In the present study, we observed that increasing blood lead levels was associated with a significantly higher risk of major depression and panic disorder in young adults from the United States. Compared with persons with a blood lead level below 0.7 μg/dL (the lowest quintile of blood lead in our study population), those with a level greater than 2.1 μg/dL (the highest quintile) had a 2.3-fold increased risk of meeting the DSM-IV criteria for major depressive disorder, and 4.9-fold increased risk for panic disorder. After excluding current smokers, the elevation in risk was increased to 2.5-fold for major depression and 8.2-fold for panic disorder. Although estimates of risk for specific quintiles were imprecise due the small number of cases, particularly for panic disorder, the trend analyses support the presence of significant increase in risk across blood lead levels. Likewise, models using a continuous parameter for blood lead level also support this conclusion.
These results support previously reported associations of mood and anxiety disorders with high occupational lead exposure,8-12
and less well documented association with lower environmental levels of exposure in older men.15, 16
Our findings extend these observations to the general United States population of younger adults. Women are at significantly increased risk of meeting the diagnostic criteria for major depression and anxiety disorders, an observation which is previously well documented.20
In exploratory analyses, we saw no evidence of differential association by sex for blood lead levels and odds for these disorders, but a larger sample would be necessary to carefully verify this hypothesis.
If lead exposure contributes to the etiology of these disorders, the mechanism of action could involve perturbation of neurochemistry, such as brain monoamine neurotransmission. Lead exposure is known to disrupt catecholaminergic systems,35-37
and depression and anxiety disorders are strongly associated with disturbances in these systems.38
Studies in animals show that chronic lead exposure can decrease serotoninergic activity in several brain regions including the nucleus accumbens, frontal cortex, and brainstem.37
In a study of patients with panic disorder, with or without depression, positron emission tomography revealed that the serotonin receptor type 1A was reduced by nearly a third in the anterior and posterior cingulate, and raphe nuclei.39
Exposure to lead in predisposed individuals could trigger the development of the depression and panic disorder, increase their severity, or modify response to treatments. Investigations on how low lead exposure disrupts neurochemistry could provide insights in the mechanisms of depressive and anxious states.
Co-morbidity was observed in the present study, particularly for the two anxiety disorders with depression. When we conducted an analysis of major depressive disorder in which we excluded persons with major depressive disorder and another disorder, the findings were similar to those in which we included all persons, suggesting that the increased odds of major depressive disorder with higher blood lead level was not explained by the anxiety disorders.
One of the strengths of the present study is the use of structured diagnostic assessments of psychiatric disorders.18
The CIDI has been widely used in psychiatric research, and has a high degree of correspondance with clinical interviews.23
Also, the prevalence observed in the present study for the three conditions studied were very comparable to other national estimates,20
i.e. major depressive disorder (7.8% versus 6.7%), panic disorder (2.6% versus 2.7%), and generalized anxiety disorder (3.0% versus 3.1%). This suggests that the results of the present study can be generalized to the broader U.S. population.
The present study has several limitations, the most important being its cross-sectional design. Thus, we cannot rule out the possibility that major depression or panic disorder leads to behavioral changes that increase exposure to lead—except in the case of smoking, for which our sensitivity analysis among current non-smokers argues strongly against this. In addition, the mental health outcomes under study here are chronic conditions often associated with genetic predisposition in conjunction with chronic stressors.40
Therefore, in assessing the role of lead as a risk factor for mental health outcomes, it would have been desirable to have an indicator of long-term lead exposure, such as bone lead level, assessed prior to onset of psychopathology. Bone lead level has a clearance half-life of years to decades, depending on the bone type.41
In a previous study, both blood and patella bone lead were associated with a combined measure of anxiety, phobic anxiety, and depression symptoms.15
In the present study, lead was measured only in blood. The half-life of lead in blood after acute exposure is short, but blood lead concentration integrates lead released from bones and current external exposures. In settings where external exposures are low, lead released from bones can be the major contributor to blood lead. Thus, blood lead may be a reasonable marker of long-term exposure when the system is in equilibrium, with little variation in intake, clearance, or bone-blood partitioning. Situations in which this would not apply are occupational exposures, which might vary greatly in time, and osteoporosis, during which lead is released from the bone matrix to the blood at an increased rate following demineralization.42
In the present study, however, few individuals were likely to suffer from osteoporosis because of their young age (maximum 40 years). We could not exclude occupationally exposed individuals because of limited information on job exposures, but our exclusion of those with elevated blood lead levels would likely capture any current work-related lead exposure and did not alter the results.
As in any observational study, the associations in our study could be biased by uncontrolled confounders. We were, however, able to adjust for several important likely confounding factors, namely sex, age, race/ethnicity, education, and income. Furthermore, our sensitivity analyses excluding current smokers indicate that residual confounding by smoking does not explain the associations of blood lead and risk of psychopathology, but in fact may partly mask it.
Current blood lead levels in the United States population are lower than those in the mid-20th
but they remain elevated from an evolutionary perspective, i.e., in relation to the natural lead levels prior to industrialization.43
Widespread lead pollution occurred only in relatively modern history as a result of anthropogenic activity.44
The finding of an association between blood lead level and major depressive disorder and panic disorder, despite the low levels and narrow range of observed lead levels, supports the contention that current lead exposures at low levels may have important effects on mental health. Since the current measurements of blood lead reflect in part lead sequestered in bone, the observed relations with increased odds for depression and panic disorder could also reflect latent effects of past exposures during critical developmental periods, which would be consistent with neurodevelopmental hypotheses of mood and anxiety disorders.45
If lead exposure contributes to the etiology of major depression and panic disorder, the continued efforts at reducing population exposures even beyond currently acceptable levels may decrease their incidence.