Review A Framework for Examining Social Stress and Susceptibility to Air Pollution in Respiratory Health Jane E. Clougherty1 and Laura D. Kubzansky 2 1Department of Environmental Health, and 2Department of Society, Human Development, and Health, Harvard School of Public Health, Boston, Massachusetts, USA Objectiv : hTere is growing interest in disentangling the health effects of spatially clustered social and physical environmental exposures and in exploring potential synergies among them, with particular attention directed to the combined effects of psychosocial stress and air pollution. Both exposures may be elevated in lower-income urban communities, and it has been hypothesized that stress, which can influence immune function and susceptibility, may potentiate the effects of air pol- lution in respiratory disease onset and exacerbation. In this paper, we attempt to synthesize the rele- vant research from social and environmental epidemiology, toxicology, immunology, and exposure assessment to provide a useful framework for environmental health researchers aiming to investigate the health effects of environmental pollution in combination with social or psychological factors. Dat syntheis : We review the existing epidemiologic and toxicologic evidence on synergistic effects of stress and pollution, and then describe the physiologic effects of stress and key issues related to measuring and evaluating stress as it relates to physical environmental exposures and sus- ceptibility. Finally, we identify some of the major methodologic challenges ahead as we work toward disentangling the health effects of clustered social and physical exposures and accurately describing the interplay among these exposures. c Onclusi Ons : There is still tremendous work to be done toward understanding the combined and potentially synergistic health effects of stress and pollution. As this research proceeds, we recommend careful attention to the relative temporalities of stress and pollution exposures, to non- linearities in their independent and combined effects, to physiologic pathways not elucidated by epidemiologic methods, and to the relative spatial distributions of social and physical exposures at multiple geographic scales. Key w Or Ds : air pollution, social stress, spatial analysis, synergistic effects, urban community health. Environ Health Perspect 117:1351–1358 (2009). doi:10.1289/ehp.0900612 available via http:// dx.doi.org/ [Online 12 May 2009] There is growing interest within environ- mental health in disentangling effects of clus- tered social and environmental exposures and exploring potential synergies among these exposures (Gee and Payne-Sturges 2004; Morello-Frosch and Shenassa 2006; O’Neill et al. 2003, 2007a, 2007b; Weiss and Bellinger 2006). This interest stems from the observation that social stressors (i.e., violence, poverty) and environmental exposures (i.e., traffic-related and industrial air pollution) are often spatially correlated and may cluster in lower-income communities, often in locations with lower property values along highways and industrial corridors (Bullard 1990; Graves 1988). Traffic- related air pollution is a complex chemical mix (Schauer et al. 2006), often spatially associ- ated with noise, poverty, and other stressors (Wheeler and Ben-Shlomo 2005). Social stres- sors may lead to poor health outcomes directly or may increase susceptibility to physical expo- sures, such as air pollution, through alterations in immune function and biological systems (McEwen and Seeman 1999). Thus, the most pollution-exposed communities may also be more susceptible because of higher prevalence of social stressors (Lipfert 2004). This poten- tial for spatial confounding and effect modifi- cation by social stressors presents a challenge to air pollution epidemiology. Disentangling social and physical environmental risks (U.S. Environmental Protection Agency 2008), understanding synergies among these expo- sures, and identifying modifiable exposures are particularly important for understanding how best to protect susceptible populations and improve overall population health. There is significant evidence linking traffic- related pollution exposure to respiratory ill- ness. Chronic exposure to traffic-related and particulate air pollution among adults has been linked to upper respiratory tract inflammation (Hiltermann et al. 1997), chronic obstructive pulmonary disease (COPD) (Schikowski et al. 2005), lung cancer (Vineis et al. 2007), and premature mortality (Dockery 1993; Pope et al. 1995). In children, traffic-related pollution exposures, often indicated by residential prox- imity to major roads, has been associated with airway hyperresponsiveness (Jang et al. 2003), wheeze (Ryan et al. 2007), asthma (McConnell et al. 2006), reduced lung function (Pekkanen et al. 1997), and asthma-related hospitalizations (Lin et al. 2002; Moore et al. 2008). There is now increased interest in understanding car- diovascular effects (Peters 2005; Rückerl et al. 2006), identifying causal constituents (Lanki et al. 2006), and characterizing susceptible sub- populations (O’Neill et al. 2007b). Psychological stress results when exter- nal demands exceed an individual’s perceived abilities and resources to meet those demands Environmental Health Perspectives • volume 117 | number 9 | September 2009 (Cohen et al. 1995) and has been linked to respiratory disease and other illness. Limited but growing epidemiologic evidence indi- cates that psychological stress may also alter susceptibility to physical exposures, such as air pollution. This work examined social– environmental interactions in respiratory and cardiovascular disease, such as stress-related modification of traffic-related air pollution effects on asthma etiology (Clougherty et al. 2007) or exacerbation (Chen et al. 2008). There is also evidence of stress-related modi- fication in the relationship between bone lead level and hypertension among older men (Peters et al. 2007). In the same data set, we recently identified modification by stress in the relation between bone lead and heart rate variability (Clougherty JE, Peters JL, Schwartz J, Kubzansky L, unpublished data). One possible pathway for these differential susceptibilities is allostatic load (McEwen and Seeman 1999). Allostasis (literally, “achiev- ing stability through change”) refers to the body’s ability to adapt to transient stressors and exposures. Over time, chronic psycho- logical stress and maladaptive behaviors (e.g., poor diet, sleep deprivation) (McEwen 2006) may impair the body’s ability to maintain allostasis, producing wear and tear on bodily systems, compromised immune function, and enhanced general susceptibility (McEwen 2006; McEwen and Seeman 1999), and enhancing responsivity to environmental toxi- cants including air pollution. For example, some toxicologic evidence suggests perma- nent alteration in hypothalamic–pituitary– adrenal (HPA) function associated with chronic stress and lead exposures (Virgolini et al. 2005, 2006). However, some biological systems involved in maintaining allostasis may also be worn down by repeated exposure to physical toxicants, as particle exposures may influence HPA function (Sirivelu et al. 2006). Finally, some air pollutants and psycho- social stress may independently affect com- mon physiologic processes such as oxidative Address correspondence to J.E. Clougherty, Harvard School of Public Health, Landmark Building, 4th Floor West, Boston, MA 02215 USA. Telephone: (617) 816-7717. Fax: (617) 384-8859. E-mail: jcloughe@hsph.harvard.edu We are very grateful to B. McEwen for his helpful suggestions on this manuscript. The authors declare they have no competing financial interests. Received 23 January 2009; accepted 12 May 2009. 1351