Person:

Bellinger, David

Background: Given the association between iron deficiency and lead absorption, we hypothesized that variants in iron metabolism genes would predict higher blood lead levels in young children. Objective: We examined the association between common missense variants in the hemochromatosis (HFE) and transferrin (TF) genes and blood lead levels in 422 Mexican children. Methods: Archived umbilical cord blood samples were genotyped for HFE (H63D and C282Y) and TF (P570S) variants. Blood lead was measured at 24, 30, 36, 42, and 48 months of age. A total of 341 subjects had at least one follow-up blood lead level available and data available on covariates of interest for inclusion in the longitudinal analyses. We used random-effects models to examine the associations between genotype (HFE, TF, and combined HFE + TF) and repeated measures of blood lead, adjusting for maternal blood lead at delivery and child’s concurrent anemia status. Results: Of 422 children genotyped, 17.7, 3.3, and 18.9% carried the HFE H63D, HFE C282Y, and TF P570S variants, respectively. One percent of children carried both the HFE C282Y and TF P570S variants, and 3% of children carried both the HFE H63D and TF P570S variants. On average, carriers of either the HFE (β = 0.11, p = 0.04) or TF (β = 0.10, p = 0.08) variant had blood lead levels that were 11% and 10% higher, respectively, than wild-type subjects. In models examining the dose effect, subjects carrying both variants (β = 0.41, p = 0.006) had blood lead 50% higher than wild-type subjects and a significantly higher odds of having a blood lead level > 10 μg/dL (odds ratio = 18.3; 95% confidence interval, 1.9–177.1). Conclusions: Iron metabolism gene variants modify lead metabolism such that HFE variants are associated with increased blood lead levels in young children. The joint presence of variant alleles in the HFE and TF genes showed the greatest effect, suggesting a gene-by-gene-by-environment interaction.

Background: A concern persists that children’s exposure to mercury vapor from dental amalgams produces neurotoxicity. Objective: Our goal was to compare the neuropsychological function of children, without prior exposure to dental amalgam, whose caries were repaired using either dental amalgam or mercury-free composite materials. Methods: We conducted a randomized controlled trial involving 534 6- to 10-year-old urban and rural children who were assessed yearly for 5 years using a battery of tests of intelligence, achievement, language, memory, learning, visual–spatial skills, verbal fluency, fine motor function, problem solving, attention, and executive function. Results: Although the mean urinary mercury concentration was greater among children in the amalgam group than the composite group (0.9 vs. 0.6 μg/g creatinine), few significant differences were found between the test scores of children in the two groups. The differences found were inconsistent in direction. Analyses using two cumulative exposure indices—surface years of amalgam and urinary mercury concentration—produced similar results. Conclusions: Exposure to elemental mercury in amalgam at the levels experienced by the children who participated in the trial did not result in significant effects on neuropsychological function within the 5-year follow-up period.

Background: Neurotoxic effects are known to occur with inhalation of manganese particulates, but very few data are available on exposure to Mn in water. We undertook a pilot study in a community in Québec (Canada) where naturally occurring high Mn levels were present in the public water system. Our objective was to test the hypothesis that greater exposure to Mn via drinking water would be reflected in higher Mn content in hair which, in turn, would be associated with increased level of hyperactive behaviors. Methods: Forty-six children participated in the study, 24 boys and 22 girls, 6–15 years of age (median, 11 years). Their homes received water from one of two wells (W) with different Mn concentrations: W1: mean 610 μg/L; W2: mean 160 μg/L. The Revised Conners’ Rating Scale for parents (CPRS-R) and for teachers (CTRS-R) were administered, providing T-scores on the following subscales: Oppositional, Hyperactivity, Cognitive Problems/Inattention, and ADHD Index. Results: Children whose houses were supplied by W1 had higher hair Mn (MnH) than those supplied by W2 (mean 6.2 ± 4.7 μg/g vs. 3.3 ± 3.0 μg/g, p = 0.025). MnH was significantly associated with T-scores on the CTRS-R Oppositional (p = 0.020) and Hyperactivity (p = 0.002) subscales, after adjustment for age, sex, and income. All children with Oppositional and Hyperactivity T-scores ≥ 65 had MnH > 3.0 μg/g. Conclusions: The findings of this pilot study are sufficiently compelling to warrant more extensive investigations into the risks of Mn exposure in drinking water.

Background: The impact of environmental chemicals on children’s neurodevelopment is sometimes dismissed as unimportant because the magnitude of the impairments are considered to be clinically insignificant. Such a judgment reflects a failure to distinguish between individual and population risk. The population impact of a risk factor depends on both its effect size and its distribution (or incidence/prevalence). Objective: The objective was to develop a strategy for taking into account the distribution (or incidence/prevalence) of a risk factor, as well as its effect size, in order to estimate its population impact on neurodevelopment of children. Methods: The total numbers of Full-Scale IQ points lost among U.S. children 0–5 years of age were estimated for chemicals (methylmercury, organophosphate pesticides, lead) and a variety of medical conditions and events (e.g., preterm birth, traumatic brain injury, brain tumors, congenital heart disease). Discussion: Although the data required for the analysis were available for only three environmental chemicals (methylmercury, organophosphate pesticides, lead), the results suggest that their contributions to neurodevelopmental morbidity are substantial, exceeding those of many nonchemical risk factors. Conclusion: A method for comparing the relative contributions of different risk factors provides a rational basis for establishing priorities for reducing neurodevelopmental morbidity in children.

Background: Lead exposure has long been associated with deficits in IQ among children. However, few studies have assessed the impact of lead on specific domains of behavior and cognition. Objective: We evaluated the associations between lead and different domains of neurobehavior and their relative sensitivity to lead. Methods: We determined blood lead levels using a LeadCare instrument in 756 children 3–7 years of age attending pre- and elementary schools in Chennai, India. Anxiety, social problems, inattention, hyperactivity, and attention deficit hyperactivity disorder (ADHD), as well as executive function were assessed in children by their schoolteachers using Conners’ Teacher Rating Scales-39, Conners’ ADHD/Diagnostic and Statistical Manual for Mental Disorders, 4th Edition Scales (CADS), and the Behavior Rating Inventory of Executive Function questionnaires, with higher scores denoting worse behavior. Analyses were carried out using multivariate generalized estimating equations with comparisons of outcome Z-scores to assess the relative strengths of the associations between log-blood lead and the different domains of behavior. Results: Mean blood lead level was 11.4 ± 5.3 μg/dL. Blood lead was associated with higher anxiety (β = 0.27, p = 0.01), social problems (β = 0.20, p = 0.02), and higher scores in the ADHD index (β = 0.17; p = 0.05). The effect estimate was highest for global executive function (β = 0.42; p < 0.001). Conclusions: Higher blood lead levels in this population of young children is associated with increased risk of neurobehavioral deficits and ADHD, with executive function and attention being particularly vulnerable domains to the effects of lead.

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.