Research Association of Biomarkers of Systemic Inflam mation with Organic Components and Source Tracers in Quasi-Ultrafine Particles Ralph J. Delfino, 1 Norbert Staimer,1 Thomas Tjoa,1 Mohammad Arhami,2,3 Andrea Polidori,2 Daniel L. Gillen,4 Michael T. Kleinman,5 James J. Schauer,6 and Constantinos Sioutas 2 1Department of Epidemiology, School of Medicine, University of California–Irvine, Irvine, California, USA; 2Department of Civil and Environmental Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA; 3Department of Civil Engineering, Sharif University of Technology, Tehran, Iran; 4Department of Statistics, School of Information and Computer Sciences, University of California–Irvine, Irvine, California, USA; 5Occupational and Environmental Medicine Division, Department of Medicine, School of Medicine, University of California–Irvine, Irvine, California, USA; 6Environmental Chemistry and Technology Program, University of Wisconsin–Madison, Madison, Wisconsin, USA c onclusi k ey Background : Evidence is needed regarding the air pollutant components and their sources responsible for associations between particle mass concentrations and human cardiovascular out- comes. We previously found associations between circulating biomarkers of inflammation and mass concentrations of quasi-ultrafine particles ≤ 0.25 µm in aerodynamic diameter (PM0.25) in a panel cohort study of 60 elderly subjects with coronary artery disease living in the Los Angeles Basin. o Bsvitcej : We reassessed biomarker associations with PM0.25 using new particle composition data. Methods : Weekly biomarkers of inflammation were plasma interleukin-6 (IL-6) and soluble tumor necrosis factor-α receptor II (sTNF-RII) (n = 578). Exposures included indoor and outdoor com- munity organic PM0.25 constituents [polycyclic aromatic hydrocarbons (PAHs), hopanes, n-alkanes, organic acids, water-soluble organic carbon, and transition metals]. We analyzed the relation between biomarkers and exposures with mixed-effects models adjusted for potential confounders. r esult : Indoor and outdoor PAHs (low-, medium-, and high-molecular-weight PAHs), followed by hopanes (vehicle emissions tracer), were positively associated with biomarkers, but other organic components and transition metals were not. sTNF-RII increased by 135 pg/mL [95% confidence interval (CI), 45–225 pg/mL], and IL-6 increased by 0.27 pg/mL (95% CI, 0.10–0.44 pg/mL) per interquartile range increase of 0.56 ng/m3 outdoor total PAHs. Two-pollutant models of PM0.25 with PAHs showed that nominal associations of IL-6 and sTNF-RII with PM0.25 mass were com- pletely confounded by PAHs. Vehicular emission sources estimated from chemical mass balance models were strongly correlated with PAHs (R = 0.71). : Traffic emission sources of organic chemicals represented by PAHs are associated with increased systemic inflammation and explain associations with quasi-ultrafine particle mass. words : air toxics, biomarkers of effect, cytokines, epidemiology, longitudinal data analysis. Environ Health Perspect 118:756–762 (2010). doi:10.1289/ehp.0901407 [Online 2 February 2010] Cardiovascular hospital admissions and mortality have been associated with ambient mass concentrations of fine particulate mat­ ter (PM) air pollution ≤ 2.5 µm in aerody­ namic diameter (PM2.5) (Pope and Dockery 2006). Questions remain regarding the under­ lying causal chemical components and sources responsible for these associations. A recent time­ series study of 106 U.S. counties showed stronger associations of cardiovascular hospital admissions with countywide averages of PM2.5 when there were higher fractions of elemental carbon (EC), nickel (Ni), and vanadium (V), suggesting that important sources included fossil fuel combustion, biomass burning, and oil combustion (Bell et al. 2009). Unlike PM2.5, ultrafine particles (UFPs; generally defined as < 0.1 µm in diameter) are not regulated by the U.S. Environmental Protection Agency (EPA), yet this is the size fraction that may have the highest toxic potential because it has magnitudes greater number concentrations and surface area than the larger particles that dominate PM2.5 mass (Oberdörster et al. 2005). On that large surface area, UFPs carry and deliver redox­ active organic chemicals, including polycyclic 756 aromatic hydrocarbons (PAHs), to the respira­ tory tract in disproportionately higher concen­ trations than do larger particles (Ntziachristos et al. 2007), possibly leading to a cascade of effects related to oxidative stress and inflam­ mation in the lungs and at extrapulmonary sites (Delfino et al. 2005). These and other effects could underlie associations of morbid­ ity and mortality with air pollutants. Except for some studies with personal or microenvironmental air pollution data (Chan et al. 2004; Delfino et al. 2008, 2009; Folino et al. 2009; Vinzents et al. 2005), regional ambient air monitoring has been the primary data source used in epidemiologic research on the importance of UFP exposure to cardio­ vascular outcomes and circulating biomarkers in individual­level studies (de Hartog et al. 2003; Henneberger et al. 2005; Ibald­Mulli et al. 2004; Lanki et al. 2008; Pekkanen et al. 2002; Rückerl et al. 2006, 2007; Timonen et al. 2006). These studies of ambient air were all conducted in Europe, and UFPs were measured as particle number concentrations at central regional sites. Exposure error from the use of ambient data is likely, because air monitors may be far from subject locations and subjects may be exposed to pollutants from local sources, including traffic. UFPs have much higher spatial variability than does PM2.5 (Sioutas et al. 2005), so exposure error is likely. In addition, UFP mass and particle number do not specifically indicate which particle com­ ponents or sources are important, although generally in urban areas UFP compositions are dominated by organic chemicals and EC and originate from combustion sources. We conducted a panel cohort study of elderly subjects with a history of coronary artery disease living in the Los Angeles Basin. This is considered a population that may have among the greatest susceptibility to the adverse effects of air pollution (von Klot et al. 2005). We made repeated measurements of blood biomarkers and air pollutant exposures. To assess the potential importance of UFPs to cardiovascular health, we measured quasi­ ultrafine particle mass < 0.25 µm in diameter (PM0.25). To address the issue of exposure error, we monitored PM0.25 at the retire­ ment communities of subjects. We previously Address correspondence to R.J. Delfino, Department of Epidemiology, School of Medicine, University of California–Irvine, 100 Theory, Suite 100, Irvine, CA 92617–7555 USA. Telephone: (949) 824­1767. Fax: (949) 824­1343. E­mail: rdelfino@uci.edu Supplemental Material is available online (doi:10.1289/ehp.0901407 via http://dx.doi.org/). We appreciate the effort of staff from the Wisconsin State Laboratory of Hygiene; the Department of Epidemiology and General Clinical Research Center, University of California–Irvine; the Department of Civil and Environmental Engineering, University of Southern California; the California Air Resources Board; and the South Coast Air Quality Management District. This project was supported by the National Institute of Environmental Health Sciences (grant ES12243) and the National Center for Research Resources (grant M01 RR00827) of the National Institutes of Health, by the California Air Resources Board (contract 03­ 329), and by the U.S. Environmental Protection Agency’s Science to Achieve Results program (grant RD83241301) to the University of California–Los Angeles. The contents of this article are solely the responsi­ bility of the authors and do not necessarily represent the official views of the funding agencies, and no official endorsement should be inferred. The authors declare they have no actual or potential competing financial interests. Received 31 August 2009; accepted 2 February 2010. ovlume 118 | number 6 | June 2010 • Environmental Health Perspectives