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PULMONARY AND SYSTEMIC EFFECTS OF ZINC-CONTAINING EMISSION PARTICLES IN THREE RAT STRAINS: MULTIPLE EXPOSURE SCENARIOS
Citation:
Kodavanti, U P., M. Schladweiler, A. D. Ledbetter, R. Hauser, D. C. Christiani, J. Samet, J K. McGee, J. H. Richards, AND D L. Costa. PULMONARY AND SYSTEMIC EFFECTS OF ZINC-CONTAINING EMISSION PARTICLES IN THREE RAT STRAINS: MULTIPLE EXPOSURE SCENARIOS. TOXICOLOGICAL SCIENCES 70(1):73-85, (2002).
Description:
Abstract
Pulmonary and Systemic Effects of Zinc-Containing Emission Particles in Three Rat Strains: Multiple Exposure Scenarios. Kodavanti, U. P., Schladweiler, M. C. J., Ledbetter, A. D., Hauser, R.*, Christiani, D. C.*, McGee, J., Richards, J. R., and Costa, D. L. (2002). Toxicol. Sci. 000, 000-000.
As a common component of ambient particulate matter (PM), zinc has been speculated to play a role in PM-induced adverse health effects. Although occupational exposures to high levels of zinc-fume have been associated with metal-fume fever accompanied by pulmonary inflammation and injury, the effects of PM associated-zinc are unclear. We hypothesized that an oil combustion emission PM (EPM) containing bioavailable zinc would induce pulmonary injury and systemic hematological changes following acute as well as longer-term exposures. To better ascertain the impact of EPM, we used three rat strains of differential susceptibility to PM, based on our previous studies. Dose-response relationships were characterized in male Sprague Dawley (SD) rats intratracheally (IT) instilled with 0.0, 0.8, 3.3, or 8.3 mg/kg EPM in saline. Similarly, male SD rats were IT instilled with either saline, whole EPM suspension, saline leachable or particulate fraction of EPM (all at 8.3 mg/kg, soluble Zn=14.5 mg/mg EPM), or ZnSO4 (0.0, 33.0, or 66.0 mg/kg Zn) to identify the putative causative constituent, zinc. To address the acute and longer-term effects of inhaled EPM, male SD, normotensive Wistar Kyoto (WKY), and Spontaneously Hypertensive (SH) rats (90-d old) were exposed nose-only to either filtered air or EPM: 2, 5 or 10 mg/m3 (6h/d?4d/wk?1wk); 10 mg/m3 (6h/d?1d/wk for 1, 4, or 16 wks) and assessed at 2 days-post exposure; or 10 mg/m3 (6h/d?2d) for assessment at 6h, 1 day, 2 day and 4 day post exposure. IT exposures to whole EPM suspensions were associated with a dose-dependent increase in protein/albumin permeability and neutrophilic inflammation. Pulmonary protein/albumin leakage and neutrophilic inflammation caused by leachable fraction of EPM and ZnSO4 were comparable to the effect of whole suspension. However, protein/albumin leakage was not associated with the particulate fraction, although significant neutrophilic inflammation did occur following instillation. With EPM nose-only inhalation, acute exposures of 4 days at 10 mg/m3 only, were associated with small increases in BALF protein, lactate dehydrogenase, and n-acetyl glucosaminidase activities (~50% above control). Surprisingly, no neutrophilic influx was detectable in BALF from any of the inhalation groups. However, the major effect of acute and long-term exposure was a significant dose and time-dependent increase in alveolar macrophages (AM) regardless of exposure protocol. Histological evidence also showed dose- and time-dependent accumulations of particle-loaded AM. Particles were also evident in interstitial spaces, and in the lung-associated lymph nodes following the inhalation exposures (SH>WKY=SD). There were strain-related differences in peripheral blood white cell types with no major EPM inhalation effect. Plasma fibrinogen appeared to be slightly, but not significantly elevated following the acute EPM inhalation exposure. The present study demonstrated the critical differences in pulmonary responsiveness to EPM between IT and inhalation exposures, probably accounted by the dose of bioavailable zinc. EPM IT exposures, but not acute and long-term inhalation of up to 10 mg/m3, caused neutrophilic inflammation. Inhalation exposures may result in particle accumulation and macrophage recruitment with potential strain differences in EPM clearance.