Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models.

The percentages of total airflows over the nasal respiratory and olfactory epithelium of female rabbits were calculated from computational fluid dynamics (CFD) simulations of steady-state inhalation. These airflow calculations, along with nasal airway geometry determinations, are critical parameters for hybrid CFD/physiologically based pharmacokinetic models that describe the nasal dosimetry of water-soluble or reactive gases and vapors in rabbits. CFD simulations were based upon three-dimensional computational meshes derived from magnetic resonance images of three adult female New Zealand White (NZW) rabbits. In the anterior portion of the nose, the maxillary turbinates of rabbits are considerably more complex than comparable regions in rats, mice, monkeys, or humans. This leads to a greater surface area to volume ratio in this region and thus the potential for increased extraction of water soluble or reactive gases and vapors in the anterior portion of the nose compared to many other species. Although there was considerable interanimal variability in the fine structures of the nasal turbinates and airflows in the anterior portions of the nose, there was remarkable consistency between rabbits in the percentage of total inspired airflows that reached the ethmoid turbinate region (approximately 50%) that is presumably lined with olfactory epithelium. These latter results (airflows reaching the ethmoid turbinate region) were higher than previous published estimates for the male F344 rat (19%) and human (7%). These differences in regional airflows can have significant implications in interspecies extrapolations of nasal dosimetry.

3D 3He diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs.

In this work, we investigate (3)He magnetic resonance imaging as a noninvasive morphometric tool to assess emphysematous disease state on a local level. Emphysema was induced intratracheally in rats with 25 U/100 g body wt of porcine pancreatic elastase dissolved in 200 microl saline. Rats were then paired with saline-dosed controls. Nine three-dimensional (3D) (3)He diffusion-weighted images were acquired at 1, 2, or 3 wk postdose, after which the lungs were harvested and prepared for histological analysis. Recently introduced indexes sensitive to the heterogeneity of the air space size distribution were calculated. These indexes, D(1) and D(2), were derived from the moments of the mean equivalent airway diameters. Averaged over the entire lung, it is shown that the average (3)He diffusivity (D(ave)) correlates well with histology (R = 0.85, P < 0.0001). By matching small (0.046 cm(2)) regions in (3)He images with corresponding regions in histological slices, D(ave) correlates significantly with both D(1) and D(2) (R = 0.88 and R = 0.90, respectively, with P < 0.0001). It is concluded that (3)He MRI is a viable noninvasive morphometric tool for localized in vivo emphysema assessment.

Potential technology for studying dosimetry and response to airborne chemical and biological pollutants.

Advances in computational, and imaging techniques have enabled the rapid development of three-dimensional (3-D) models of biological systems in unprecedented detail. Using these advances, 3-D models of the lungs and nasal passages of the rat and human are being developed to ultimately improve predictions of airborne pollutant dosimetry. Techniques for imaging the respiratory tract by magnetic resonance imaging (MRI) were developed to improve the speed and accuracy of geometric data collection for mesh reconstruction. The MRI resolution is comparable to that obtained by manual measurements but at much greater speed and accuracy. Newly developed software (NWGrid) was utilized to translate imaging data from MR into 3-D mesh structures. Together, these approaches significantly reduced the time to develop a 3-D model. This more robust airway structure will ultimately facilitate modeling gas or vapor exchange between the respiratory tract and vasculature as well as enable linkages of dosimetry with cell response models. The 3-D, finite volume, viscoelastic mesh structures form the geometric basis for computational fluid dynamics modeling of inhalation, exhalation and the delivery of individual particles (or concentrations of gas or vapors) to discrete regions of the respiratory tract. The ability of these 3-D models to resolve dosimetry at such a high level of detail will require new techniques to measure regional airflows and particulate deposition for model validation.

An integrated confocal and magnetic resonance microscope for cellular research.

Complementary data acquired with different microscopy techniques provide a basis for establishing a more comprehensive understanding of health and disease at a cellular level, particularly when data acquired with different methodologies can be correlated in both time and space. In this Communication, a brief description of a novel instrument capable of simultaneously performing confocal optical and magnetic resonance microscopy is presented, and the first combined images of live Xenopus laevis oocytes are shown. Also, the potential benefits of combined microscopy are discussed, and it is shown that the a priori knowledge of the high-resolution optical images can be used to enhance the boundary resolution and contrast of the MR images.

A compact respiratory-triggering device for routine microimaging of laboratory mice.

A partial-body plethysmograph was developed for measuring the respiratory flow of anesthetized mice during routine microimaging experiments performed in the close confines of an 89-mm-diameter, vertical-bore magnet. Respiratory flow patterns were used for synchronizing conventional T2-weighted spin-echo imaging with the respiratory cycle, thereby, significantly reducing motion-induced artifacts and increasing observed liver lesion contrast.

Quantitative 1H MRI and MRS microscopy of individual V79 lung tumor spheroids.

In this Communication 1H MRI and MRS microscopy experiments of individual V79 lung tumor spheroids with diameters between 550 and 650 micrometer are reported. The results have been used to determine the T1, T2, and D values as well as the concentrations of water, total choline, creatine/phosphocreatine, and mobile lipids in the viable rims and in the necrotic centers.