Research Medium-Term Exposure to Traffic-Related Air Pollution and Markers of Inflammation and Endothelial Function Stacey E. Alexeeff,1 Brent A. Coull,2 Alexandros Gryparis,2 Helen Suh,1 David Sparrow,3 Pantel S. Vokonas,3 and Joel Schwartz1 1Department of Environmental Health, and 2Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA; 3VA Normative Aging Study, VA Boston Healthcare System, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA Background : Exposure to traffic-related air pollution (TRAP) contributes to increased cardio- vascular risk. Land-use regression models can improve exposure assessment for TRAP. o Bjectivs : We examined the association between medium-term concentrations of black carbon (BC) estimated by land-use regression and levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), both markers of inflamma- tory and endothelial response. Msdohte : We studied 642 elderly men participating in the Veterans Administration (VA) Normative Aging Study with repeated measurements of sICAM-1 and sVCAM-1 during 1999–2008. Daily estimates of BC exposure at each geocoded participant address were derived using a validated spatio- temporal model and averaged to form 4-, 8-, and 12-week exposures. We used linear mixed models to estimate associations, controlling for confounders. We examined effect modification by statin use, obesity, and diabetes. r sulte : We found statistically significant positive associations between BC and sICAM-1 for aver- ages of 4, 8, and 12 weeks. An interquartile-range increase in 8-week BC exposure (0.30 gμ/m 3) was associated with a 1.58% increase in sICAM-1 (95% confidence interval, 0.18–3.00%). Overall asso- ciations between sVCAM-1 and BC exposures were suggestive but not statistically significant. We found a significant interaction with diabetes—where diabetics were more susceptible to the effect of BC—for both sICAM-1 and sVCAM-1. We also observed an interaction with statin use, which was statistically significant for sVCAM-1 and suggestive for sICAM-1. We found no evidence of an interaction with obesity. c onclusi : Our results suggest that medium-term exposure to TRAP may induce an increased inflammatory/endothelial response, especially among diabetics and those not using statins. k ye sdrow : adhesion molecules, air, cardiovascular, environmental, outdoor air, roadway proximity. Environ Health Perspect 119:481–486 (2011). doi:10.1289/ehp.1002560 [Online 24 February 2011] There is strong epidemiological evidence that short-term air pollution exposure (i.e., < 24 hr to 3 weeks) is related to mortality and other cardiovascular events (Brook et al. 2010). Much of this evidence involves exposure to ambient particulate matter (PM) with aero- dynamic diameter ≤ 2.5 μm (PM2.5), which comprises many components and varies regionally. Contributions of specific compo- nents and sources to these effects are not well understood but are critical for informing the development of regulations. Short-term exposure studies often use sta- tionary monitors to estimate exposure in a nearby region. However, specific components of traffic-related air pollution (TRAP) vary substantially within cities, and traffic variables may contribute to this variation (Brauer et al. 2003; Clougherty et al. 2008; Kinney et al. 2000). This suggests that a geographically based approach could substantially improve assessment of black carbon (BC) exposure. Long-term exposure to TRAP (i.e., aver- ages ≥ 1 year) has also been associated with cardiovascular mortality, often based on studies using nitrogen dioxide as a surrogate for traffic pollutants and spatial modeling of exposures (Brunekreef et al. 2009; Gehring et al. 2006; Yorifuji et al. 2010). In a Boston, Massachusetts–area case-crossover analysis, we reported an association between mortality and BC exposure on the day before death, using spatiotemporally modeled BC exposure estimates as a marker of TRAP (Maynard et al. 2007). Intercellularadhesionmolecule-1(ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are markers of inflammation and endothelial function that are expressed on cell surfaces and are also found in soluble form in the plasma (sICAM-1 and sVCAM-1). These markers are independently and jointly associ- ated with increased risk of cardiovascular dis- ease (Albert and Ridker 1999; Pradhan et al. 2002; Rana et al. 2011; Ridker et al. 2003). Recent studies have reported associations between inflammatory markers and short-term exposure to TRAP, but studies have varied in both PM exposure type and inflamma- tory markers examined (Delfino et al. 2008; Madrigano et al. 2010; Zeka et al. 2006). Obesity and diabetes are becoming increas- ingly prevalent, and these conditions may increase susceptibility to the adverse health effects of air pollution (Forastiere et al. 2008; O’Neill et al. 2005; Zanobetti and Schwartz Environmental Health Perspectives • volume 119 | number 4 | April 2011 2002). Prospective and randomized clini- cal trials, as well as laboratory studies, have demonstrated that statins, a widely prescribed class of drugs with anti-inflammatory and anti- oxidant activity (Haendeler et al. 2004), can decrease C-reactive protein (CRP), ICAM-1, and VCAM-1 levels (Albert et al. 2001; Blanco-Colio et al. 2007; Liang et al. 2008; Montecucco et al. 2009). Thus, it is plausible that statin use could attenuate proinflammatory effects of air pollution, and reduced effects of air pollution on inflammation and heart-rate variability among statin users compared with nonusers have been reported (Schwartz et al. 2005; Zeka et al. 2006). The primary objective of the present study was to estimate the cumulative effects of exposure to TRAP over several weeks on inflammation and endothelial function. Previous findings based on BC measured at a central-site monitor suggested associations between inflammatory markers and air pollu- tion exposure averaged over the prior 4 weeks (Zeka et al. 2006). Because BC concentration varies spatially and averaging over a longer period of time decreases the temporal varia- tion in the data, we wanted to examine effects of 4- to 12-week average exposures estimated using a land-use regression model. We chose sICAM-1 and sVCAM-1 as outcomes because they reflect changes in inflammation, are asso- ciated with cardiovascular disease risk, and are relatively stable within individuals over 4-week periods (Eschen et al. 2008). We hypothesized that increases in medium-term BC concentrations estimated by land-use regressions would be associated with an increased inflammatory response in elderly Address correspondence to S.E. Alexeeff, 401 Park Dr., Ste. 415 West, Landmark Center, Boston, MA 02215 USA. Telephone: (617) 384-8753. Fax: (617) 384-8745. E-mail: salexeeff@fas.harvard.edu This work was supported by grants ES015172-01 and ES00002 from the National Institute of Environmental Health Sciences, and grant R832416 from the U.S. Environmental Protection Agency. The Normative Aging Study is supported by the Cooperative Studies Program/Epidemiology Research and Information Center of the U.S. Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (Boston, MA, USA). The authors declare they have no actual or potential competing financial interests. Received 15 June 2010; accepted 24 February 2011. 481