Clougherty and Kubzansky Spatial correlations among social and physical exposures. Both social and physical exposures vary across communities, and lower- income and minority communities may be disproportionately exposed to both (Evans and English 2002; Lupien et al. 2001; Morello- Frosch and Shenassa 2006). Strong spatial covariance among stress, SES, and pollution has confounded geographic information sys- tems (GIS)–based air pollution epidemiology, and spatial epidemiologists are challenged to differentiate health effects of traffic-related pol- lution from those of spatially correlated noise, stress, or poverty. Evidence suggests that road- way noise, a spatial stressor correlated with pollution, increases heart rate among adults and children (Belojevic et al. 2008; Belojevic and Saric-Tanaskovic 2002), and living in high-traffic areas predicts higher stress, lower self-reported health, and depressive symptoms (Gee and Takeuchi 2004), effects distinct from those of pollution per se. Because of spatial autocorrelation and pos- sible confounding, accurate fine-scale expo- sure assessment for both stress and pollution is critical. GIS-based exposure models, now common in environmental epidemiology, should be validated to the spatial extent of the cohort examined, and spatial patterns in stres- sors and pollution, at multiple levels, should be carefully considered to avoid spatial mis- classification and confounding. Social–physical correlations may vary by region or context, and the appropriate geographic scale of analy- sis may vary as well. The 1995–1997 Health Survey for England found that in urban areas, lower-SES households experienced worse air quality, although the opposite was true in rural regions. Air quality and SES independently predicted lung function in both settings, with greater pollution susceptibility among lower- SES men, but not women (Wheeler and Ben- Shlomo 2005). Although some neighborhoods may expe- rience higher average levels of pollution and stressors (variation across neighborhoods), one should not assume that individuals or resi- dences within these neighborhoods are rela- tively more exposed to both (variation within neighborhoods). Individuals living closer to highways likely have higher pollution expo- sures than do other community residents but are not necessarily more exposed to violence or family stress. Similarly, U.S. census tracts, selected to be relatively homogeneous for key sociodemographic indicators, may be a mean- ingful unit of analysis for some social and eco- nomic factors (Subramanian et al. 2005). All persons within a census tract, however, do not have similar traffic-related pollution exposures, which vary dramatically within 50–200 m of major roadways (Zhu et al. 2002). Nonlinear, threshold, and saturation effects. There is evidence linking stress and 1354 air pollution, separately, to asthma onset and exacerbation. Because both exposures inde- pendently influence respiratory health, we might expect that with especially high levels of either exposure, exacerbations likely occur, regardless of the second exposure. Effectively, very high exposures may overpower any potential interaction effects. Potential saturation effects call for careful attention to the exposure range observed in any study, relative to normal exposure lev- els, to inform whether interactions should be expected and how to interpret observed interactions. For example, our group reported that asthmatic children of families reporting higher fear of violence showed less symptom improvement with allergen-reducing indoor environmental interventions (Clougherty et al. 2006). Counter to initial hypotheses, this result suggested saturation effects in our very high-exposure public housing cohort. Either fear of violence or allergen exposures may have been high enough to independently induce or maintain symptoms. The need for toxicologic research. Because of strong potential confounding between stressors and pollution, epidemiologic methods alone are unlikely to fully differentiate their effects or resolve spatial confounding. Additionally, chronic air pollution exposure may contrib- ute to HPA-axis stimulation and stress pro- cesses (Sirivelu et al. 2006). Thus, experimental studies using well-developed animal models of social stress (e.g., monkeys, rats) are needed to delineate these effects. Toxicologic data can improve causal inference and interpretability by randomizing exposures, controlling their temporality and intensity, and, importantly, can help elucidate physiologic mechanisms for stress-pollution interactions. Several authors have investigated stress as a modifier of neurologic effects of lead in ani- mal models. Cory-Slechta et al. (2004) exam- ined separate and combined effects of restraint stress and lead in pregnant dams on corticos- terone, neurotransmitter levels, and behavioral learning. They found significant interactions, generally more prominent in female offspring, and noted that lead alone influenced corti- costerone, suggesting that lead may influ- ence later-life susceptibility (Virgolini et al. 2005, 2006). They observed strongly altered HPA-axis function with both lead and stress, separately and in combination, providing a model for better understanding the etiology of conditions linked to both exposures and potentially mediated through HPA function, including obesity, hypertension, diabetes, anxiety, schizophrenia, and depression (Rossi- George et al. 2009). We recently compared short-term respira- tory response to concentrated fine particu- late air pollution (CAPs) among chronically stressed and unstressed rats. Using the social dominance paradigm, a rat model of social stress (Hotsenpiller and Williams 1996; Luciano and Lore 1975), we introduced male test rats individually into the cage of an older, larger male, over an 8-week period, to estab- lish chronic stress conditions. Test animals were exposed to controlled CAPs for 5 hr on days after stress exposures. Across four expo- sure groups [stress/CAPs; stress/filtered air (FA); nonstress/CAPs; nonstress/FA], ani- mals exposed to both stress and CAPs dis- played elevated C-reactive protein and altered respiratory function relative to other groups, with higher frequencies and briefer pauses after inspiration and expiration, suggesting a shallower, more rapid breathing pattern (Clougherty et al. 2008). Experimental studies involving humans. Experimental studies have identified physio- logic parameters associated with stressors in humans (exam stress, public speaking). Although these studies can examine only short- term, relatively benign stressors, they do allow for controlled, randomized stressor exposures that are not feasible in the community set- ting. Fiedler et al. (2005) examined combined effects of stressors (public speaking, math chal- lenge) and oxidation by-products of indoor volatile organic carbons and ozone, prevalent in office settings, on cortisol, respiratory func- tion, and symptoms (anxiety, eye/nose irrita- tion, respiratory symptoms) at multiple time points. They found that stress predicted anxi- ety symptoms and cortisol, outweighing any potential interaction with pollution (Fiedler et al. 2005). Such experimental studies can- not mimic the lifelong stress and pollution exposures associated with low SES but help to elucidate some mechanisms for stress-related susceptibility and, importantly, allow for the separation of persistently correlated exposures, otherwise difficult to delineate. Pollution and pollution sources as psycho- social stressors. Health geographers influenced by the environmental justice movement have long understood that neighborhood pol- lution sources, including highways, power plants, and smokestacks, can send strong messages to residents about the value of their health and well-being to the larger society (Bullard 1990). Indeed, the study of air pol- lution effects on health has historically con- sidered its psychological effects (Colligan 1981; Strahilevitz et al. 1979), including psychosocial impacts of perceived exposure (Rotton et al. 1979) on vigilance (Horvath and Dahms 1971; Putz et al. 1977), test per- formance (Hore and Gibson 1968), irritation (Jones 1978), aggression (Rotton et al. 1979), behavior (Evans and Jacobs 1981), neurologic effects (Hore and Gibson 1968), and vision impairment (Lagerwerff 1963). More recent evidence indicates that air quality below regulatory guidelines can be detected by ovlume 117 | number 9 | September 2009 • Environmental Health Perspectives