Particle Deposition in Spontaneously Hypertensive Rats Exposed via Whole-Body Inhalation: Measured and Estimated Dose

Abstract

A plethora of epidemiological studies have shown that exposure to elevated levels of ambient particulate matter (PM) can lead to adverse health outcomes, including cardiopulmonary-related mortality. Subsequent animal toxicological studies have attempted to mimic these cardiovascular and respiratory responses, in order to better understand underlying mechanisms. However, it is difficult to quantitate the amount of PM deposited in rodent lungs following inhalation exposure, thus making fundamental dose-to-effect assessment and linkages to human responses problematic. To address this need, spontaneously hypertensive rats were exposed to an oil combustion-derived PM (HP12) via inhalation while being maintained in whole-body plethysmograph chambers. Rats were exposed 6 h/day to 13 mg/m(3) of HP12 for 1 or 4 days. Immediately following the last exposure, rats were sacrificed and their tracheas and lung lobes harvested and separated for neutron activation analysis. Total lower respiratory tract deposition ranged from 20-60 microg to 89-139 microg for 1- and 4-day exposures, respectively. Deposition data were compared to default and rat-specific estimates provided by the Multiple Path Particle Deposition (MPPD) model, yielding model predictions that were < 33% of the measured dose. This study suggests that HP12 exposure decreased particle clearance, as the mass of HP12 in the lungs following a 4-day protocol was nearly four times that observed after a 1-day exposure. This work should improve the ability of risk assessors to extrapolate rat-to-human exposure concentrations on the basis of lung burdens and, thus, better relate inhaled doses and resultant toxicological effects.

Airflow and Particle Deposition Simulations in Health and Emphysema: From In Vivo to In Silico Animal Experiments

“…Despite their extensive use in toxicology 52 and therapeutic studies 1 relatively few studies have simulated airflow 32 and particle deposition in the rat lung. In a recent study, CFD and MRI steady flow measurements agreed well in the conducting airways.…”

Comparison of Predicted and Experimentally Measured Aerosol Deposition Efficiency in BALB/C Mice in a New Nose-Only Exposure System

“…Most animal inhalation studies quantify the exposure concentration; however, there are relatively few that quantitatively measure respiratory tract deposition (Raabe et al 1988;Yeh et al 1990;Nadithe et al 2003;Hofstetter et al 2004;Oldham et al 2004;Wichers et al 2006;Alessandrini et al 2008). A few of these studies have attempted to verify dosimetry model predictions.…”

“…Nadithe et al (2003) designed a nose-only exposure system and used a proprietary dosimetry code to compare experimental and predicted particle deposition for 3.9 (±0.5) micrometer diameter particles. Wichers et al (2006) compared experimentally measured deposition with predictions from the MPPD dosimetry code (MPPD 2002) for 1.95 micrometer diameter particles. Neither of these studies were able to utilize strain specific respiratory tract anatomy and respiratory physiology parameters.…”

“…Their dosimetry predictions did not differ significantly from their in-vivo measurements. Wichers et al (2006) exposed spontaneously hypertensive rats and their dosimetry predictions used Long Evans Hooded rat anatomy with their spontaneously hypertensive rat respiratory physiology. Their dosimetry predictions were <33% of their measured dose.…”

Rat airway morphometry measured from in situ MRI-based geometric models

“…Rats have been widely used in experimental deposition studies (24,35) and in studies aimed at understanding the influence of particle composition on lung pathology (7,26) as well as aiding in the development of drugs delivered as aerosols (XX). Therefore, an improved understanding of the rat 3D airway morphometry may establish links between aerosol deposition and airway geometry.…”