Hsieh et al. about the effects of lead on brain metabolism in vivo or about the structural and functional correlates of lead-related brain dysfunction (Seeber et al. 2002). Thus, there has been a growing interest in the mechanisms through which lead affects brain function. MRS is used widely to assess both neu- ronal viability and demyelination and can detect both NAA and creatine in discrete tissue volumes. A decrease in NAA, which is located in neuronal cell bodies, has been proposed to indicate possible neuronal and axonal damage or loss, and, practically, the decrease in NAA is measured relative to the level of creatine, a stable metabolite whose level is constant after neuronal loss (van der Knaap et al. 1992). In the present study, we found a significant decline in NAA:tCr ratio in the presence of increased blood and patella lead levels in both the gray and white matter in the frontal lobe, an area of the brain that plays a critical role in the retrieval of source information. The memory component in the frontal lobe is more restricted to working memory, which is a component of executive function. This finding may help explain the lower memory task in neurobehavioral perfor- mance in lead workers (Chuang et al. 2005; Schwartz et al. 2000, 2005; Seeber et al. 2002; Shih et al. 2007). In the present study, the intensity of the Cho MRS signal was also reduced with increases in all blood and bone lead measures in the occipital lobe. The occipital lobe is the visual processing center of the mammalian brain and contains most of the anatomical region of the visual cortex. Lead exposure and exposed workers have indeed been found to have poor visuospatial/visuomotor domain processing on neurobehavioral tests (Schwartz et al. 2000, 2005; Seeber et al. 2002; Shih et al. 2007; Weisskopf et al. 2007b). A low Cho signal may indicate decreased cell mem- brane turnover or myelin alterations that can lead to brain shrinkage (Cox 1996; Ross et al. 2006). The findings of reduced Cho:tCr ratios in the exposure group were similar to the findings in the hepatic encephalopathy that may alter transport of Cho, decrease nutri- tional uptake, and impair brain metabolism (Zwingmann 2007). These previous studies suggest that lead-induced neurotoxicity might alter the neural transmitters, although underly- ing mechanisms are not clear. Changes of the neural transmitters may be one of the possible reasons for the reduction in Cho:tCr ratios. In our study, reduced NAA:tCr and Cho:tCr ratios in the basal ganglia, the corti- cal gray matter, the subcortical white matter, and the deep white matter suggests that lead- induced encephalopathy affects the gray mat- ter and the white matter in a similar manner and that closer attention should be paid to systemic influences. Reductions in the cortical gray matter and the subcortical white matter, both high-function areas of the brain, may explain at least in part the impaired cognitive functions previously reported in relation to lead exposure. The previous MRI studies sug- gest that progressive and irreversible changes to the brain architecture may be caused by lead exposure (Schwartz et al. 2000; Stewart et al. 2006). The white matter changes in our study are consistent with these MRI findings. O u r s t u d y h a s s e v e r a l l i m i t a t i o n s . Technically, two-dimensional MRS can pro- vide data from a larger region than can single- voxel MRS. However, increased background noise made the myoinositol and the glutamate complex undetectable in our study. Recent Table 3. Regression coefficients of human brain Cho:tCr and NAA:tCr ratios influenced by blood and bone lead levels (independent variables) with adjustment of sex, age, and smoking status. Blood lead β (SE) Patella lead Tibia lead β (SE) Sdβa β (SE) improvements in hardware and software, which produce a better signal-to-noise ratio, may improve estimation in future two-dimen- sional MRS studies. The small sample size is also a limitation affecting the power of this study. Only 22 lead workers in a small factory and 18 nonexposed volunteers participated in the MRS measurements. An extended study with larger screening might provide more information about the association between lead and brain damage. In summary, lead toxicity to the human brain is complex and not well recognized. Our study showed that brain metabolism, especially NAA:tCr and Cho:tCr ratios, might be disturbed by lead. Brain NAA and Cho were negatively correlated with blood and bone lead levels, suggesting that lead may induce neuronal and axonal damage or loss. 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Epidemiology 16(1):106–113. ovlume 117 | number 6 | June 2009 • Environmental Health Perspectives Dependent variable Cho:tCr Frontal lobe Gray matter Subcortical white matter Subcortical white matter White matter Subcortical white matter White matter Basal ganglion Occipital lobe Gray matter NAA:tCr Frontal lobe Gray matter White matter Basal ganglion Occipital lobe Gray matter 944 Subcortical white matter White matter aStandard regression coefficients. *p < 0.05. –0.014 (0.005)* –0.005 (0.005) –0.013 (0.005)* 0.002 (0.004) –0.016 (0.005)* –0.013 (0.006)* –0.018 (0.007)* –0.023 (0.005)* –0.011 (0.005)* –0.015 (0.006)* –0.005 (0.005) –0.003 (0.007) –0.001 (0.005) –0.018 (0.007)* Sdβa –0.566 –0.187 –0.459 –0.086 –0.526 –0.448 –0.486 –0.764 –0.451 –0.465 –0.219 –0.087 –0.045 –0.425 –0.004 (0.001)* –0.002 (0.001) –0.003 (0.001) 0.005 (0.001) –0.004 (0.001)* –0.004 (0.001)* –0.006 (0.002)* –0.004 (0.001)* –0.003 (0.001)* –0.004 (0.002)* –0.002 (0.001) –0.002 (0.002) –0.002 (0.001) –0.006 (0.002)* –0.549 –0.203 –0.296 –0.086 –0.382 –0.457 –0.499 –0.480 –0.442 –0.436 –0.280 –0.233 –0.268 –0.477 –0.004 (0.001)* –0.001 (0.001) –0.002 (0.001) 0.005 (0.001) –0.004 (0.001)* –0.005 (0.001)* –0.004 (0.002)* –0.003 (0.001)* –0.002 (0.001) –0.001 (0.002) –0.001 (0.001) –0.003 (0.002) –0.001 (0.001) –0.005 (0.002)* Sdβa –0.495 –0.100 –0.187 –0.084 –0.423 –0.546 –0.395 –0.392 –0.259 –0.122 –0.134 –0.243 –0.142 –0.369