influence on the associations reported here between tibia lead and ECG characteristics is less likely; however, were it to be present, it would suggest that the adverse associations we found would be underestimates. These asso- ciations were observed among men with rela- tively low blood and bone lead concentrations that were similar to other general population samples of similar age and much lower than the levels found among people occupation- ally exposed to lead (Navas-Acien et al. 2008; Shih et al. 2007). Several studies conducted in high-exposure settings have reported evidence of an effect of lead exposure on cardiac conduction times. Among 30 children with lead poisoning (range of blood lead concentration of 60–200 µg/dL), 15 (50%) had prolongation of QTc interval (> QTc 420), which recovered to normal range after chelation therapy (Silver and Rodriguez- Torres 1968). These results suggest that acute changes in blood lead levels can affect cardiac conduction parameters. In contrast, our cur- rent results suggest effects of long-term cumu- lative lead exposure rather than short-term effects. This difference is likely related to the fact that the finding of acute effects was among children and at exposure levels far higher than those in our study. In occupational settings, highly lead-exposed workers have been found to have increased QT interval, QRS duration, P-Q interval, and S-T segment compared with less exposed groups, although whether these effects are related to acute or more long-term lead exposures is not clear (Navas-Acien et al. 2007). A previous cross-sectional study of NAS participants reported positive associa- tions between tibia lead level and QTc inter- val, QRSc duration, and odds for IVCD, but only among men < 65 years of age (Cheng et al. 1998). In contrast with our study, nei- ther tibia nor patella lead levels were associated with QT prolongation in any age group. These limited findings may have reflected limitations of the study design, specifically, the simultane- ous measurement of the exposures and out- comes and inclusion of participants with ECG abnormalities in the analyses. There are several mechanisms through which exposure to lead could induce cardiac conductivity disturbances in the ventricles. Lead exposure is associated with hypertension and several markers of increased cardiac afterload and hypertrophy, including increased ventricu- lar mass and decreased ejection fraction and stroke volume (Gump et al. 2005; Kasperczyk et al. 2005; Navas-Acien et al. 2007; Schwartz 1991). Ventricular hypertrophy is a known risk factor for QT prolongation and altered ven- tricular conduction and repolarization (Ben- David et al. 1992; Kang 2006; Kowey et al. 1991). Thus, chronic lead exposure may give rise to disturbances in ventricular conduc- tion and result in QT prolongation, through Cumulative lead exposure and cardiac conductivity cardiac afterload, via lead-induced elevation in vascular resistance. This is also suggested by the only other study of lower exposure levels, a cross-sectional study that found a significantly increased prevalence of left ventricular hyper- trophy associated with increased blood lead concentration among U.S. adults (Schwartz 1991). Lead may also lead to ischemic myocar- dial dysfunction. Many observational studies in workers (Gatagonova 1995a, 1995b, 1995c; Krotkiewski et al. 1964; Shcherbak 1988; Sroczynski et al. 1985) and in the general popu- lation (Jain et al. 2007; Weisskopf et al. 2009) have found associations of lead exposure with ischemic cardiac end points. Coronary artery disease and myocardial ischemia can also lead to ventricular hypertrophy and disturbances in conductivity (Rubulis et al. 2006; Vrtovec et al. 2005). Lead is also a well-known neurotoxicant (Lidsky and Schneider 2003) and may induce ECG conduction abnormalities via adverse effects on the control of the heart by the auto- nomic nervous system. The particular strength of this study is the prospective cohort study design, with an 8 year average follow-up of men who were free of ECG conductivity abnormalities at base- line. However, several limitations existed in our analysis. Although the prospective design helps minimize many forms of bias, and we Table 2. Adjusted 8-year change (95% CI) in QTc interval, QRSc duration, and JTc intervala from baseline to follow-up ECG examination, by lead biomarker concentration at baseline, among participants who were free of IVCD, AVCD, and arrhythmia at baseline ECG. Lead biomarker level n QTc QRSc JTc Tibia lead tertile (µg/g) < 16 191 Reference Reference Reference 16.0–23 208 7.49 (1.22 to 13.75) 0.52 (–3.60 to 4.65) 7.84 (1.23 to 14.45) > 23 195 7.94 (1.42 to 14.45) 5.94 (1.66 to 10.22) 3.19 (–3.68 to 10.05) p for trend test 0.03 0.005 0.52 Patella lead tertile (µg/g) < 22 207 Reference Reference Reference 22–33 190 4.14 (–2.19 to 10.46) 2.87 (–1.02 to 7.33) 0.94 (–5.73 to 7.61) > 33 202 2.69 (–3.68 to 9.06) 3.16 (–1.34 to 7.07) 0.53 (–6.18 to 7.23) p for trend test 0.45 0.20 0.90 Blood lead tertile (µg/dL) < 4 240 Reference Reference Reference 4–6 153 1.72 (–4.94 to 8.38) 2.76 (–1.65 to 7.17) –0.11 (–7.09 to 6.87) > 6 196 –3.54 (–9.74 to 2.66) 1.51 (–2.58 to 5.61) –6.15 (–12.63 to 0.34) p for trend test 0.32 0.40 0.08 aAdjusted for age (years) and age squared, education (≤ high school, some college, college graduate, or graduate school), smoking (never, former, or current and pack-years), BMI (kg/m2), albumin-adjusted serum calcium (mg/dL), and diabetes status (yes/no) at baseline, as well as years between ECG tests and QT-prolongation drugs (yes/no) at the time of ECG measurement. The measures analysis approach includes participants who did not have a follow-up ECG (see “Materials and Methods”). Table 3. ORs (95% CIs)a of incident abnormal cardiac conductivity at follow-up ECG by lead biomarker concentration at baseline among participants free of IVCD, AVCD, and arrhythmia at baseline ECG. QT JT prolongationb prolongationc IVCDd AVCDe Arrhythmiaf Lead biomarker level OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) OR (95% CI) Tibia lead tertile (µg/g) Case/control 67/387 32/425 33/458 25/466 92/399 < 16 Reference Reference Reference Reference Reference 16.0–23 0.86 (0.39–1.88) 0.93 (0.32–2.72) 1.46 (0.56–3.85) 0.77 (0.29–2.09) 0.53 (0.28–1.01) > 23 2.53 (1.22–5.25) 2.53 (0.93–6.91) 1.45 (0.52–4.08) 0.23 (0.06–0.87) 1.18 (0.64–2.16) p for trend test 0.003 0.04 0.55 0.03 0.32 Patella lead tertile (µg/g) Case/control 68/391 32/429 33/463 26/470 96/400 < 22 Reference Reference Reference Reference Reference 22–33 2.67 (1.28–5.56) 2.24 (0.81–6.20) 3.77 (1.37–10.33) 0.49 (0.18–1.31) 1.06 (0.59–1.91) > 33 2.10 (0.96–4.60) 2.18 (0.75–6.35) 1.57 (0.49–5.00) 0.19 (0.05–0.68) 1.09 (0.59–2.02) p for trend test 0.14 0.21 0.75 0.01 0.78 Blood lead tertile (µg/dL) Case/control 68/383 32/421 31/457 25/463 94/394 < 4 Reference Reference Reference Reference Reference 4–6 1.19 (0.60–2.37) 0.94 (0.38–2.34) 0.59 (0.20–1.81) 0.44 (0.13–1.47) 1.42 (0.80–2.51) > 6 1.31 (0.69–2.48) 0.66 (0.26–1.67) 1.27 (0.54–3.02) 0.52 (0.19–1.45) 0.85 (0.48–1.52) p for trend test 0.41 0.40 0.65 0.16 0.75 aAdjusted for age (years) and age squared, education (≤ high school, some college, college graduate, or graduate school), smoking (never, former, or current and pack-years), body mass index (kg/m2), albumin-adjusted serum calcium (mg/dL), and diabetes status (yes/no) at baseline, as well as years between ECG tests and QT-prolongation drugs (yes/ no) at the time of ECG measurement. bHeart rate–corrected QT interval of ≥ 440 msec; 37 participants with QT prolonga- tion at baseline were excluded. cHeart rate–corrected JT interval of ≥ 360 msec; 34 participants with JT prolongation at baseline were excluded. dDefined MCs including 7-1-1, 7-2-1, 7-4. eDefined MCs including 6-3, 6-2-x, 6-1. fDefined MCs including 8-1-1, 8-1-2, 8-1-3, 8-3-x, 6-4-x. Environmental Health Perspectives • volume 119 | number 7 | July 2011 943