Table 2.
Detailed summary and main findings of studies on cognitive function with recent and cumulative lead dose biomarkers.
| Author | Sample size (no.) | Design | Percent male [mean age in years (SD)] | Race/ethnicity (%) | Source of Pb exposure | Primarily current/past exposure | Lead dose measure [mean (SD)] | Covariates adjusted for outcome measures | Summary of findings |
|---|---|---|---|---|---|---|---|---|---|
| Nonoccupational lead exposure | |||||||||
| Stokes et al. 1998 | 257 (E)
276 (R) |
XS | 47.7% (E)
24.3 (3.2) 49.6% (R) 24.2 (3.0) |
White (E)
98 White (R) 94.2 |
Resided near lead smelter during childhood (E)
Random sample of licensed drivers (R) |
Past (E)
~ 20 years prior |
Blood: (E) 2.9 (3.3) (R) 1.6 (1.4)
Tibia: (E) 4.6 (range, –28.9 to 37) (R) 0.6 (range, –46.4 to 17.4) |
Age, education, sex, height, BMI
Battery of tests—6 domains |
Dichotomized exposure group associated with neurobehavioral outcomes, but no significant associations between tibia lead and neurobehavioral outcomes |
| Payton et al. 1998 | 141 | XS | 100%
66.8 (6.8) |
White
94 |
Environmental (Normative Aging Study) | Past | Blood: 5.5 (3.5)
Tibia: 22.5 (12.2) Patella: 31.7 (19.2) |
Age, education
Battery of tests— 8 domains |
Blood lead significant predictor of performance on speed, memory, spatial copying, and vocabulary
Tibia lead associated with pattern memory and spatial copying Patella lead had less significant relationships with test scores than tibia lead |
| Wright et al. 2003 | 736 blood, tibia, patella lead
295 blood only |
XS | 100%
68.2 (6.9) |
White
94 |
Environmental (Normative Aging Study) | Past | Blood: 4.5 (2.5)
Tibia: 22.4 (15.3) Patella: 29.5 (21.2) |
Age, education, alcohol intake
MMSE score < 24 |
Blood lead OR = 1.21 (95% CI, 1.07–1.36) for MMSE < 24
Tibia lead OR = 1.02 (95% CI, 1.00–1.03) for MMSE < 24 Patella lead OR = 1.02 (95% CI, 1.00–1.04) for MMSE < 24 Patella and blood lead levels modified the effect of increasing age on MMSE score |
| Weisskopf et al. 2004 | 466
F/U = 61.9% |
L | 100%
67.4 (6.6) |
White
94 |
Environmental (Normative Aging Study) | Past | Median [IQR]
Blood: 4 [3, 5] Tibia: 19 [12, 26] Patella: 23 [15, 35] |
Age, smoking, education, alcohol intake, and years between MMSE tests
Change in MMSE score |
Null association between baseline blood lead and change in MMSE
Patella lead significantly associated with decline in MMSE (an IQR higher patella lead = ~ 5 years of aging on baseline MMSE) Tibia lead similar to patella but not quite significant |
| Weisskopf et al. 2007 | 1,089 blood
761 tibia 760 patella |
XS and L | 100%
68.7 (7.4) |
White
98 |
Environmental (Normative Aging Study) | Past | Median [IQR]
Blood: 5 [3, 6] Tibia: 20 [13, 28] Patella: 25 [17, 37] |
Age, age squared, education, smoking, and alcohol intake
Battery of 10 cognitive tests |
XS analysis: blood lead significant predictor of performance on vocabulary test
L analysis: tibia lead associated with pattern comparison L analysis: patella lead associated with pattern comparison and spatial copying |
| Shih, et al. 2006 | 994 | XS | 34.1%
59.4 (6.0) |
African
American 40.1 |
Environmental (Baltimore Memory Study) | Past | Blood: 3.5 (2.2)
Tibia: 18.7 (11.2) |
Series of 5 models adjusting for age, sex, APOE e4 allele, education, race, wealth Scores in 7 cognitive domains | Tibia lead was consistently associated with lower test scores in all 7 cognitive domains
Blood lead was not associated with any cognitive domain |
| Occupational lead exposure | |||||||||
| Lindgren et al. 1996 | 467 | XS | 100%
43.4 (11) |
White
100 |
Canadian lead smelter (Canada Lead Study) | 370 currently employed
97 previously employed |
Blood: 36
IBLa: mean across groups, 268.6–1,227.7 TWAb: mean across groups, 26.1–52.8 |
Age, education, language, depressive scale score, head injury, neurological disorder, alcohol use
Battery of tests— 8 domains |
Lack of association between neuropsychologic performance and blood lead or TWA
IBL related to visuomotor skills, psychomotor speed and dexterity, motor speed, and verbal memory performance |
| Bleecker et al. 1997 | 80 | XS | 100
44.1 (8.4) |
White
100 |
Canadian lead smelter (Canada Lead Study) | Current 4–26 years of exposure | Blood: 26.4 (7.1)
IBLa: 903.1 (305.9) TWAb: 42.3 (8.4) Tibia: 41.0 (24.4) |
Age, education
Battery of tests— 5 domains |
Significant amount of variance in verbal memory performance accounted for only by measures of blood lead and TWA
Visuomotor ability had significant variance accounted for by measures of TWA, IBL and tibia lead |
| Chia et al. 1997 | 50 (E)
97 (NE) |
XS | 100
(E) 35.7 (10.6) (NE) 33.9 (3.7) |
100%
Asian (48 Chinese) (E) 100 Asian (43 Chinese) (NE) |
Lead battery manufacturing factory (E)
Vehicle maintenance workshop (NE) |
Current | Blood: (E) 37.1 (range, 13.2–64.6) (NE) 6.14 (range, 2.4–12.4)
CumPbc: (E) 175.9 (range, 10.0–1146.2) |
Age, education, smoking history, ethnic groups, drinking habits
Battery of tests— 5 domains |
E and NE groups significantly different in tests involving motor dexterity, and visuomotor and psychomotor speed
Cumulative blood associated with Digit Symbol and Trail Making Part A scores Cumulative blood lead a stronger predictor of neurobehavioral effects than concurrent blood lead levels |
| Osterberg et al. 1997 | 38 (E)
19 (NE) |
XS | 100
(E) median: 41.5 |
NR | Secondary lead smelter— inorganic lead (E)
Nearby mechancal manufacturing plant (NE) |
Current 2–35 years of exposure | Current blood leadd:
&(E) median, 1.8 (range, 0.9–2.4) (NE) median, 0.18 (range, 0.07–0.34) Peak blood leadd: (E) median, 3.0 (range, 2.2–4.3) CBLIe: (E) median, 233 (range, 74–948) Finger bone: (E) median, 32 (range, 17–101) (NE) median, 4 (range, –19 to 18) |
Matched on age, education, job level
Battery of tests—5 domains |
Neither blood (current or peak) lead nor finger bone lead levels were associated with any neurobehavioral measures |
| Hanninen et al. 1998 | 54 | XS | 79.6
Low blood lead 41.7 (9.3) High blood lead 46.6 (6.2) |
NR | Helsinki lead acid battery factories | Past
12.3, 20.5 years of exposure (means across groups) |
Low blood leadd:
TWAf: 1.4 (0.3) Peak blood leadd: 1.9 (0.4) IBLg: 15.7 (9.5) Calcaneus: 78.6 (62.4) mg/kg Tibia: 19.8 (13.7) mg/kg High blood leadd TWAf : 1.9 (0.4) Peak blood leadd: 3.3 (0.7) IBLg: 39.2 (18.5) Calcaneus: 100.4 (43.1) mg/kg Tibia: 35.3 (16.6) mg/kg |
Age, sex, education
Battery of tests— 6 domains |
None of the bone lead measures were significantly associated with any test scores
The low blood lead group showed associations between historical blood lead measures and visuospatial, visuomotor, attention and verbal comprehension performance The high blood lead group had worse performance than the low blood lead group on tests of attention (Digit Symbol), visual memory (memory for design), and visuoperception (embedded figures) |
| Stewart et al. 1999 | 543 | XS | 100
38% were ≥ 60 years of age (range, 40–70) |
White
92.8 |
Eastern U.S. tetraethyl and tetramethyl lead manufacturing facility (U.S. Organolead Study) | Past
Mean of 17.8 years since last exposure at time tibia lead obtained |
Tibia: 14.4 (9.3)
Peak tibia: 23.7 (17.4) |
Age, race, education, testing, lead measures, years since last exposure, depressive score, tobacco, alcohol consumption, visit number
Battery of tests— 8 domains |
Peak tibia lead strongest and most consistent predictor of test scores: manual dexterity, executive ability, verbal intelligence and memory
Current tibia lead also associated with same domains except verbal memory On average, an increase in 22 μg/g peak tibia lead was equivalent to an increase in 5 years of age |
| Lucchini et al. 2000 | 66 (E)
86 (NE) |
XS | 100 (E) 40.1 (8.7) (NE) 42.6 (8.8) | NR | Lead accumulators and bullet manufacturers and 2 lead smelters in Northern Italy (E)
Hospital (NE) |
Current
1–33 years of exposure |
Blood: 27.5 (11.0) (E) 8.1 (4.5) (NE)
IBLa: 409.8 (360.8) (E) TWAb: 31.7 (14.1) (E) |
Age, education, alcohol, smoking, coffee intake
Neurological symptoms and a battery of 4 neurobehavioral tests |
Neurologic symptoms (neuropsychologic, sensory motor) more frequent, and decreased sensitivity to visual contrast sensitivity test in exposed workers. These associations are with current blood lead and not cumulative lead measures (on a E vs. NE comparison, but not individual level)
No differences between groups on neurobehavioral tests Significant differences between low and high IBL groups on neuropsychologic scores |
| Schwartz et al. 2000 | 535 (E) F/U = 99.8% with 1 + visit
118 (NE) F/U = 91.6% with 1 + visit |
L | 100
55.6 (7.4) at first visit (E) 58.6 (7.0) (NE) |
White
93.1 |
Eastern U.S. tetraethyl and tetramethyl lead manufacturing facility (E)
Community-based random sampling from residential areas of former lead workers (NE) (U.S. Organolead Study) |
Past
Mean of 16 years since exposure at last baseline |
Blood: 4.26 (2.6) (E)
Tibia: 14.4 (9.3) (E) Peak tibia: 22.6 (16.5) (E) |
Frequency matched on age, education and race
Battery of tests— 8 domains |
Exposed workers showed greater annual declines than controls in verbal memory, visuoconstruction domains
Peak tibia lead, but not blood lead, consistently predicted declines in test scores: symbol digit, verbal and visual memory, motor speed, and executive ability On average, an increase of 15.7 μg/g peak tibia lead was equivalent to annual test decline to ≥ 5 years of age at baseline |
| Schwartz et al. 2001 | 803 (E)
135 (NE) |
XS | (E) 79.6
40.4 (10.1) (NE) 91.9 34.5 (9.1) |
Asian
100 |
Battery, lead oxide or car radiator manufacturing and secondary lead smelters (E)
Air conditioner manufacturing or university (NE) (Korea Lead Study) |
Current (8 retired) | Blood: 32 (15) (E) 5.3 (1.8) (NE)
Tibia: 37.1 (40.3) (E) 5.8 (7.0) (NE) |
Age, sex, education, each lead measure, height, BMI
Battery of tests— 9 domains |
Blood lead was a better predictor of tests of executive abilities, manual dexterity, and peripheral motor strength than tibia or DMSA-chelatable lead
On average, an increase of 5 μg/dL blood lead was equivalent to an increase of 1.05 years in age |
| Barth et al. 2002 | 47 (E)
53 (NE) |
XS | 100 39.5 (9.7) (E) 39.3 (8.4) (NE) | NR | Storage-battery plant (E)
Steel production plant (NE) (Austria Lead Study) |
Current 0.1–36.1 years of exposure (E) | Blood lead: 30.8 (11.2) (E) 4.32 (2.0) NE)
IBLh: 4,613.5 (4,187.6) (E) |
Age, years of education, verbal intelligence, number of alcoholic drinks per week/grams of alcohol per week
Battery of tests— 5 domains |
Current blood lead levels, but not cumulative blood lead levels, were correlated with executive functions and visuospatial abilities
Executive functioning and visuospatial abilities differed significantly between exposed and control groups |
| Bleecker et al. 2005 | 254 | XS | 100
41 (9.4) |
White
100 |
Canadian lead smelter (Canada Lead Study) | Past | Blood: 27.7 (8.8)
IBLa: 728.2 (434.4) TWAb: 39.0 (12.3) |
Age, educational achievement
Verbal learning and memory |
Significant amount of variance in recognition and delayed recall accounted for only by measures of IBL and TWA
The “generalized memory impairment group” had the highest TWA and IBL compared with the “no impairment” and “retrieval difficulties” groups |
| Schwartz et al. 2005 | 576 with all visits
F/U: all 3 visits, 2 visits, 1 visit = 72%, 16%, 12% |
L | 76
41.4 (9.5) at visit 1 |
Asian
100 |
Battery, lead oxide or car radiator manufacturing and secondary lead smelters (Korea Lead Study) | Current
Mean job duration: 8.5 (6.3) (71, 97, 150 no longer working in lead industry at visits 1,2,3) |
Blood: 31.4 (14.2)
Tibia: 38.4 (43) |
Age, education, sex, height, BMI
Battery of tests—9 domains |
Blood lead cross-sectionally was associated with lower executive ability and manual dexterity scores
Change in blood lead was associated with longitudinal declines in few tests Tibia lead was associated with longitudinal declines in manual dexterity, executive abilities, neuropsychiatric and peripheral sensory function |
| Winker et al. 2005 | 48 (E)
48 (NE) |
XS | 100
39.6 (8.8) (E) 39.9 (8.8) (NE) |
NR | Storage-battery plant (E)
Steel production plant (NE) (Austria Lead Study) |
Past
Mean of 5.2 years since last exposure |
Blood lead:
5.4 (2.7) (E) 4.7 (2.5) (NE) IBLh: 4,153.3 (3,690.3) (E) |
Age, years of education, verbal intelligence, number of alcoholic drinks per week/grams of alcohol per week
Battery of tests—5 domains |
Blood lead was correlated with visuospatial abilities, attention, visual scanning, and visuomotor speed. IBL was correlated only with choice reaction
No differences between groups on neurobehavioral tests, and no differences between groups stratified by high IBL (> 4,500) vs. low IBL (< 4,500) |
| Dorsey et al. 2006 | 652 | XS | 77
43.4 (9.6) |
Asian
100 |
Battery, lead oxide or car radiator manufacturing and secondary lead smelters (Korea Lead Study) | Current
Mean job duration: 10 (6.5) |
Blood: 30.9 (16.7)
Tibia: 33.5 (43.4) Patella: 75.1 (101.1) |
Series of four models adjusting for age, sex, education, job duration, height, BMI
Battery of tests—14 neurobehavioral, 4 peripheral nervous system measures, and psychiatric symptoms |
Ranked blood lead was associated with executive ability, manual dexterity, and PNS sensory function
Ranked tibia lead was similar to blood lead but also associated with psychomotor speed Ranked patella lead was associated with executive ability, manual dexterity, depressive symptoms, and PNS sensory function. Adjustment for blood lead attenuated these associations |
| Winker et al. 2006 | 47 (E)
48 (formerly E) |
XS | 100
39.5 (9.7) (E) 39.6 (8.8) (Formerly E) |
NR | Storage-battery plant (E)
Storage-battery plant, police officers (Formerly E) (Austria Lead Study) |
Current
11.7 (9.0) mean years of exposure duration Past 5.26 (3.5) mean years since last exposure |
Blood lead:
30.8 (11.2) (E) 5.4 (2.7) (Formerly E) IBLh: 4,613.5 (4,187.6) (E) 4,153.3 (3,690.3) (Formerly E) |
Age
Battery of tests—5 domains |
Visuospatial abilities and executive functioning performance decreased linearly from workers with short exposure duration and long absence from exposure, to the worst performing group with long exposure and short/no absence from exposure |
Abbreviations: APOE, apolipoprotein E; BMI, body mass index; CI, confidence interval; E, exposed; F/U, follow-up rate; IQR, Interquartile range; L, longitudinal; MMSE, Mini-Mental State Examination; NB, neurobehavioral; NE, nonexposed; Pb, lead; PNS, peripheral nervous system; OR, odds ratio; R, reference; XS, cross-sectional.
Blood lead units: μg/dL; tibia/patella lead units: μg/g (unless noted otherwise). IBL: integrated blood lead calculated from blood measures during a time period, a measure of cumulative dose:
a
μg-years/dL;
g
μmol-years/l;
h
μg-months/dL. TWA: time weighted average calculated by dividing IBL by number of years exposed, a measure of average intensity of lead exposure:
b
μg/dL;
f
μmol/L.
c
CumPb: Area under the curve of blood lead levels over time: μg-years/dL.
d
Current and peak blood lead measured in units μmol/L.
e
CBLI: cumulative blood lead index: product of blood lead and employment time: μmol-months/L.