title: Pulmonary and systemic effects of zinc-containing emission particles in three rat strains: multiple exposure scenarios.
abstract: As a common component of ambient particulate matter (PM), zinc has been proposed 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 attributable to the leachable zinc following acute as well as longer-term exposures in a rat strain-specific manner. In order to initially characterize the pulmonary response to EPM, male Sprague-Dawley (SD) rats were intratracheally (IT) instilled with 0.0, 0.8, 3.3, or 8.3 mg/kg EPM in saline. To further determine if the pulmonary injury was associated with the EPM leachable zinc, subsequent studies included IT instillation of SD rats with either saline, whole EPM suspension, the saline leachable fraction of EPM, the particulate fraction of EPM (all at 8.3 mg/kg, soluble Zn = 14.5 microg/mg EPM), or ZnSO(4) (0.0, 33.0, or 66.0 microg/kg Zn). Finally, to ascertain the cumulative impact of inhaled EPM in the causation of acute pulmonary and systemic effects as well as long-term fibrotic responses, we exposed three rat strains of differential susceptibility to PM. Male SD, normotensive Wistar-Kyoto (WKY), and spontaneously hypertensive (SH) rats (90 days old) were exposed nose-only to either filtered air or EPM: 2, 5, or 10 mg/m(3) (6 h/day x 4 days/week x 1 week); or 10 mg/m(3) (6 h/day x 1 day/week for 1, 4, or 16 weeks) and assessed at 2 days postexposure. 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 the leachable fraction of EPM and ZnSO(4) 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 (10 mg/m(3) only) for 4 days resulted in small increases in bronchoalveolar lavage fluid (BALF) protein and n-acetyl glucosaminidase activities (approximately 50% above control). Surprisingly, unlike IT exposures, no neutrophilic influx was detectable in BALF from any of the inhalation groups. The only major effect of acute and long-term EPM inhalation was a dose- and time-dependent increase in alveolar macrophages (AM) regardless of the rat strain. 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 white blood cell counts and plasma fibrinogen with no major EPM inhalation effect. The present study demonstrated the critical differences in pulmonary responsiveness to EPM between IT and inhalation exposures, probably attributable to the dose of bioavailable zinc. EPM IT exposures, but not acute and long-term inhalation of up to 10 mg/m(3), caused neutrophilic inflammation. Inhalation exposures may result in particle accumulation and macrophage recruitment with potential strain differences in EPM clearance.
authors.affiliation: Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kodavanti.urmila@epa.gov
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: Mette C J
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: Russ
authors.initials: R
authors.lastname: Hauser
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: James M
authors.initials: JM
authors.lastname: Samet
authors.forename: John
authors.initials: J
authors.lastname: McGee
authors.forename: Judy H
authors.initials: JH
authors.lastname: Richards
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
mesh_terms: D000280:Administration, Inhalation; D000393:Air Pollutants / Q000633:toxicity*; D000418:Albumins / Q000032:analysis; D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000032:analysis; D006973:Hypertension / Q000503:physiopathology; D007322:Instillation, Drug; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009821:Oils; D010316:Particle Size; D011210:Power Plants; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013045:Species Specificity; D013997:Time Factors; D018675:Toxicity Tests; D015032:Zinc / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D000418:Albumins; D009821:Oils; D005340:Fibrinogen; D015032:Zinc