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Table 3 Summary of results from studies examining manganese concentrations in blood (blood-Mn)

From: Measuring the impact of manganese exposure on children’s neurodevelopment: advances and research gaps in biomarker-based approaches

Study Mean Mn Level (μg/L),(SD) Association with Environmental Mn Association with
Association of other metals’ mean (SD) concentrations in blood, with the outcome
Wasserman et al. (2006) [18] 10 year olds
12.8 (3.2)
No association was found with water-Mn (Mean: 795 μg/L). No association was found between blood-Mn concentrations and overall, verbal and performance IQ scores in adjusted analyses, but water-Mn was associated with lower full-scale, performance and verbal IQ raw scores in a dose-dependent fashion. Blood-Mn was not significantly correlated with blood-Pb or blood-As. When all three blood metals were included in analyses only mean blood-Pb concentrations,12 μg/dL (3.7) were associated with IQ scores.
Kim et al. (2009) [26] 8–11 years olds
14.3 (3.8)
None measured Lower overall and verbal (but not performance) IQ scores were associated with blood-Mn in analyses adjusted for maternal age, parental education and smoking, SES, child gender and age and other confounders. Blood-Pb concentrations of 1.73 μg/dL (0.8) were associated with IQ scores in adjusted analyses with evidence of an additive interaction with blood-Mn. Effect modification was suggested as IQ scores of children with blood-Mn > 14 μg/L were significantly associated with blood-Pb whereas scores for children with blood-Mn < 14 μg/L were not.
Claus Henn et al. (2010) [44] 12 month:
24.3 (4.5)
24 month:
21.1 (6.2)
None measured Blood-Mn had an inverse, U-shaped association with a concurrent measure of the Mental Development Index (MDI) scores at 12 months of age. Declines of 3.4 and 2.8 MDI points for the lowest and highest quintiles of blood-Mn relative to the middle three quintiles, correspond to declines of 0.37 and 0.31 SD units in the MDI. This association declined by 24 months and was nonsignificant in adjusted analyses including blood-Pb, sex, maternal IQ and education, hemoglobin and gestational age. No association was found with the PDI score. Blood-Pb (cord, 12 and 24 month) concentrations were positively associated with 24 month blood-Mn concentrations. Indices of iron status (hemoglobin, ferritin) were inversely associated with Mn at 12 and 24 months of age.
Riojas-Rodriguez et al.(2010) [31] 7–11 year olds
9.7a (Exposed)
.2 (Control)
24-h median Mn in PM10 for the exposed (0.13 μg/m3) and control (0.02 μg/m3) communities Exposed children showed nonsignificant, inverse associations of blood-Mn with lower full scale, verbal and performance IQ scores compared to controls. Analyses were adjusted for age, sex, hemoglobin, maternal education, blood-Pb. Differences by sex were nonsignificant. Blood-Pb was higher in control (7.96 μg/dL) versus Mn-exposed (3.37 μg/dL) children and was correlated with blood-Mn (r - 0.24) in the population. It was not significantly associated with IQ outcomes.
Hernández-Bonilla et al. (2011) [48] 7–11 year olds
9.5 (Exposed)
8.0 (Control)
Prior studies show
airborne Mn levels
(median 0.10 μg/m3)
exceed EPA 1999 Reference Concentrations (0.05 μg/m3).
Blood-Mn was inversely associated with poorer finger tapping in analyses adjusted for age, sex, maternal education, hemoglobin and blood-Pb. Other motor function measures (grooved pegboard and Santa Anna test scores) were not significantly associated with blood-Mn. Sex differences for blood-Mn were nonsignificant. Blood-Pb concentrations were higher in the Mn control (median: 8 μg/dL) versus the Mn exposed (median: 3.3 μg/dL) children. The associations with the outcomes were not reported.
Kahn et al. (2011) [29] 8–11 year olds
15.1 (3.9)
Non-significant association of blood-Mn with water-Mn (mean: 900 μg/L). No association was found between blood-Mn and externalizing (attention problems and aggression) and internalizing (anxiety) behaviors and a total behavioral score in analyses adjusted for water-As, water-Mn, urinary creatin-adjusted As and blood-As, sex, maternal education and other variables. There was no statistical association between biomarkers of As (blood or urine) with blood-Mn.
Menzes-Filho et al. (2011) [35] 6–12 year olds
8.2 (3.6)
None measured; Mn exposure was due to home proximity to Mn alloy production. Blood-Mn concentrations were not associated with IQ scores in analyses adjusted for blood-Pb or low serum iron levels. Blood-Pb was above 2 μg/dL for 51 % (n = 36) and there was no association with blood-Mn or serum-Fe (mean: 55.6 μg/dL).
Parvez et al.
(2011) [49]
8–11 year olds
17.7 (3.7)
Water-Mn (mean: 725.5 μg/L). Children with higher water Mn (>500 μg/L) did not have higher levels of blood-Mn (14.5 vs. 15.0 μg/L; p < 0.05). No significant associations were found between blood-Mn and motor function measures (fine manual control, manual and body coordination, strength and agility). Blood-Mn correlated slightly with blood-As (mean: 4.8 μg/L; SD: 3.2; r = 0.12; p = 0.02) and moderately with blood-Se (mean: 104.9 μg/L; SD:17.2; r = -0.33, p < 0.0001). There was a significant, inverse association between As exposure measures (blood, water, urinary and nails) and overall motor function, and a significant association between blood-Se and manual coordination in adjusted analyses. No significant association was found between blood-Pb and motor function.
Wasserman et al. (2011) [30] 8–11 year olds
14.78 (3.7)
Water-Mn (mean: 725.54) and blood-Mn did not vary predictably across groups with high and low levels of water-Mn. Higher blood-Mn was associated with lower perceptual reasoning and working memory scores in analyses adjusted for maternal intelligence and age, children’s time in school, plasma ferritin, blood-As and other variables. Significant associations were not found for full scale IQ, verbal comprehension or processing speed scores. Increased concentrations of blood-As (mean: 4.81 μg/L; SD: 3.22) were significantly associated with lower verbal comprehension in adjusted analyses. However, Mn by As interactions were not significant in adjusted models predicting IQ.
Claus Henn et al. (2012) [27] 12 months:
24.7 (5.9)
24 months:
21.5 (7.4)
None measured A synergistic interaction between lead and Mn for mental and psychomotor development scores was found at 12 (but not 24) months; greater lead toxicity with higher Mn levels in analyses adjusted for sex, hemoglobin, gestational age, maternal education and IQ. There were no significant sex differences in blood-Mn. Concentrations of blood-Pb at 12 (mean:5.1 μg/dL; SD: 2.6) and 24 months (mean: 4.8 μg/dL; SD: 2.5).
Lucchini et al. (2012) [33] 11–14 year olds
11.11 μg/dL
Mn was measured in air PM10 airborne particles (median: 31.4 ng/m3 vs. 24.7 ng/m3) and soil (median:897 ppm vs. 409 ng/m3) in impacted compared to control areas, and water (below LD at 1 μg/L) and diet (median 2.66 mg/day) with no differences by locations. Soil-Mn was significantly, inversely associated with performance on the olfactory test. Tremor intensity, dominant hand, was significantly and positively associated with blood-Mn in adjusted models (including parental smoking and alcohol use, and Mn in soil, air and hair). Sex differences were found with boys having lower increased tremor intensity. Blood-Pb concentrations in the Mn exposed (mean: 1.72 μg/dL) and control (mean: 1.6 μg/dL) communities were very low.
Lucchini et al. (2012) [41] 11–14 year olds
11.11 μg/dL
Mn was measured in soil (median: 529.12 ppm), air: (median: 29.37 μg/m3), water, and diet Mn was not associated with IQ (full scale, verbal and performance) or behavioral (hyperactivity, attention deficit) scores in adjusted analyses. Blood-Pb concentrations averaged 1.71 μg/dL and were adversely associated with cognitive measures in adjusted analyses declining about 2.4 IQ points with a two-fold increase of blood-Pb. A bench-mark level of blood-Pb was associated with loss of 1 IQ point at 0.19 μg/dL and a lower 95%CI of 0.11 μg/dL. No interaction of Pb and Mn was observed.
Torres-Agustín et al. (2013) [54] 7–11 year olds Exposed: 9.5b Unexposed: 8.0 Air sampling (PM10) conducted and Mn concentrations in outdoor air from Mn mining significantly higher for exposed (Outdoor median: 0.08 mg/m3) versus comparison group (Outdoor median: 0.08 mg/m3) Significantly greater blood-Mn concentrations in exposed than comparison children. No significant associations between blood-Mn and verbal learning or memory in adjusted analyses. Blood-Pb concentrations were significantly higher in the comparison group (8.0 μg/dL) than the Mn exposed group (3.3 μg/dL) and included in multivariate models of Mn exposure.
Bhang et al. (2013) [40] 8–11 year olds
14.42 (4.1)
None measured Excess blood-Mn was associated with lower scores in thinking, reading, calculation, and learning scores and higher cognitive inhibition test scores in analyses adjusted for maternal and child age and IQ, child sex, and age, cotinine, blood-Pb and other variables. Lower blood-Mn was associated with lower cognitive inhibition scores. Analyses were adjusted for blood-Pb and cotinine.
Chung et al. (2015) [42] Maternal, pre- delivery, 30.1 ± 3.5 years; 22.5 (6.5) Not measured Inverted U-shaped dose- response curve with lower psychomotor development scores in infants at 6 months with both low and high levels of Mn. Adjusted mean PDI (but not MDI) scores differed significantly across Mn concentration groups. No differences in effects by sex were observed. None reported.
do Nascimento et al. (2015) [37] 6–12 year olds
Rural: 16.0 (4.2)
Urban: 19.0 (4.3)
Water-Mn concentrations differed significantly between rural (mean: 0.20 μg/L) and urban (mean:1.0 μg/L) children; associations with blood-Mn were not reported. No significant associations found for blood-Mn and nonverbal IQ in analyses adjusting for age, parents education and child sex. No associations were found between metals in blood and serum (Pb, Cr, As, Hg and Fe) and nonverbal IQ.
Haynes et al. (2015) [15] 7–9 year olds
9.67 (1.27)c [2]
Mn exposure resulted from residential proximity to ferromanganese refinery although measurements relative to the blood-Mn and the cognitive outcomes were not reported. Blood-Mn was significantly associated with lower full scale IQ, perceptual reasoning, lower processing speed scores in analyses adjusted for hair-Mn, serum cotinine, blood-Pb, and community residence. Full scale IQ scores among children in the highest quartile of blood-Mn (>11.2 μg/L) were significantly lower than scores in children with blood-Mn between 8.2 μg/L to 11.2 μg/L (-3.51 points; 95 % CI:-6.64, -0.38). Children with the lowest quartile of blood-Mn (<8.2 μg/L) also had lower full scale IQ scores than children in the reference group although findings were nonsignificant (-2.14 points; 95%CI: -5.37, 1.09). The perceptual reasoning and processing speed scores had the strongest negative associations with blood-Mn. Correlations between biomarkers found statistically significant included: blood-Mn and serum ferratin (mean: 34.4 ng/mL; r - 0.19, p < 0.01), blood-Mn and blood-Pb (mean: 0.82 μg/dL; r - 0.13, p = 0.02), and serum cotinine (0.08 μg/L) and blood-Pb (r = 0.34, p < 0.0001). Blood-Pb was significantly associated with processing speed, but not full scale IQ or other subscales. Cotinine was significantly associated with full scale IQ, perceptual reasoning, working memory and verbal comprehension.
Sun et al. (2015) [38] 8–12 year olds
16.2 μg/L
Not measured Blood-Mn was not significantly associated with IQ, but it was associated with urinary retinol binding protein (RBP) which was associated with blood-Mn. Blood-Pb (GM: 33.7 μg/L) was significantly, inversely associated with IQ.
  1. a Geometric Means are given for exposed and control groups
  2. b Median values for BMn
  3. c Geometric Mean (GM) and Standard Deviation (GSD)