Eum et al. thereby leading to a spurious association. However, both of these possibilities are argued against by the fact that our results were essen- tially unchanged when adjusted for a marker of childhood socioeconomic status and pack- years of smoking. All of this suggests that some phobic anxiety may be sensitive to later- life risk factors. Also, the association between lead and CCI phobic anxiety score may not be restricted to phobic anxiety because the symp- toms captured by the CCI scale have some overlap with other types of anxiety (Burgess et al. 1987; Crown and Crisp 1966). Our data are limited to the available MHI-5 and CCI assessments for our study population; thus, we cannot determine whether the observed phobic anxiety symptoms are an exacerbation of previous symptoms from a younger age. Furthermore, neither the MHI-5 nor the CCI are diagnostic tools. Despite these limitations, both assessments have demon- strated strong relations with clinical disorders. In comparing scores on the MHI-5 with DSM- based diagnoses, the area under the receiver operating characteristic curve was found to be quite high for depression (0.892) and anxi- ety disorders (0.739) (Berwick et al. 1991). The latter likely reflects both the fact that the MHI-5 is not completely specific to depres- sion symptoms and that there is frequently comorbidity between depression and anxiety. The CCI has been found to discriminate well between patients with anxiety disorders and agoraphobia and patients with other mental health disorders (Mavissakalian and Michelson 1981). Furthermore, symptoms ascertained by these measures have been associated with a number of clinical outcomes known to cor- relate with clinical depression and/or anxiety such as Parkinson’s disease (Weisskopf et al. 2003), coronary heart disease, and sudden cor- onary death (Kawachi et al. 1994; Whang et al. 2009). Thus, despite limitations, there is strong evidence that the study measures capture clini- cally relevant symptoms. Low-level environmental exposure to lead and psychological distress has been explored only in two other settings, older men in the NAS and adult men and women in NHANES. Among 526 NAS men (67 ± 7 years, mean ± SD), higher patella bone lead concentra- tion was significantly associated with scoring worse on the phobic anxiety scale of the Brief Symptom Inventory (BSI), and higher blood, patella, and tibia lead were all associated with scoring worse on an index that combined the BSI anxiety, depression, and phobic anxiety scales (Rhodes et al. 2003). Slightly weaker associations were seen in a follow-up study of this cohort (Rajan et al. 2007). In data from 1,987 men and women 20–39 years of age in the 1999–2004 NHANES cycles, higher blood lead level was significantly associated with prevalent diagnoses of major depressive 822 disorder and panic disorder based on the fourth edition of the DSM, but not generalized anxiety disorder as assessed with the World Health Organization Composite International Diagnostic Interview (Bouchard et al. 2009). Bone lead concentration was not available in these data. A later study of 4,159 adults ≥ 20 years of age in the 2005–2006 NHANES cycle did not find a significant association between blood lead and depression symptom scores on the Patient Health Questionnaire-9 (PHQ-9), although PHQ-9 scores increased with increasing quintiles of blood lead concen- tration (Golub et al. 2010). Lead is a neurotoxicant (Bressler et al. 1999) with known effects on neural systems that underlie mood and anxiety symptoms. For example, lead exposure has been found to specifically disrupt signaling in monoaminergic signaling systems that are frequent targets for medications to treat these symptoms (Haider et al. 2005; Kala and Jadhav 1995; Lasley et al. 1984; Virgolini et al. 2005). Lead can alter synaptic signaling and second-messenger systems much more generally, to a large extent as a result of its ability to substitute for calcium (Garza et al. 2006), and thus disrupt multiple neurotransmitter systems that are implicated in mood disorders (Werner and Covenas 2010; Wu et al. 2008). Lead exposure also disrupts the HPA axis leading to altered glucocorticoid and catecholaminergic signaling (Cory-Slechta et al. 2008; Virgolini et al. 2005), with mood disorder as a proposed consequence (Cory-Slechta et al. 2008). HPA axis function, corticotrophin-releasing hormone, and cortisol levels are found to be altered among people with depression compared with population norms or controls without psychiatric disease (Holsboer 2000; Vreeburg et al. 2009). Lead also has well- known adverse effects on the cardiovascular system (Eum et al. 2011; Navas-Acien et al. 2007; Weisskopf et al. 2009), and many cardiovascular risk factors have been found to predict depression. There is a high rate of depression among people with hypertension, diabetes, coronary artery disease, and stroke, as well as frequent occurrence of white matter hyperintensities and silent stroke (on brain magnetic resonance imaging) in geriatric depression. This has led to a vascular theory of depression that posits these factors disrupt neural systems in the prefrontal region of the brain (Alexopoulos et al. 1997; Vink et al. 2008). Thus, lead exposure could be related to psychological distress in older women via cardiovascular effects. Strengths of our study include having a large group of women with bone lead measurements—a marker of cumulative lead exposure—and extensive covariate data. One limitation is that the women who were recruited for the original lead exposure studies were, excepting the subset with hypertension, selected to be particularly healthy, which may have made it more difficult to identify associations between lead and psychological symptoms. Given lead’s association with a number of chronic diseases, including cardiovascular, renal, and neurocognitive disorders (Ekong et al. 2006; Navas-Acien et al. 2007; Shih et al. 2007), women excluded because of chronic disease may have been more likely to both have higher lead exposure and lead-related disorders, including psychiatric symptoms. We did not have data on family history of psychiatric disorders and so could not adjust analyses for this. An additional limitation is that we did not have standardized clinical assessments for psychiatric disorders. Although such assessments would have been useful for purposes of establishing DSM- criteria disorders, our questionnaires include reliable and valid measures that have been used extensively for research purposes (Albert et al. 2005; Berwick et al. 1991; Burgess et al. 1987; Kawachi et al. 1994; Mavissakalian and Michelson 1981; Weisskopf et al. 2003; Whang et al. 2009). Furthermore, there is growing consideration of the value of dimensional measurement of psychological symptoms, for example, characterizing symptoms continuously across a spectrum of severity as we have done (National Institute of Mental Health 2010). Nevertheless, we also found similar results using the cutoffs of < 60 or < 53 for the MHI-5, both of which have been validated against clinical measures (Berwick et al. 1991; Friedman et al. 2005; Holmes 1998). Conclusion Our results provide support for associations between lead exposure and both depression and anxiety among older women with commu- nity-level exposures. Specifically, these findings were present among premenopausal women and postmenopausal women consistently on HRT. This may relate to the reduced effec- tiveness of bone lead as a cumulative marker of lead exposure in postmenopausal women not taking HRT, but this warrants further confirmation. These results were found among women with low lead exposure levels that were similar to their same-age peers in NHANES data. Thus, these findings underscore the need to consider environmental contaminants as risk factors for psychological distress. Ref Rencs Albert CM, Chae CU, Rexrode KM, Manson JE, Kawachi I. 2005. Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women. Circulation 111(4):480–487. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. 1997. “Vascular depression” hypothesis. Arch Gen Psychiatry 54(10):915–922. American Psychiatric Association. 1987. Diagnostic and Statistical Manual of Mental Disorders. Revised Third Edition. Washington, DC:American Psychiatric Association. American Psychiatric Association. 1994. Diagnostic and ovlume 120 | number 6 | June 2012 • Environmental Health Perspectives