Cumulative lead exposure and depression and anxiety MHI-5 asks respondents how much of the time over the past month (all, most, good bit, some, little, or none; ranked 1–6) they felt nervous, felt so down that nothing could cheer them up, felt calm and peaceful, felt down and blue, or felt happy. The two positively worded questions are reverse coded so that lower scores indicate more depressive symptoms; all item scores are summed, and then the sum is rescaled to obtain a total score ranging from 0 to 100 (Ware et al. 2000). An MHI-5 score < 60 denotes the pres- ence of severe depressive symptoms and predicts major depression as identified using the Mini- International Neuropsychiatric Interview Major Depressive Episode module with high sensi- tivity and specificity among adults ≥ 65 years of age (Friedman et al. 2005). We also used an alternative cutoff score of < 53, which has been validated for identifying major depression in younger populations (Berwick et al. 1991; Holmes 1998). The phobic anxiety scale of the CCI mea- sures personality symptoms of phobic anxiety (Crown and Crisp 1966). It is a brief self- rating inventory of eight questions on com- mon phobias—such as fear of enclosed spaces, illness, going out alone, heights, and crowds— with two yes or no questions (scored 2 or 0) and six three-level response questions (e.g., never/sometimes/often or not at all/moder- ately/very; scored 0/1/2). Scores range from 0 to 16, with higher scores corresponding with higher levels of phobic anxiety. The CCI has been validated in psychiatric outpatient clinic settings and found to discriminate patients with anxiety disorders and agoraphobia from those with other mental health disorders (Mavissakalian and Michelson 1981). The validity of the phobic anxiety subscale of the CCI in the NHS population has been tested previously, where scores were shown to be associated with use of tranquilizer medications (Albert et al. 2005). A CCI score of ≥ 4 has been related to several adverse outcomes in the NHS population, for example, Parkinson’s disease (Weisskopf et al. 2003), coronary heart disease, and sudden coronary death (Kawachi et al. 1994; Whang et al. 2009). Statistical analysis. We used the generalized linear model framework to analyze repeated outcome measurements and used an unstruc- tured covariance matrix to account for corre- lations in scores within individuals. Primary analyses treated MHI-5 scores as a continuous variable. Because the distribution of scores on the CCI was skewed, we used generalized esti- mating equations to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for scoring ≥ 4 on any CCI measurement (i.e., high phobic anxiety; n = 188 women, 244 assessments). We conducted additional analyses using this same approach to estimate ORs for scoring < 60 on the MHI-5 (i.e., severe depressive symp- toms; n = 96 women, 121 assessments) or the alternative cutoff of < 53. When using dichoto- mous outcomes, additional sensitivity analyses were performed that included as “cases” women taking antidepressant or antianxiety medication who did not meet criteria for major depression by MHI-5 scores (n = 63 women; 84 observa- tions) or high phobic anxiety by CCI scores (n = 56 women; 56 observations)—along with women who were cases based on their symptom scores. For women missing one or two CCI responses (n = 55 women, 57 observations) or one MHI-5 response (n = 44 women, 46 observations), we used the standard approach of imputing the total score for the scale by dividing their score by the fraction of questions answered and rounding to the nearest integer (DeVellis 1991; Ware et al. 2000). We specifically addressed the potential impact of menopause status in separate analyses. Menopause is associated with increased bone turnover that mobilizes stored lead from bone into circulating blood, increasing blood lead levels (Korrick et al. 2002). An increased rate of bone remodeling means that the lead concentration in bone is increasingly in flux during this period, which may compromise the utility of the bone lead concentration as a measure of cumulative lead exposure. Bone turnover with menopause is reduced in women who have taken HRT (Nelson et al. 2002). Therefore, we conducted additional analyses restricted to women either who were premenopausal at bone lead measurement (n = 45) or who had consistently taken HRT between menopause and bone lead measurement (n = 97). Menopausal status was based on each woman’s self report on the regular NHS biennial questionnaires of permanent cessation of natural menses, as well as the age at which this occurred. For women who underwent hysterectomy without bilateral oophorectomy, a life table was used to assign an age at menopause based on the date of surgery, smoking, and hormonal status. We performed separate analyses for patella and tibia bone lead biomarkers. Bone lead ter- tiles were calculated based on the distributions among women who were premenopausal or consistently on HRT between menopause and bone lead measurements. Covariates in our models were obtained from biennial question- naires and included age (years) at psychological symptom measurement, education (registered nurse, bachelor’s degree, master’s or doctor- ate degree), alcohol consumption (tertiles of grams per day: < 1.8, 1.8–8.69, ≥ 8.7), and pack-years of smoking (0 and tertiles among smokers: 1–8.9, 9–21.9, ≥ 22), because these variables have been associated with lead expo- sure and psychological symptoms (Bjelland et al. 2008; Boden and Fergusson 2011; Hu et al. 1996; Kessler et al. 1994; Korrick et al. 2002; Theppeang et al. 2008; Wiesbeck et al. 2008). We also included husband’s education Environmental Health Perspectives • volume 120 | number 6 | June 2012 (high school or less, college education, gradu- ate school, or not married) and employment status at psychological symptom measure- ment (retired/homemaker, part-time worker, full-time worker) as indicators of socioeco- nomic status, which may be related to both lead exposure and psychological symptoms (Kessler et al. 1994; Theppeang et al. 2008). We adjusted for substudy to account for both the different KXRF machines used in the two substudies, as well as secular trends in lead exposure and possibly psychological symp- tom reporting, and age (years) at bone lead measurement, which is related to measured bone lead concentrations (Wilker et al. 2011). About half of the participants were women from a case–control study of hypertension. Because the selection of hypertension cases and controls could have introduced selec- tion bias, we conducted additional sensitivity analyses adjusting for hypertensive status in this substudy. Hypertension cases were iden- tified based on self-reported physician diag- nosis on the NHS biennial questionnaires. We also conducted sensitivity analyses adding adjustment for whether the nurse’s parents owned their own home when she was born, an additional socioeconomic status indicator that reflects status in childhood. The women responded to items on some covariate data in more than one questionnaire cycle, and for our analyses, we used responses from the NHS questionnaire closest to the psychological symptom assessment. We used missing indi- cator variables for the small amount of miss- ing data. Tests for trend with increasing lead concentration were computed by including a continuous term for lead that was formed by assigning to each woman the median lead concentration of the tertile in which she was classified. This approach minimizes the influ- ence of extreme exposure values. A two-sided p-value ≤ 0.05 was considered statistically sig- nificant. We conducted all analyses in SAS (version 9; SAS Institute Inc., Cary, NC). Results The mean ± SD (range) age of women in our study was 60.9 ± 6.0 (46–74) years at the time of lead measurement. Age at the time of MHI-5 assessment was 59.4 ± 7.3 (45–79) years, and at CCI assessment was 59.2 ± 10.2 (41–83) years. The mean ± SD levels of tibia lead and patella lead were 10.3 ± 9.5 gμ/g and 12.5 ± 11.2 μg/g, respectively. As has been previously reported (Korrick et al. 2002), both patella and tibia bone lead levels were higher with older age, more pack-years of smoking, and alcohol consumption (Table 1). There were less consistent associations between other covariates and bone lead levels. Although MHI-5 and CCI were designed to target different types of psychological distress, they are often correlated because depression 819