title: Effects of exposure to ultrafine carbon particles in healthy subjects and subjects with asthma.
abstract: Increased levels of particulate air pollution are associated with increased respiratory and cardiovascular mortality and morbidity as well as worsening of asthma. Ultrafine particles (UFP; less than 0.1 microm in aerodynamic diameter) may contribute to the health effects of particulate matter (PM) for a number of reasons. Compared with larger particles on a mass basis, UFP have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation, larger surface area, and enhanced oxidant capacity. UFP also have the potential to cross the epithelium and enter the systemic circulation. We hypothesized that exposure to UFP causes airway inflammation in susceptible humans with activation of circulating leukocytes and vascular endothelium, a systemic acute phase response, and transient hypercoagulability. We further hypothesized that in people with asthma, UFP deposition would be increased and underlying airway inflammation enhanced. Our objectives were: to develop a system for controlled exposures of humans to UFP; to measure the pulmonary fractional deposition of UFP; to assess the effects of UFP exposure on blood leukocyte and endothelial adhesion molecule expression and activation, on airway nitric oxide (NO) production, on the systemic acute phase response, on blood coagulability, and on cardiac electrical activity and repolarization; and to evaluate these responses in both healthy subjects and people with asthma. We developed and validated a mouthpiece exposure system for human studies of carbon UFP and then conducted three clinical exposure studies: healthy subjects breathing filtered air and UFP (10 microg/m3) at rest (UPREST); healthy subjects breathing air and UFP (10 and 25 microg/m3) with intermittent exercise (UPDOSE); and subjects with mild asthma breathing air and UFP (10 microg/m3) with intermittent exercise (UPASTHMA). All exposures were for 2 hours on the mouthpiece system. Exposures were separated by at least 2 (UPREST and UPDOSE) or 3 (UPASTHMA) weeks. Prior to and at intervals after each exposure, we assessed symptoms, pulmonary function, blood markers of inflammation and coagulation, and airway NO production. Sputum inflammatory cells were assessed 21 hours after exposure. Continuous 12-lead electrocardiography (ECG) recordings were analyzed for changes in heart rate variability, repolarization, and arrhythmias. For healthy subjects, the fractional deposition of UFP at rest was 0.66 +/- 0.11 (mean +/- SD) by particle number, confirming the high deposition for UFP predicted by models. Deposition further increased during exercise (0.83 +/- 0.04). Asthmatic subjects showed higher UFP deposition than did healthy subjects when breathing at rest (0.76 +/- 0.05). During the UPREST protocol, there were no convincing effects for any outcome measures. Breathing 25 microg/m3 UFP with exercise (UPDOSE) was associated with reductions in blood monocytes and activation of T lymphocytes in healthy females. In asthmatic subjects (UPASTHMA), breathing 10 microg/m3 UFP was associated with reduced numbers of blood eosinophils and CD4+ T lymphocytes. In the UPDOSE group, monocyte expression of intercellular adhesion molecule-1 (ICAM-1) was reduced in a concentration-related manner (P = 0.001). In the UPASTHMA group, CD11b expression was reduced on monocytes and eosinophils, and ICAM-1 expression was reduced on polymorphonuclear leukocytes (PMNs). ECG analyses of UPDOSE subjects showed transient reductions in parasympathetic influence on heart rate variability and a reduced repolarization (QT) interval. In UPASTHMA subjects, ECG analyses showed decreased QT variability, but no effect on the QT interval. There were no significant effects in any of the studies on symptoms, pulmonary function, or markers of airway inflammation. We found no increases in soluble markers of systemic inflammation or coagulation. Our hypothesis that inhalation of carbon UFP causes pulmonary inflammation and an acute phase response was not confirmed. However, the observed subtle changes in leukocyte subsets and adhesion molecule expression are consistent with effects on vascular endothelial function. We also found effects on heart rate variability and on cardiac repolarization in healthy subjects. If confirmed, the finding that very low mass concentrations of particles have cardiovascular effects would have important implications for future PM regulatory strategies.
authors.affiliation: University of Rochester Medical Center, NY 14642-8692, USA. mark_frampton@urmc.rochester.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Frampton
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Utell
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Günter
authors.initials: G
authors.lastname: Oberdörster
authors.forename: Christopher
authors.initials: C
authors.lastname: Cox
authors.forename: Li-Shan
authors.initials: LS
authors.lastname: Huang
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morrow
authors.forename: F Eun-Hyung
authors.initials: FE
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Chalupa
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Frasier
authors.forename: Donna M
authors.initials: DM
authors.lastname: Speers
authors.forename: Judith
authors.initials: J
authors.lastname: Stewart
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism / Q000503:physiopathology*; D015415:Biomarkers; D001777:Blood Coagulation; D002244:Carbon / Q000009:adverse effects*; D002319:Cardiovascular System / Q000503:physiopathology; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D004781:Environmental Exposure; D005260:Female; D006801:Humans; D016131:Lymphocyte Subsets; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010316:Particle Size; D012119:Respiration; D013183:Sputum
chemical_list: D015415:Biomarkers; D016207:Cytokines; D009569:Nitric Oxide; D002244:Carbon