Shih et al. information on the effects of lead on cognitive function and called for prospective studies that would evaluate cognitive function before and after exposure. There was no discussion about whether examining relations of blood lead lev- els with cognitive function was the most rele- vant question if the hypothesis was that cumulative lead dose was most important to cognitive function. There was little explicit discussion of whether lead may have acute effects as a function of recent dose, and chronic effects as a function of cumulative dose, or how this could be assessed by review of epidemiologic studies. Meyer-Baron and Seeber (2000) per- formed a meta-analysis of 12 studies using selection criteria similar to Goodman et al. (2002) but also with the requirement for reporting means and standard deviations of dependent variables (Meyer-Baron and Seeber 2000). They concluded that there were obvi- ous neurobehavioral deﬁcits at current blood lead levels < 40 µg/dL. Again, the focus was on associations with blood lead levels, and there was little formal discussion about which lead biomarker was most relevant to hypotheses about how cumulative lead dose may inﬂuence cognitive function. Thus, this is the ﬁrst review to evaluate epidemiologic studies that distin- guish between the acute effects of recent dose from the chronic effects of cumulative dose. Methods Methodologic considerations for relations of lead dose and cognitive function. Many methodologic issues of relevance to the epi- demiologic investigation of lead and cognitive function have been addressed elsewhere in this mini-monograph (Hu et al. 2007). When evaluating the associations of cumulative lead dose with cognitive function, it is important to acknowledge that nonoccupational sources of lead exposure were present for all members of the general population, including lead workers throughout the early part of this cen- tury until public health interventions progres- sively removed lead from gasoline and many consumer products during the 1970s and 1980s (Agency for Toxic Substances and Disease Registry 1999; Annest et al. 1983; Pirkle et al. 1998). Lead remains a low-level and ubiquitous neurotoxicant in the environ- ment and is found in measurable levels in all individuals (Hoppin et al. 1995). Thus, cur- rent tibia lead levels represent a mix of occu- pational and environmental exposures. This review does not try to determine whether the main source of lead was occupational or envi- ronmental but rather focuses on whether lead in blood or bone is associated with adverse cognitive outcomes in adults. Identiﬁcation of studies. We conducted a systematic literature review of the association between blood and bone lead biomarkers and 484 cognitive functioning in adults. Our aim was to select studies that compared markers of both recent and cumulative lead dose in their relations with cognitive function. Both occu- pationally and environmentally exposed adult populations were included. We searched the PubMed (National Library of Medicine 2006) and PsycINFO databases (American Psychological Association 2006) for epidemi- ologic studies using keywords such as blood, bone, lead, cumulative, cognitive, and neu- robehavior. There were no date or language restrictions. From the identiﬁed publications and relevant review articles, we examined ref- erence lists to locate additional studies that measured both recent and cumulative lead dose. This includes blood lead levels, bone lead levels, or a surrogate measure of cumula- tive lead dose such as integrated blood lead (IBL), area under the curve of blood lead lev- els over time, or the product of blood lead level and employment time. Studies were not considered for the review if they a) contained no original research, b) were conducted on nonhuman subjects, c) were case reports, d) contained no standardized neurocognitive assessment outcomes, or e) lacked measures of both recent and cumulative lead dose. Data abstraction. We abstracted data from articles meeting the selection criteria. Study quality was assessed with the following criteria: a) exposure was assessed at an indi- vidual level; b) exposure was assessed with a biomarker; c) cognitive outcomes were objec- tive, standardized tests; d) statistical adjust- ment for potential confounders including age, sex (in studies with both men and women), and education; e) data collection was similar in exposed and nonexposed participants; f ) time period of study was the same in exposed and nonexposed participants; and g) there was a detailed description of the approach to data analysis. We decided not to try to derive a pooled estimate across studies of the associations of lead dose biomarkers with cognitive function because of differences in methods for subject selection, blood and bone lead measurements, neurobehavioral outcomes, approach to regression modeling, and presentation of results across studies. Pooled estimates from metaanalysis also can be highly influenced by decisions regarding how and whether to pool certain results. We thus decided to present details for each study and discuss them in turn. Results Overview of evidence. We identified three main types of studies that reported cross-sec- tional or longitudinal associations of blood and bone lead levels with cognitive function. These were of a) environmentally exposed individuals in the general population, b) work- ers with current occupational exposure, and c) former lead workers without current occu- pational exposure to lead. We have summa- rized these studies in Table 1, provided details in Table 2, and discuss them in order below. Studies of adults without occupational lead exposure. We identiﬁed six articles from three studies [i.e., residents near a lead smelter, the Normative Aging Study (NAS), and the Baltimore Memory Study] that evaluated sub- jects with mainly environmental exposure to lead (Tables 1 and 2). One study of young adults 19–29 years of age compared 257 indi- viduals with high childhood blood lead levels from exposure 20 years previously from a lead smelter to 276 age- and sex-matched controls. This study found impairment on many cogni- tive tests among the highly exposed group, but minimal association on most tests with tibia lead levels measured during young adulthood (Stokes et al. 1998). Four articles from the NAS reported asso- ciations of blood and bone lead levels in a cohort of older men. One of these articles (Payton et al. 1998) was a first report that examined scores on a large battery of cogni- tive tests of a small sample (n = 141) of NAS participants. This was subsequently followed up with a report on a much larger number of NAS participants (n = 1,089 with blood lead levels and n = 760 with bone lead levels, Table 1. Study characteristics of 21 articles on adult cognitive function (1996–2006) with biomarker meas- ures of recent and cumulative lead dose. No. (percent of total no. of papers) Article feature Main source of lead exposure Occupational Environmental Demographics Age (years) Mean < 50 Mean ≥ 50 Sex > 80% male ≤ 80% male Race/ethnicity Mixed Not mixed (> 80% one group) Not reported Type of lead dosea Blood lead (µg/dL) Peak/median/mean < 10 Peak/median/mean ≥ 10 Tibia lead (µg/g) Mean < 25 Mean ≥ 25 Patella lead (µg/g) Mean < 25 Mean ≥ 25 Cumulative dose measure Tibia Patella Integrated blood lead Other 15 (71.4) 6 (28.6) 15 (71.4) 6 (28.6) 16 (76.2) 5 (23.8) 1 (4.8) 14 (66.6) 6 (28.6) 10 (47.6) 11 (52.4) 9 (42.9) 5 (28.6) 1 (4.8) 4 (19.0) 13 (61.9) 5 (28.6) 8 (38.1) 3 (14.3) aTime-integrated blood lead was not summarized here because of differences in the way it is calculated for each study. VOLUME 115 | NUMBER 3 | March 2007 • Environmental Health Perspectives