Blood lead, bone lead, and adult cognitive function In occupationally exposed South Korean lead workers, tibia lead levels were signiﬁcantly associated with more depressive symptoms measured by the Center for Epidemiologic Studies Depression scale (CES-D; Radloff 1977) after adjusting for age, sex, education, job duration, and blood lead level (Schwartz et al. 2001). However, only one recent study has examined a direct measure of cumulative dose with bone measurements in a community sample (Rhodes et al. 2003). These authors used the Brief Symptom Inventory (BSI; Derogatis and Melisaratos 1983) to show that patella bone lead levels were associated with an increased risk of anxiety and depression sub- scale scores. The logistic regression estimate for the phobic anxiety subscale was statistically sig- niﬁcant (p < 0.05), as well as for the combined measure of all three BSI subscales (anxiety, depression, and phobic anxiety). Psychiatric symptoms, specifically symp- toms of depression, potentially share the same neural substrates with components of cogni- tion, and thus may be important to late-life cognitive functioning. Compared with nonde- pressed elderly individuals, depressed elderly perform more poorly on tests involving atten- tion, memory encoding, and retrieval. However, intelligence tests are more resistant to these effects of depression (Arnett et al. 1999; Naismith et al. 2003; Weingartner et al. 1981). Depressive symptoms (as measured by the CES-D) are positively associated with both the risk of Alzheimer disease and a steeper rate of cognitive decline (Wilson et al. 2002). Because late-life symptoms of depres- sion are closely associated with dementia, investigators have put forth a number of hypotheses that suggest depression a) may be a risk factor for cognitive decline, b) has risk factors in common with dementia, c) is an early reaction to declining cognition, and d) inﬂuences the threshold at which dementia emerges [for review see Jorm (2000)]. The exact temporal and mechanistic relation remains unclear. Regardless of the exact rela- tion between depressive symptoms and cogni- tive function, however, the assessment of the impact of lead exposure on these outcomes is not compromised. Whatever the associations with these outcomes, they would still be attributed to lead—that is, even if depressive symptoms lead to worse cognitive perfor- mance, and lead leads to symptoms of depres- sion, the cognitive impairment as a result of that depression could still be considered part of the total effect of lead. Lead–gene interactions. In the former organolead worker studies discussed above, possessing at least one apolipoprotein E (APOE) ε4 allele magnified the negative cross-sectional association of tibia lead levels with performance on the cognitive domains of executive ability, manual dexterity, and psychomotor skills (Stewart et al. 2002). No direct effects of the APOE ε4 allele were observed on cognitive function in this study, presumably because of the sample’s younger age (range, 41–73 years). Other studies have found that APOE ε4 modiﬁes dementia out- come in individuals with previous traumatic head injury, suggesting that APOE ε4 plays a role in recovery from brain insults (Mayeux et al. 1995), which may be extended to include insult from lead exposure. Discussion Summary of evidence for a causal relationship. The literature on associations of recent and cumulative dose biomarkers with cognitive function has grown impressively since the 1995 review (Balbus-Kornfeld et al. 1995). We believe sufficient evidence exists to conclude that there is an association between lead dose and decrements in cognitive function in adults. Overall, while the association between blood lead levels and cognitive function is more pro- nounced in occupational groups with high cur- rent lead exposures, associations between bone lead levels and cognitive function are more evident in studies of older subjects with lower current blood lead levels, particularly in longitudinal studies of cognitive decline. Consistency of associations. Following is a summary of the findings from each of the three types of populations. First, cross-sec- tional studies of currently exposed lead work- ers showed that associations of blood lead levels and cognitive function were clearer than the associations for tibia, patella, or calcaneus lead levels, perhaps because the acute effects of recent dose in an occupational setting masked the chronic effects of cumulative lead dose. Second, previously exposed occupational pop- ulations demonstrated a stronger association between cumulative lead dose measured in tibia bone with cognitive deficits compared with blood lead levels. The two studies that deviated from these otherwise consistent ﬁnd- ings may not have had sufficient power to detect any associations (n < 60). Last, studies of environmentally exposed adults who had notably higher exposures in the past suggest that bone lead level is more consistently associ- ated with performance on cognitive tests than is blood lead level. The domains associated with lead dose do not differ in general by lead biomarker (blood, tibia, patella). The cogni- tive domains consistently associated with each biomarker in both environmental and occupa- tional studies on adults include verbal and visual memory, visuospatial ability, motor and psychomotor speed, manual dexterity, atten- tion, executive functioning, and peripheral motor strength. Comparisons of lead and psy- chiatric symptom associations in previously and currently exposed samples lend credence, although perhaps at higher thresholds than for Environmental Health Perspectives • VOLUME 115 | NUMBER 3 | March 2007 cognitive outcomes, that neurobehavioral functioning is consistently associated with blood lead when exposure is currently high (e.g., occupational) and bone lead when expo- sure is primarily from past chronic exposure. These associations exist in multiple settings, including both occupational and non- occupational, in men and women, and in pop- ulations with diversity by socioeconomic status and race/ethnicity. This reduces the likelihood of associations by statistical chance or due to unmeasured confounding. However, this con- sistency cannot completely rule out the possi- bility of uncontrolled confounding or effect modification (Martin et al. 2006; Shih et al. 2006). In addition, in studies of general popu- lations with diversity by socioeconomic status and race/ethnicity, the ability to disentangle social, cultural, and biological factors from the “independent” inﬂuence of lead dose may be a futile exercise (Weiss and Bellinger 2006). Strength of association. The strength of associations between lead and cognitive func- tion is strong and can be compared to the influence of age on cognitive function. The comparative magnitude of these effects has been reported in several studies. In currently exposed lead workers, cross-sectional associa- tions showed that a 5-µg/dL increase in blood lead was equivalent to an increase of 1.05 years in age (Schwartz et al. 2001). The magnitude of cross-sectional associations with tibia lead levels in the BMS was moderate to large. A proportion comparison of the direct effect of age and the direct effect of tibia lead levels on cognitive outcomes demonstrated that the magnitude of the association with tibia lead levels was moderate to large, equiva- lent to 22–60% of the magnitude of the age effect in its relations with cognitive domain scores. Specifically, an interquartile range increase in tibia lead levels was equivalent to 2–6 more years of age at baseline across all seven domains (Shih et al. 2006). Longitudinal analyses in the NAS observed that an interquartile range higher patella lead level was approximately equivalent to that of aging 5 years in relation to the baseline MMSE score (Weisskopf et al. 2004) and an interquartile range higher bone (patella or tibia, depending on the speciﬁc cognitive out- come) lead level was approximately equivalent to that of aging 1 year in relation to the base- line test scores on a battery of cognitive tests (Weisskopf et al. 2007). Specificity. Lead has adverse effects on many other health outcomes in addition to cognitive function. This is not surprising given lead’s numerous biologic effects, includ- ing calcium agnonism and antagonism (Ferguson et al. 2000), binding to sulfhydryl and carboxyl groups on proteins, and activa- tion of nuclear transcription factors (Ramesh et al. 2001), for example. It is thus not 489