Claus Henn et al. correlation = 0.61, p < 0.0001). At 24 months, manganese and lead concentrations were also positively, but weakly, correlated (Spearman correlation = 0.14, p = 0.004). Lead concen- trations were higher among boys than among girls at 12 and 24 months, although the differ- ence was significant only at 24 months (mean ± SD: 12 months, boys, 5.3 ± 2.7 gμ/dL ; girls, 4.9 ± 2.5 gμ/dL; 24 months, boys, 5.3 ± 3.3 μg/dL ; girls, 4.7 ± 2.4 μg/dL). We observed no significant sex differences in blood manga- nese levels. There were negligible differences in mean lead concentrations among manganese quintiles (data not shown). Associations of coexposure with mental development. Twelve-month blood metals. Table 2 summarizes results from adjusted mixed-effects models of 12-month blood metals, which included MDI scores at all five time points. We observed a significant man- ganese–lead interaction over time for children in the highest quintile of 12-month blood manganese [adjusted β = –1.27 (95% con- fidence interval [CI]: –2.18, –0.37)]. Given these estimates, we expect MDI scores to decline by 0.07 points per 1-μg/dL increase in lead among children with midrange man- ganese levels, compared with a decline of 2.23 points (i.e., βmanganese quintile 5 + βlead + βmanganese quintile 5 × lead = –0.89 + –0.07 + –1.27) per 1-μg/dL increase in lead among children with high manganese levels. Results from adjusted regression models of 12-month blood metals with MDI scores at five sepa- rate time points are presented in Table 3. A significant manganese–lead interaction was Table 1. Sociodemographic characteristics of study participants and nonparticipants (mean ± SD or %). Characteristic Children included in analysesa Nonparticipantsb Sex (% male) 50.6 44.2 Birth weight (kg) 3.1 ± 0.4 3.1 ± 0.5 Estimated gestational age (weeks) 38.9 ± 1.3 38.4 ± 2.1 Birth length (cm) 49.8 ± 2.2 49.5 ± 3.1 Head circumference at delivery (cm) 34.1 ± 1.6 34.0 ± 1.6 Blood manganese (μg/L) 12 monthsc 24.7 ± 5.9 — 24 monthsd 21.5 ± 7.4 — Blood lead (μg/dL) Umbilical corde 4.7 ± 3.1 4.8 ± 2.6 12 monthsc 5.1 ± 2.6 — 24 monthsd 5.0 ± 2.9 — Hemoglobin (g/dL) 12 months 11.8 ± 1.3 11.8 ± 1.3 24 months 12.6 ± 1.1 12.1 ± 1.4 Bayley MDI Score (36 months)f 93.2 ± 9.1 93.1 ± 8.9 Bayley PDI Score (36 months)f 95.8 ± 10.9 95.6 ± 11.5 Maternal marital status (% married) 72.6 75.9 Maternal IQ 88.0 ± 13.0 89.0 ± 11.7 Maternal education (years) 10.7 ± 2.8 11.2 ± 3.6 Maternal age at delivery (years) 25.8 ± 5.3 27.8 ± 5.4 Maternal whole-blood lead (μg/dL)g 7.5 ± 4.6 7.3 ± 4.2 an = 455 except where noted. bNonparticipants (n = 165) are children who did not provide a blood sample (n = 127) or Bayley score (n = 2), had incomplete covariate data (n = 33) or inadequate blood data (n = 1), or were low gestational age (< 32 weeks, n = 2). cn = 275. dn = 437. en = 290. fOnly 36-month Bayley scores are provided, for brevity; scores at other time points are similar. gCollected at 1-month postpartum. Table 2. Effect estimates from mixed modelsa of 12- and 24-month metal concentrations with repeated measures of Bayleyb scores [β-coefficient (95% CI)]. Exposure Twelve monthsc Twenty-four monthsd MDI Manganese (quintile 1e vs. quintiles 2–4) –2.08 (–3.98, –0.19) –0.34 (–2.35, 1.67) Manganese (quintile 5f vs. quintiles 2–4) –0.89 (–2.79, 1.00) 0.01 (–1.97, 2.00) Lead (μg/dL)g –0.07 (–0.39, 0.25) –0.08 (–0.46, 0.30) Manganese (quintile 1) × lead –0.31 (–1.25, 0.62) –0.02 (–0.98, 0.94) Manganese (quintile 5) × lead –1.27 (–2.18, –0.37) –0.09 (–0.63, 0.45) PDI Manganese (quintile 1 vs. quintiles 2–4) 0.47 (–1.28, 2.22) –0.22 (–2.08, 1.65) Manganese (quintile 5 vs. quintiles 2–4) –0.05 (–1.80, 1.70) 0.06 (–1.77, 1.90) Lead (μg/dL) –0.27 (–0.56, 0.02) –0.18 (–0.53, 0.17) Manganese (quintile 1) × lead 0.10 (–0.76, 0.97) 0.23 (–0.66, 1.13) Manganese (quintile 5) × lead –0.92 (–1.76, –0.09) 0.18 (–0.32, 0.68) aAdjusted for sex, gestational age, hemoglobin, maternal IQ, maternal education, and visit. bEffect estimates for 12-month metals are from repeated measures models that included Bayley scores at 12, 18, 24, 30, and 36 months. Effect estimates for 24-month metals are from repeated measures models that included Bayley scores at 24, 30, and 36 months. cn = 275. For MDI, number of observations = 1,330; for PDI, number of observations = 1,329. dn = 437. For MDI and PDI, number of observations = 1,240. eRange: 12 months, 15.30–20.16 μg/L; 24 months, 5.06–15.57 μg/L. fRange: 12 months, 28.14–73.95 μg/L; 24 months, 25.78–93.53 μg/L. gBlood lead centered at mean: 12 months, 5.09 μg/dL; 24 months, 4.98 μg/dL. observed only at 18 months for children in the highest quintile of 12-month blood man- ganese [β = –1.74 (95% CI: –3.00, –0.49)]. At 18 months, MDI scores are expected to decline 0.01 points per 1-μg/dL increase in lead among children with midrange man- ganese levels, compared with 1.80 points (i.e., –0.05 + –0.01 + –1.74) among children with high manganese levels. Although effect estimates at other time points of MDI were not statistically significant, coefficients were all negative and approached significance at 24 months of age (p = 0.07). Furthermore, when we included a three-way interaction term (i.e., lead × highest quintile of manga- nese × time) in the mixed-effects model to examine whether the manganese–lead interac- tion changed over time, we observed no time trend [β = –0.07 (95% CI: –0.46, 0.32)]. We observed no manganese–lead interac- tion among children in the lowest quintile of 12-month blood manganese [Table 2; adjusted β = –0.31 (95% CI: –1.25, 0.62)]. Therefore, we collapsed quintiles 1–4 and compared the association between lead and MDI in the highest manganese quintile to that in the lower four manganese quintiles. Figure 1 shows a steeper regression line for the association of lead with 18-month MDI among children in manganese quintile 5 versus quintiles 1–4, providing evidence for increased lead toxicity in the presence of high manganese levels [lead × quintile 5 manganese, adjusted β = –1.70 (95% CI: –2.95, –0.44)]. Twenty-four–month blood metals. We fit regression models for 24-month blood metals with 24-, 30-, and 36-month MDI separately, as well as in repeated measures models, but observed no significant manga- nese–lead interaction at either low or high manganese (Table 2). Associations of coexposure with psychomotor development. Twelve-month blood metals. From repeated measures models, PDI scores are expected to decline by 0.27 points per 1-gμ/dL increase in lead among children with midrange manganese levels, compared with a decline of 1.24 points (i.e., βmanganese quintile 5 + βlead + βmanganese quintile 5 × lead = –0.05 + –0.27 + –0.92) per 1-gμ/dL increase in lead among children with high manganese levels (Table 2). This suggests more severe adverse effects of lead on psychomotor development among children with high manganese. Lower PDI scores were also observed in separate models at 18, 24, 30, and 36 months among children with a 1-gμ/dL increase in 12-month lead and high manganese coexposure, compared with children with a 1-μg/dL increase in lead but only midrange manganese levels (Table 3). Effect estimates were consistent from 18 to 36 months and were statistically signifi- cant at 24, 30, and 36 months [24 months, adjusted β = –1.60 (95% CI: –2.93, –0.27); 128 ovlume 120 | number 1 | January 2012 • Environmental Health Perspectives