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, human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Nanomaterial translocation–the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs–a review

“…To address (at least partially) some of these issues computational modelling of dose deposition (i.e. multipath particle deposition model or MPPD) can be utilised to extrapolate doses and deposition patterns from animals to humans (Asgharian et al 2014, Kuempel et al 2006. It is important to state that these models are far from perfect and are governed by a number of assumptions and simplifications which may differ from actual physiological exposures.…”

“…In addition, the differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of materials in the lung in these species. It is commonly accepted that the variances in regional lung tissue doses cannot currently be measured experimentally (Asgharian et al 2014). Next, differences in respiratory tract geometry, breathing parameters and clearance kinetics exist amongst humans and rodents which will result in changes in the deposited and retained tissues doses in the respiratory tract of these species (Gillespie et al 2010).…”

A Critical Review of in Vitro Dosimetry for Engineered Nanomaterials

“…Numerical models, such as the widely used and well-accepted multiplepath particle dosimetry model (MPPD) [86,87] have long been employed to estimate the delivered in vivo dose of inhaled particles. Recent advancements to the MMPD have now extended its use to computational modeling of nanoparticle deposition in the mouse lung [88]. Demokritou et al recently employed the MPPD model to estimate lung surface mass deposition per unit surface are associated with rodent in vivo inhalation exposures with CeO 2 ENMs [3].…”

Long-Term Exposure to Traffic Emissions and Fine Particulate Matter and Lung Function Decline in the Framingham Heart Study

“…Most particles less than 2.5 mm in diameter deposit in the lower respiratory tract, whereas the larger particles included in PM 10 , including most particles greater than 4 mm in diameter, deposit in the upper airways (14). It is possible that the fine particle fraction of PM 10 , which includes submicron particles emitted by traffic and industrial processes, are more toxic to the lung, although there are very few studies on long-term traffic and PM 2.5 exposure to support this assumption.…”