(McEwen and Seeman 1999). Building on Hans Selye’s model of nonspecific suscepti- bility and allostatic load models of cumula- tive wear and tear, attention is increasingly being directed toward identifying biological mediators linking chronic stress to immune and endocrine function (Miller et al. 2002; Segerstrom and Miller 2004). Chronic stress and associated negative emotional states (e.g., depression, anxiety, anger) may mediate immune and endocrine processes (Kiecolt-Glaser et al. 2002), with associations so consistent that some research- ers have proposed reconceptualizing depres- sion as dysfunction in HPA-axis regulation and stress response (Sternberg et al. 1992). Endocrine responses to chronic stress include dysregulation in production of catecholamines (epinephrine, norepinephrine), adrenocor- ticotropin, cortisol, growth hormone, and prolactin. Cytokines, particularly IL-6, stimulate corticotrophin-releasing hormone and HPA-axis activity, increasing plasma adrenocorticotropin hormone and cortisol (Hellhammer et al. 1997; Kirschbaum et al. 1995; Ockenfels et al. 1995; Seeman et al. 1997). Frequent activation of the glucocorti- coid receptor by cortisol can lead to blunted glucocorticoid response (Miller et al. 2002), increased nuclear factor-κB signaling (Miller et al. 2008), and dysregulated catecholamine production (Glaser and Kiecolt-Glaser 2005). Immune-linked inflammatory response may infleunce asthma and related airway disease. Asthma-linked parameters responsive to stress include IgE (Wright et al. 2004) and cytokine production (Chen et al. 2003) and respiratory inflammation (Umetsu et al. 2002). Early life chronic stress may alter T-helper (Th)1–Th2 immune cell balance (Umetsu et al. 2002), which is linked with childhood asthma, allergy, and inflammatory responses (Miller and Chen 2007). Impacts on common physiologic systems. Growing evidence suggests complex dose- dependent interactions among multiple pollu- tants (Mauderly and Samet 2009), mediated through the same mechanistic pathway, or some pollutants may potentiate effects of others. Similarly, stress may potentiate pollu- tion health effects through immune and inflammatory processes, or stress and pollution may affect common physiologic systems. Both early childhood environmental exposures and stress-related catecholamines affect Th1–Th2 balance (Umetsu et al. 2002). Psychological stress (Epel et al. 2004), polycyclic aromatic hydrocarbons, cigarette smoke (Adcock and Ito 2005), and ozone (Fugisawa 2005) affect oxidative stress, which is linked to asthma and COPD (Rahman and MacNee 2000). Both stress and diesel exhaust particles are associated with elevated cytokines (e.g., IL-2, IL-6, and local IgE in nasal mucosa) (Diaz-Sanchez et al. 2000; Nel 2001). Some evidence suggests that stress may alter permeability of bodily mem- branes to chemical exposures, such that stress may alter systemic transport and chemical uptake into organs including the brain (Sinton et al. 2000), facilitating combined and syn- ergistic effects of stressors and pollution on many bodily systems. Key Issues to be Addressed as This Work Progresses Careful attention to stress measurement. For environmental researchers, social epidemio- logic theory and methods for stress meas- urement may be unfamiliar, but accurately understanding and applying these principles is necessary to produce meaningful analyses of interactions among stressors and pollution exposures. Careful attention to stress processes and distinction among the major components is needed to accurately capture and interpret stress effects on susceptibility. Moreover, because perceived stress is highly variable over time, it is important that measured stress peri- ods are temporally appropriate to the pollu- tion exposures and outcomes under study. The stress process is often described in three phases: a) the stressor (i.e., any event, condi- tion, or external stimuli posing a physical or psychological challenge), b) stress appraisal (i.e., how one experiences, perceives, or inter- prets the event), and c) stress response (e.g., psychological and physiologic sequelae). These phases are interdependent. A stres- sor appraised as benign or beneficial, rather than threatening, generally produces no stress response. Highly thorough stress assessments would measure each stage, which is rarely fea- sible. Most studies focus on a single, chronic stressor (e.g., caregiver burden) or one unlikely to be positively appraised (e.g., exposure to violence, natural disaster). Newer measures emphasize later stages of the stress process. Because of inconsistent findings with stressor measures (e.g., life event scales assessing major life changes) (Dohrenwend et al. 1993), more researchers today use perceived stress measures, which capture response to multiple stressors (Cohen et al. 1983, 1995). Recent evidence indicates, however, that subjective stress may poorly predict immune change (Segerstrom and Miller 2004); thus, another approach emphasizes negative affect (e.g., anxiety, depression) as a cumulative indicator of men- tal distress and psychosocial stress. Negative affect may serve as a common final pathway for multiple psychological stressors, possibly providing a more stable indicator of cumula- tive stress and susceptibility (Kubzansky et al. 2000; Seeman et al. 2002). Other approaches include using bio- markers—hormones or immune markers associated with physiological stress responses, including glucocorticoids or cytokines (Miller Environmental Health Perspectives • volume 117 | number 9 | September 2009 Stress and air pollution susceptibility et al. 2002). Although many physiologic sys- tems are influenced by acute and chronic stress, there is relatively little consensus on optimal biomarkers to capture physiologic changes with acute or chronic stress. Formerly, corti- costeroids (e.g., cortisol) in blood or saliva were emphasized as markers of HPA-axis activity, although stress-related HPA function changes lead to cortisol dysregulation (via glucorticoid resistance and HPA regulation), not simply increased cortisol production. Thus, cortisol can be difficult to interpret and better indi- cates acute rather than chronic stress. Recent research emphasizes indicators of glucocorti- coid resistance and neuroendocrine signaling (Miller et al. 2008). Other evidence suggests that C-reactive protein (Miller G, personal communication) and tumor necrosis factor-α (Clougherty JE, Rossi CA, Lawrence J, Long M, Diaz E, Koutrakis P, et al., unpub- lished data) may capture chronic stress in rats. Although no single biomarker is appropriate for all applications (Brunner 2007), suites of physiologic parameters have been developed to represent allostatic load in humans, includ- ing indicators of cardiovascular function, metabolism, cholesterol, glucose metabolism, HPA-axis function, and sympathetic nervous system activity (Kubzansky et al. 2000; Seeman and Singer 2002). Several studies document chronic stress effects on cardiovascular risk indicators (abdominal obesity, elevated serum triglycerides, low high-density lipoprotein cho- lesterol, glucose intolerance, elevated blood pressure) (Brunner et al. 1997), known collec- tively as metabolic syndrome, and may provide a method for capturing cumulative stress effects on cardiovascular and systemic function. Relative temporality in stress and pollu- tion exposures. Generally, stressors must pre- cede or be contemporaneous with pollution exposures to plausibly modify their effects. The actual periods of stress and pollution expo- sures, their overlap, and temporal relation to health outcomes, deserve careful attention, because temporal exposure misclassification may nullify or even reverse the directionality of observed interactions. For example, if stress exposure occurs after or very late in a pollu- tion exposure interval, interpreting observed interactions is problematic. If perceived stress is stable over time, the report will accurately reflect stress during the hypothesized period of susceptibility. If perceived stress varies over the period, however, and respondents com- pare current stress to prior experiences, then individuals reporting high stress likely experi- enced relatively lower stress previously, during the pollution exposure period. Such temporal misclassification may significantly confound results, and researchers should ensure that stress and pollution measurement periods support a plausible physiologic interaction in relation to the health outcome of interest. 1353