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PARTICLE DEPOSITION IN SPONTANEOUSLY HYPERTENSIVE RATS EXPOSED VIA WHOLE-BODY INHALATION: MEASURED AND ESTIMATED DOSE
Citation:
WICHERS, L., W. ROWAN, J. NOLAN, A. D. LEDBETTER, J. K. MCGEE, D. L. COSTA, AND W. P. WATKINSON. PARTICLE DEPOSITION IN SPONTANEOUSLY HYPERTENSIVE RATS EXPOSED VIA WHOLE-BODY INHALATION: MEASURED AND ESTIMATED DOSE. TOXICOLOGICAL SCIENCES. Oxford University Press, Cary, NC, 93(2):400-410, (2006).
Impact/Purpose:
To improve the ability of risk assessors to extrapolate rat-to-human exposure concentrations on the basis of lung burdens
Description:
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 outcomes problematic. To address this need, Spontaneously Hypertensive rats were exposed to an oil combustion-derived PM (HP12) via
inhalation while maintained in whole-body plethysmograph chambers. Rats (n=16) were exposed 6 h/day to air (n=2/group) or 13 mg/m3 of HP12 (n=6/group) for one or four 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
¿g to 89¿139 ¿g for 1- and 4-day exposures, respectively. Deposition data were compared to both default and rat-specific retention estimates provided by the Multiple Path Particle Deposition (MPPD)
model, yielding model predictions that were <33% of the measured dose. These studies indicate that HP12 exposure altered particle clearance mechanisms, as the mass of HP12 in the lungs following a
4-day protocol was nearly four times that observed after a 1-day exposure. The results of this study< also provide measured and modeled PM doses per lung lobe from whole-body inhalation exposure to PM. 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.