Research Relation of Cumulative Low-Level Lead Exposure to Depressive and Phobic Anxiety Symptom Scores in Middle-Age and Elderly Women Ki-Do Eum,1 Susan A. Korrick,1,2 Jennifer Weuve,3 Olivia Okereke,2,4 Laura D. Kubzansky,5 Howard Hu,6 and Marc G. Weisskopf 1,2,4 1Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 2Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA; 3Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois, USA; 4Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA; 5Department of Society, Human Development and Health, Harvard School of Public Health, Boston, Massachusetts, USA; 6Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA Background : Different lines of evidence suggest that low-level lead exposure could be a modifiable risk factor for adverse psychological symptoms, but little work has explored this relation. o Bvitcej : We assessed whether bone lead—a biomarker of cumulative lead exposure—is associated with depression and anxiety symptoms among middle-age and elderly women. Methods : Participants were 617 Nurses’ Health Study participants with K-shell X-ray fluorescence bone lead measures and who had completed at last one Mental Health Index 5-item scale (MHI-5) and the phobic anxiety scale of the Crown-Crisp Index (CCI) assessment at mean ± SD age of 59 ± 9 years (range, 41–83 years). With exposure expressed as tertiles of bone lead, we analyzed MHI-5 scores as a continuous variable using linear regression and estimated the odds ratio (OR) of a CCI score ≥ 4 using generalized estimating equations. r tluse : There were no significant associations between lead and either outcome in the full sample, but associations were found among premenopausal women and women who consistently took hormone replacement therapy (HRT) between menopause and bone lead measurement (n = 142). Compared with women in the lowest tertile of tibia lead, those in the highest scored 7.78 points worse [95% confidence interval (CI): –11.73, –3.83] on the MHI-5 (p-trend = 0.0001). The corre- sponding OR for CCI ≥ 4 was 2.79 (95% CI: 1.02, 7.59; p-trend = 0.05). No consistent associations were found with patella lead. c onclusi : These results provide support for an association of low-level cumulative lead expo- sure with increased depressive and phobic anxiety symptoms among older women who are pre- menopausal or who consistently take postmenopausal HRT. k ey w ords : anxiety, depression, environmental exposure, epidemiology, lead, longitudinal study. Environ Health Perspect 120:817–823 (2012). http://dx.doi.org/10.1289/ehp.1104395 [Online 29 February 2012] The public health burden of psychiatric dis- orders such as depression and anxiety is tre- mendous—an estimated 450 million people worldwide suffer from psychiatric disorders [World Health Organization (WHO) 2001]. In the United States, the lifetime preva- lence of major depressive disorder [using survey ascertainment of symptoms consis- tent with Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic crite- ria (American Psychiatric Association 1987, 1994)] is approximately 10% for men and 20% for women (Kessler et al. 1994; Steffens et al. 2000). Furthermore, very high percent- ages of older people suffer from depressive (10–30%) or anxiety (~ 20%) symptoms that do not meet full diagnostic criteria (Beekman et al. 1999; Himmelfarb and Murrell 1984) but are associated with excess morbidity and functional impairment (Beekman et al. 1999; de Beurs et al. 1999; Himmelfarb and Murrell 1984; Lyness et al. 2007), greater risk of subsequent clinical diagnoses of depression and anxiety (Horwath et al. 1992; van’t Veer- Tazelaar et al. 2009), and greater health care service use and costs (de Beurs et al. 1999; Simon et al. 1995). Improved understanding of risk factors for anxiety and depressive symptoms could help address the public health burden of these disorders. Few studies have considered the possible link between environmental toxicant expo- sures at low levels found in the community and mental health outcomes, despite the evi- dence from occupational studies that aspects of mood may be particularly sensitive to such exposures (Johnson et al. 1987). Given that many toxicant exposures are potentially modi- fiable, this group of potential risk factors for mental health outcomes should be of interest. Lead exposure is of particular interest because it is an established neurotoxicant (Bressler et al. 1999) with known effects on several brain systems implicated in depression and anxi- ety, including monoaminergic signaling (Kala and Jadhav 1995; Lasley et al. 1984; Virgolini et al. 2005) and the hypothalamic–pituitary– adrenal (HPA) axis (Cory-Slechta et al. 2008; Virgolini et al. 2005). Lead exposure is also a known risk factor for many cardiovascular end points (Eum et al. 2011; Navas-Acien et al. 2007; Weisskopf et al. 2009), which have also been demonstrated to be associ- ated with adverse psychological symptoms, Environmental Health Perspectives • volume 120 | number 6 | June 2012 particularly in older adults (Alexopoulos et al. 1997; Vink et al. 2008). Furthermore, several studies among occupationally exposed adults have found lead exposure to be related to mood disorders and psychological symptoms (Balbus-Kornfeld et al. 1995; Schwartz et al. 2005; Shih et al. 2007). However, large-scale epidemiological studies of low-level environ- mental exposure to lead and psychological symptoms have been conducted in only two settings, the Normative Aging Study (NAS) and the National Health and Nutrition Examination Survey (NHANES), with some studies (Bouchard et al. 2009; Rajan et al. 2007; Rhodes et al. 2003), but not all (Golub et al. 2010), suggesting associations. Only one of the prior studies of low-level lead exposure and mental health included older women, and even in that study the average age was only 46.5 years (Golub et al. 2010). Focusing on women of all ages Address correspondence to M. Weisskopf, Department of Environmental Health/EOME, Harvard School of Public Health, Landmark Center, 401 Park Dr., P.O. Box 15697, Boston, MA 02215 USA. Telephone: (617) 384-8872. Fax: (617) 384-8994. E-mail: mweissko@hsph.harvard.edu Supplemental Material is available online (http:// dx.doi.org/10.1289/ehp.1104395). Support for this research was provided by National Institute of Environmental Health Sciences (NIEHS) grants R01-ES05257 and R01-ES08074 and NIEHS Center grant P30-ES00002. Participants were evaluated in the outpatient facility of the Brigham and Women’s Hospital General Clinical Research Center with support from a grant from the National Institutes of Health (National Center for Research Resources, General Clinical Research Center, grant M01 RR02635). The K-shell X-ray fluores- cence instrument used in this work was developed by ABIOMED Inc. (Danvers, MA) with support from National Institutes of Health grant ES03918. K.-D.E. was supported, in part, by a Korean Research Foundation grant (KRF-2008-357-E00019) funded by the Korean government. The funding organizations played no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manu- script. M.G.W. takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors had full access to all the data in the study. The authors declare they have no actual or potential competing financial interests. Received 24 August 2011; accepted 29 February 2012. 817