was difficult, thus making measurement of their breathing parameters difficult as well. This would affect calculation of total inhaled aerosol, and therefore fractional deposition.

A new version of MPPD based the model of nanoparticle deposition was developed that serves as a very useful tool for the risk assessment from exposure to nanoparticles. Input to the software are nanosized particle characteristics, breathing parameters, and exposure concentration. The software calculates regional, lobar, and local deposition of nanosized particles and produces textual and graphical outputs. The ease of use makes the software desirable for design of toxicity and other related experimental studies in the same way as that with the previous version of model for larger size particles.

Conclusions:

Particles in the nanometer size range deposit in the nasal airways by the diffusion mechanism. Our experimental measurements show that nanoparticles in the 100 to 30 nm size range do not deposit efficiently in the upper respiratory tract (URT). As particle size decreases from 30 to 5 nm, the efficiency of deposition increases. Rat nasal airways are more efficient than human nasal airways for depositing 5 nm nanoparticles. Therefore, the URT is a potential target for deposition and subsequent biological effects of nanoparticles in the smallest size range.

A predictive model for deposition of nanoparticles in nasal airways of humans and rats was developed. This model of nasal airway deposition can be used to predict the amount of particles that penetrate to the lower respiratory tract for deposition. The combination of upper and lower respiratory tract deposition models can be used to provide estimates for human deposition from extrapolation of rat deposition measurements in laboratory studies.

TB deposition of nanoparticles was less sensitive to lung structure when compared with PUL deposition. The addition of axial diffusion and dispersion was found to raise predicted deposition in the PUL region up to 10% depending on particle size.

Further studies are necessary to bring theoretical calculations and experimental results closer together. For instance, continual model development is a very important avenue to continue to explore. As this development occurs, inclusion of more aerosol specific parameters such as solubility constants may help to bring predictions and experimental results closer. Another route that could be taken would be to examine several other aerosols composed of compounds of varying hygroscopic nature in order to see at what point theory and experiment are most closely matched. Finally, further development of equipment such as exposure towers and nose-only tubes that would help reduce animal stress and allow them to breathe more normally would be extremely valuable to reduce experimental data scatter and more accurately represent real breathing and therefore deposition conditions as used in the models.

Journal Articles on this Report : 1 Displayed | Download in RIS Format

Publications Views

Other project views:	All 5 publications	1 publications in selected types	All 1 journal articles

Publications

Type	Citation	Project	Document Sources
Journal Article	Asgharian B, Price OT. Deposition of ultrafine (NANO) particles in the human lung. Inhalation Toxicology 2007;19(13):1045-1054.	R832531 (Final)	Abstract from PubMed Abstract: Inhalation Toxicology - Abstract Exit

Supplemental Keywords:

rat lung deposition, nasal deposition, deposition efficiency,, Health, Scientific Discipline, Health Risk Assessment, Risk Assessments, Biochemistry, animal model, bioaccumulation, fate and transport, inhalation toxicology, toxicology, metal oxide nanoscale materials, human health risk, biochemical research

Relevant Websites:

http://www.ciit.org/techtransfer/tt_technologies.asp Exit

Progress and Final Reports:

Original Abstract

2006 Progress Report