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

Abstract

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.

Keywords: Lung deposition, nanosized particles, particle retention, rats and mice.

Figure 1

Particle inhalability in human, rats, and mice for minute ventilation rates of 7.5 LPM, 8.3 cm³/s, and 2 cm³/s respectively.

Figure 2

Comparison of predicted nasal deposition of particles by the derived semi-empirical relationship for the mouse URT with Raabe et al. (1988) measurements on which the derived semi-empirical relationship is built.

Figure 3

Deposition efficiency of inhaled particles in the URT of human, rats, and mice for minute ventilation rates of 7.5 LPM, 8.3 cm³/s, and 2 cm³/s respectively.

Figure 4

Comparison of respirable fractions of particles that reach the lungs of humans, rats, and mice at different particles sizes for minute ventilation rates of 7.5 LPM, 8.3 cm³/s, and 2 cm³/s respectively.

Figure 5

Comparison of predicted deposition fraction in the mouse lung with available measurements in the literature, or reported here.

Figure 6

Regional deposition fraction of inhaled particles in the LRT of B6C3F1 and BALB/C mice via endotracheal breathing for identical lung and breathing parameters.

Figure 7

Regional deposition fraction of inhaled particles in the LRT of B6C3F1 and BALB/C mice via nasal breathing for identical lung and breathing parameters.

Figure 8

Comparison of predicted retained mass in the conducting airways mice with reported measurements by Teeguarden et al. (2014) shown by open squares with standard deviation.

Figure 9

Comparison of predicted clearance rate constants by the curve-fit model (equation (9) with that obtained based on measured retained mass.

Figure 10

Retained mass burden in the LRT of B6C3F1 mice for a 13 week exposure followed by 200 days post exposure: A. Nano-sized C60-fullerene particles, B. Microsized C60-fullerene particles.