Lourdes Schnaas

Low-Level Environmental Lead Exposure and Children's Intellectual Function: An International Pooled Analysis

Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 μg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 μg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5–10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 μg/dL and declined to 9.4 μg/dL by 5–7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 μg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 μg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2–9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 μg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 μg/dL, 10 to 20 μg/dL, and 20 to 30 μg/dL were 3.9 (95% CI, 2.4–5.3), 1.9 (95% CI, 1.2–2.6), and 1.1 (95% CI, 0.7–1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 μg/dL was significantly greater than that observed for those with a maximal blood lead level ≥7.5 μg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 μg/dL is associated with intellectual deficits.

Reduced Intellectual Development in Children with Prenatal Lead Exposure

Objective Low-level postnatal lead exposure is associated with poor intellectual development in children, although effects of prenatal exposure are less well studied. We hypothesized that prenatal lead exposure would have a more powerful and lasting impact on child development than postnatal exposure. Design We used generalized linear mixed models with random intercept and slope to analyze the pattern of lead effect of the cohort from pregnancy through 10 years of age on child IQ from 6 to 10 years. We statistically evaluated dose–response nonlinearity. Participants A cohort of 175 children, 150 of whom had complete data for all included covariates, attended the National Institute of Perinatology in Mexico City from 1987 through 2002. Evaluations/Measurements We used the Wechsler Intelligence Scale for Children–Revised, Spanish version, to measure IQ. Blood lead (BPb) was measured by a reference laboratory of the Centers for Disease Control and Prevention (CDC) quality assurance program for BPb. Results Geometric mean BPb during pregnancy was 8.0 μg/dL (range, 1–33 μg/dL), from 1 through 5 years was 9.8 μg/dL (2.8–36.4 μg/dL), and from 6 through 10 years was 6.2 μg/dL (2.2–18.6 μg/dL). IQ at 6–10 years decreased significantly only with increasing natural-log third-trimester BPb (β = −3.90; 95% confidence interval, −6.45 to −1.36), controlling for other BPb and covariates. The dose–response BPb–IQ function was log-linear, not linear–linear. Conclusions Lead exposure around 28 weeks gestation is a critical period for later child intellectual development, with lasting and possibly permanent effects. There was no evidence of a threshold; the strongest lead effects on IQ occurred within the first few micrograms of BPb. Relevance to Clinical Practice Current CDC action limits for children applied to pregnant women permit most lead-associated child IQ decreases measured over the studied BPb range.

Fetal Lead Exposure at Each Stage of Pregnancy as a Predictor of Infant Mental Development

Background The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure. Objective We studied prenatal lead exposure’s impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels. Methods We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose. Results Maternal lead levels were moderately high with a first-trimester blood lead mean (± SD) value of 7.1 ± 5.1 μg/dL and 14% of values ≥10 μg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores. Conclusions Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood.

In Utero p,p′-DDE Exposure and Infant Neurodevelopment: A Perinatal Cohort in Mexico

Background Evidence suggests that p,p′-dichlorodiphenyldichloroethene (DDE) affects neurodevelopment in infants, although a critical exposure window has not yet been identified. Objectives Our goal was to assess the prenatal DDE exposure window and its effect on the psychomotor development index (PDI) and mental development index (MDI) during the first year of life. Methods We recruited 244 children whose pregnancies and deliveries were uncomplicated, and whose mothers were monitored throughout the pregnancy. Participating mothers were not occupationally exposed to DDT (dichlorodiphenyltrichloroethane) but were residents of a zone in Mexico with endemic malaria. We measured serum levels of DDE before pregnancy and during each trimester of the pregnancy. We evaluated PDI and MDI of the Bayley Scales for Infant Development (BSID-II), at 1, 3, 6, and 12 months of age. We adjusted for quality of the home environment and maternal intellectual coefficient (IQ). We used generalized mixed-effects models for statistical analysis. Results Third-trimester DDE level (7.8 ± 2.8 ppb) was significantly higher than the level at baseline, first, and second trimesters, but the differences never exceeded 20%. Only DDE levels during the first trimester of pregnancy were associated with a significant reduction in PDI (every doubled increase of DDE level reduced the PDI 0.5 points). DDE was not associated with MDI. Conclusions A critical window of exposure to DDE in utero may be the first trimester of the pregnancy, and psychomotor development is a target of this compound. Residues of DDT metabolites may present a risk of developmental delay for years after termination of DDT use.

Early postnatal blood manganese levels and children's neurodevelopment.

Background: Recent evidence suggests that low-level environmental exposure to manganese adversely affects child growth and neurodevelopment. Previous studies have addressed the effects of prenatal exposure, but little is known about developmental effects of early postnatal exposure. Methods: We studied 448 children born in Mexico City from 1997 through 2000, using a longitudinal study to investigate neurotoxic effects of early-life manganese exposure. Archived blood samples, collected from children at 12 and 24 months of age, were analyzed for manganese levels using inductively coupled plasma mass spectrometry. Mental and psychomotor development were scored using Bayley Scales of Infant Development at 6-month intervals between 12 and 36 months of age. Results: At 12 months of age, the mean (SD) blood manganese level was 24.3 (4.5) &mgr;g/L and the median was 23.7 &mgr;g/L; at 24 months, these values were 21.1 (6.2) &mgr;g/L and 20.3 &mgr;g/L, respectively. Twelve- and 24-month manganese concentrations were correlated (Spearman correlation = 0.55) and levels declined over time (&bgr; = −5.7 [95% CI = −6.2 to −5.1]). We observed an inverted U-shaped association between 12-month blood manganese and concurrent mental development scores (compared with the middle 3 manganese quintiles, for the lowest manganese quintile, &bgr; = −3.3 [−6.0 to −0.7] and for the highest manganese quintile, &bgr; = −2.8 [−5.5 to −0.2]). This 12-month manganese effect was apparent but diminished with mental development scores at later ages. The 24-month manganese levels were not associated with neurodevelopment. Conclusions: These results suggest a possible biphasic dose-response relationship between early-life manganese exposure at lower exposure levels and infant neurodevelopment. The data are consistent with manganese as both an essential nutrient and a toxicant.

Associations of Early Childhood Manganese and Lead Coexposure with Neurodevelopment

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals. Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone. Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II. Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels. Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.

Effect of Maternal Bone Lead on Length and Head Circumference of Newborns and 1-Month-Old Infants

Abstract The authors evaluated the effects that maternal bone lead stores have in anthropometry at birth in 223 mother-infant pairs. The participants were recruited between April and November 1994. Anthropometric data were collected within the first 12 hr following delivery. Maternal information was obtained 1 mo after delivery occurred. Bone lead burden was determined with in-vivo K-x-ray fluorescence of the tibia (cortical bone) and the patella (trabecular bone). The authors transformed anthropometric measurements to an ordinal 5-category scale, and the association of measurements with other factors was evaluated with ordinal logistic-regression models. Mean bone lead levels were 9.8 μg/gm bone mineral and 14.4 μg/gm bone mineral for the tibia and patella, respectively. Birth length of newborns decreased as tibia lead levels increased. Compared with women in the lower quintiles of the distribution of tibia lead, those in the upper quintile had a 79% increase in risk of having a lower birth length newborn (odds ratio = 1.79; 95% confidence interval = 1.10, 3.22). The authors adjusted by birth weight, and the effect was attenuated—but nonetheless significant. Patella lead was positively and significantly related to the risk of a low head circumference score; this score remained unaffected by inclusion of birth weight. The authors estimated the increased risk to be 1.02 per μg lead/gm bone mineral (95% confidence interval = 1.01, 1.04 per μg lead/gm bone mineral). Odds ratios did not vary substantially after the authors adjusted for birth weight and other important determinants of head circumference.

Maternal MTHFR 677C>T genotype and dietary intake of folate and vitamin B12: their impact on child neurodevelopment

Abstract Using the Bayley test, the mental and psychomotor development in a cohort of 253 children were evaluated. Maternal dietary intake of vitamin B12 and folate was assessed from a semiquantitative questionnaire administered during the first trimester of pregnancy. Maternal genotypes of MTHFR (677C>T and 1298A>C), were ascertained by PCR-RFLP. The 677T and 1298C variant alleles were present in 59% and 10% of participants, respectively. A dietary deficiency of vitamin B12 was negatively associated with mental development (β = −1.6; 95% CI = −2.8 to −0.3). In contrast, dietary intake of folate (< 400 mg/day) reduced the mental development index only among children of mothers who were carriers of the TT genotype (β = −1.8; 95% CI = −3.6 to −0.04; P for interaction = 0.07). Vitamin B12 and folate supplementation during pregnancy could have a favorable impact on the mental development of children during their first year of life, mainly in populations that are genetically susceptible.

Erythrocyte cell membrane phospholipid levels compared against reported dietary intakes of polyunsaturated fatty acids in pregnant Mexican women.

OBJECTIVE To evaluate the validity of a food-frequency questionnaire (FFQ) for assessment of the dietary intakes of polyunsaturated fatty acids (PUFAs) against a biochemical marker of fat intake, erythrocyte cell membrane phospholipid levels, during pregnancy. DESIGN Cross-sectional analysis. SETTING Developmental Neurobiology Department, National Institute of Perinatology, Mexico City. SUBJECTS One hundred forty-six healthy pregnant women during the last trimester of pregnancy. Among women enrolled, the first 35 pregnant women (24%) had their erythrocytes analysed for fatty acid status. METHODS We administered an FFQ and compared intakes of PUFAs against their erythrocyte cell membrane concentrations, processed by gas chromatography. RESULTS Pearson correlation coefficients among alpha-linolenic acid (ALN), docosahexaenoic acid (DHA) and eicosapentaenoic acid in erythrocyte cell membranes against their crude dietary counterparts were 0.32, 0.35 and 0.36 (each P < 0.05). In a simple linear regression, erythrocyte DHA and arachidonic acid (AA) were significantly related to their respective dietary intakes (beta = 0.30, 95% confidence interval (CI): 0.007-0.60, P=0.045 for DHA; beta = 0.49, 95% CI: 0.010-0.98, P=0.044 for AA). Erythrocyte cell membrane ALN concentration (%/total) was only marginally related to ALN dietary intake (mg day-1) (beta = 0.52, 95% CI: -0.020-1.10, P=0.061). However, after adjustment for long-chain n-3 PUFA/AA, this association reached significance (beta = 0.44, 95% CI: 0.026-0.825, P=0.038). Main dietary sources for n-3 PUFAs were canned tuna fish and fresh catfish; for n-6 these were eggs and cows milk. The use of this FFQ in these pregnant Mexican women provided estimates of average long-term intakes of PUFAs and correlated reasonably well with their erythrocyte cell membrane phospholipid status. However, we need to consider that, during pregnancy, there is a faster turnover of PUFAs from fat storage that may modify the profile of erythrocyte PUFAs and lower the correlation between dietary intake and erythrocyte PUFAs.

Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age.

BACKGROUND Previous studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life. OBJECTIVES To evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24-36 months of age. METHODS This analysis was conducted on the first three years of life among a subsample of 136 mother-child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di-2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36 months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level. RESULTS No significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (β=-2.11 [95% CI: -3.73, -0.49]), MEHHP (β=-1.89 [95% CI: -3.64, -0.15]), MEOHP (β=-1.80 [95% CI: -3.58, -0.03]) MECPP (β=-2.52 [95% CI: -4.44, -0.61]), and ΣDEHP (β=-3.41 [95% CI: -5.26, -1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (β=1.79 [95% CI: 0.14, 3.45]) and MCPP (β=1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls. CONCLUSION This study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment.