Research | Mini-Monograph Cumulative Lead Dose and Cognitive Function in Adults: A Review of Studies That Measured Both Blood Lead and Bone Lead Regina A. Shih,1 Howard Hu,2,3 Marc G. Weisskopf,2,3 and Brian S. Schwartz 4,5 1Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA; 2Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; 3Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; 4Departments of Environmental Health Sciences and Epidemiology, Johns Hopkins Bloomberg School of Public Health, and 5Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA OBJECTIVE: We review empirical evidence for the relations of recent and cumulative lead dose with cognitive function in adults. DATA SOURCES: A systematic search of electronic databases resulted in 21 environmental and occu- pational studies from 1996 to 2006 that examined and compared associations of recent (in blood) and cumulative (in bone) lead doses with neurobehavioral outcomes. DATA EXTRACTION: Data were abstracted after consideration of exclusion criteria and quality assess- ment, and then compiled into summary tables. CONCLUSIONS: At exposure levels encountered after environmental exposure, associations with bio- markers of cumulative dose (mainly lead in tibia) were stronger and more consistent than associa- tions with blood lead levels. Similarly, in studies of former workers with past occupational lead exposure, associations were also stronger and more consistent with cumulative dose than with recent dose (in blood). In contrast, studies of currently exposed workers generally found associa- tions that were more apparent with blood lead levels; we speculate that the acute effects of high, recent dose may mask the chronic effects of cumulative dose. There is moderate evidence for an association between psychiatric symptoms and lead dose but only at high levels of current occupa- tional lead exposure or with cumulative dose in environmentally exposed adults. KEY WORDS: adults, blood, bone, cognitive function, lead, neurobehavior. Environ Health Perspect 115:483–492 (2007). doi:10.1289/ehp.9786 available via http://dx.doi.org/ [Online 22 December 2006] In the development of the adult lead manage- ment guidelines (see Kosnett et al. 2007), a number of health outcomes adversely affected by lead exposure were discussed. Cognitive function was an important consideration of because of the growing number of studies in this area and increasing concern that cogni- tive function in adulthood may be affected by relatively low lead doses. In this article, we systematically review recent evidence con- cerning recent and cumulative lead dose and adult cognitive function. Measurement of lead dose. In reviewing studies of the health effects of lead, it is criti- cal to understand the available lead biomark- ers in terms of how they represent external exposure (in terms of timing, duration, mag- nitude, and accumulation); how they are inﬂuenced by metabolic factors (organ distri- bution, compartmental dynamics, the influ- ence of physiologic factors); and how the combination of these considerations affects inferences regarding the health effects of lead (Hu et al. 2007). We conclude from these important methodologic issues that the most informative recent epidemiologic studies of lead’s impact on health are those that were able to derive estimates of both recent and cumulative lead exposure for each study par- ticipant. To achieve this end with the greatest precision and accuracy, such studies have incorporated measurements of lead in both blood (whole blood, using standard chemical assays such as graphite furnace atomic absorp- tion spectroscopy) and bone [using noninva- sive in vivo K-shell X-ray fluorescence (KXRF) instruments]. Blood lead levels measured in epidemio- logic studies with valid instruments and stan- dardized calibration and quality control procedures have been reported in the litera- ture for > 35 years. Bone lead levels measured by in vivo KXRF were begun in some research laboratories in the 1980s, but it was not until the mid-1990s that reports began to emerge of KXRF-measured bone lead levels in relation to potential health indicators from epidemiologic studies with sufficient sample sizes (for example, ≥ 100 subjects) to have substantial statistical power. Thus, in this review we summarize all studies to date that measure cognitive function and both blood and bone lead levels (or acceptable surrogate for cumulative lead dose). Published reviews of relevance to this review. We begin our review with a discus- sion of three other reviews on the topic of lead dose and cognitive function (Balbus- Kornfeld et al. 1995; Goodman et al. 2002; Meyer-Baron and Seeber 2000). Balbus- Kornfeld et al. (1995) reviewed the evidence on cumulative lead exposure and cognitive function from studies published from 1976 to 1991. Among 21 unique studies that were Environmental Health Perspectives • VOLUME 115 | NUMBER 3 | March 2007 identiﬁed at the time of the authors’ review, none used a biomarker of cumulative dose. Of the four longitudinal studies, all were small (mean sample size in the analysis of 47 lead-exposed subjects), with relatively low follow-up rates and relatively short durations of follow-up. The authors thus concluded that the available literature provided inade- quate evidence to conclude whether cumula- tive exposure or absorption of lead adversely affected cognitive function in adults. Goodman et al. (2002) and Meyer-Baron and Seeber (2000) are reviewed here because they had generally opposite conclusions, which led to considerable controversy and dis- cussion (Goodman et al. 2001; Schwartz et al. 2002; Seeber and Meyer-Baron 2003; Seeber et al. 2002). The Goodman et al. (2002) arti- cle was funded by the German Battery Association, apparently in anticipation of con- sideration in Germany of lowering the blood lead standard in lead workers (Seeber and Meyer-Baron 2003). Goodman et al. (2002) reviewed 22 studies published between 1974 and 1999 with the expressed aim of evaluating associations between moderate blood lead lev- els and neurobehavioral test scores after occu- pational exposure to lead. Studies were included if the central tendency for blood lead levels was < 70 µg/dL, the numbers of exposed and unexposed were reported, and test score arithmetic means and measures of variability were reported for exposed and unexposed workers (Goodman et al. 2002). The authors concluded that none of the individual studies were conclusive or adequate in providing This article is part of the mini-monograph “Lead Exposure and Health Effects in Adults: Evidence, Management, and Implications for Policy.” Address correspondence to B.S. Schwartz, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe St., Rm. W7041, Baltimore, Maryland 21205 USA. Telephone: (410) 955-4130. Fax: (410) 955-1811. E-mail: bschwart@jhsph.edu This work was supported in part by National Institute of Aging R01-AG19604 and R01-AG10785; National Institute of Environmental Health Sciences R01-ES07198, R01-ES05257, R01-ES10798, P42- ES05947, P30-ES00002, and K01-ES012653; and intramural funds from NICHD. The authors declare they have no competing ﬁnancial interests. Received 3 October 2006; accepted 15 November 2006. 483