Richard L. Canfield

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.

Blood lead concentrations < 10 microg/dL and child intelligence at 6 years of age.

Background Few studies provide data directly relevant to the question of whether blood lead concentrations < 10 μg/dL adversely affect children’s cognitive function. Objective We examined the association between blood lead concentrations assessed throughout early childhood and children’s IQ at 6 years of age. Methods Children were followed from 6 months to 6 years of age, with determination of blood lead concentrations at 6, 12, 18, and 24 months, and 3, 4, 5, and 6 years of age. At 6 years of age, intelligence was assessed in 194 children using the Wechsler Preschool and Primary Scale of Intelligence–Revised. We used general linear and semiparametic models to estimate and test the association between blood lead concentration and IQ. Results After adjustment for maternal IQ, HOME scale scores, and other potential confounding factors, lifetime average blood lead concentration (mean = 7.2 μg/dL; median = 6.2 μg/dL) was inversely associated with Full-Scale IQ (p = 0.006) and Performance IQ scores (p = 0.002). Compared with children who had lifetime average blood lead concentrations < 5 μg/dL, children with lifetime average concentrations between 5 and 9.9 μg/dL scored 4.9 points lower on Full-Scale IQ (91.3 vs. 86.4, p = 0.03). Nonlinear modeling of the peak blood lead concentration revealed an inverse association (p = 0.003) between peak blood lead levels and Full-Scale IQ down to 2.1 μg/dL, the lowest observed peak blood lead concentration in our study. Conclusions Evidence from this cohort indicates that children’s intellectual functioning at 6 years of age is impaired by blood lead concentrations well below 10 μg/dL, the Centers for Disease Control and Prevention definition of an elevated blood lead level.

Prenatal Phthalate Exposure Is Associated with Childhood Behavior and Executive Functioning

Background Experimental and observational studies have reported biological consequences of phthalate exposure relevant to neurodevelopment. Objective Our goal was to examine the association of prenatal phthalate exposure with behavior and executive functioning at 4–9 years of age. Methods The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urines were collected and analyzed for phthalate metabolites. Children (n = 188, n = 365 visits) were assessed for cognitive and behavioral development between the ages of 4 and 9 years. Results In multivariate adjusted models, increased loge concentrations of low molecular weight (LMW) phthalate metabolites were associated with poorer scores on the aggression [β = 1.24; 95% confidence interval (CI), 0.15– 2.34], conduct problems (β = 2.40; 95% CI, 1.34–3.46), attention problems (β = 1.29; 95% CI, 0.16– 2.41), and depression (β = 1.18; 95% CI, 0.11–2.24) clinical scales; and externalizing problems (β = 1.75; 95% CI, 0.61–2.88) and behavioral symptom index (β = 1.55; 95% CI, 0.39–2.71) composite scales. Increased loge concentrations of LMW phthalates were also associated with poorer scores on the global executive composite index (β = 1.23; 95% CI, 0.09–2.36) and the emotional control scale (β = 1.33; 95% CI, 0.18– 2.49). Conclusion Behavioral domains adversely associated with prenatal exposure to LMW phthalates in our study are commonly found to be affected in children clinically diagnosed with conduct or attention deficit hyperactivity disorders.

Prenatal Exposure to Organophosphates, Paraoxonase 1, and Cognitive Development in Childhood

Background: Prenatal exposure to organophosphate pesticides has been shown to negatively affect child neurobehavioral development. Paraoxonase 1 (PON1) is a key enzyme in the metabolism of organophosphates. Objective: We examined the relationship between biomarkers of organophosphate exposure, PON1, and cognitive development at ages 12 and 24 months and 6–9 years. Methods: The Mount Sinai Children’s Environmental Health Study enrolled a multiethnic prenatal population in New York City between 1998 and 2002 (n = 404). Third-trimester maternal urine samples were collected and analyzed for organophosphate metabolites (n = 360). Prenatal maternal blood was analyzed for PON1 activity and genotype. Children returned for neurodevelopment assessments ages 12 months (n = 200), 24 months (n = 276), and 6–9 (n = 169) years of age. Results: Prenatal total dialkylphosphate metabolite level was associated with a decrement in mental development at 12 months among blacks and Hispanics. These associations appeared to be enhanced among children of mothers who carried the PON1 Q192R QR/RR genotype. In later childhood, increasing prenatal total dialkyl- and dimethylphosphate metabolites were associated with decrements in perceptual reasoning in the maternal PON1 Q192R QQ genotype, which imparts slow catalytic activity for chlorpyrifos oxon, with a monotonic trend consistent with greater decrements with increasing prenatal exposure. Conclusion: Our findings suggest that prenatal exposure to organophosphates is negatively associated with cognitive development, particularly perceptual reasoning, with evidence of effects beginning at 12 months and continuing through early childhood. PON1 may be an important susceptibility factor for these deleterious effects.

Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study.

Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined a priori models of Omega-3 and Omega-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Omega-3 LCPUFA and negatively associated with the ratio of Omega-6/Omega-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Omega-6/Omega-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Omega-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.

Neurodevelopmental Effects of Maternal Nutritional Status and Exposure to Methylmercury from Eating Fish during Pregnancy

Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537 g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9 ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and childrens scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.

Information processing through the first year of life : a longitudinal study using the visual expectation paradigm

This Monograph uses a developmental function approach to describe age-related change and individual differences in infant information processing during the first year of life. The Visual Expectation Paradigm (VExP) is used to measure speed of information processing, response variability, and expectancy formation. Eye-movement reaction times and anticipatory saccades were gathered from 13 infants assessed monthly from 2 to 9 months and then again at 12 months. Analysis of response patterns demonstrated the applicability of the paradigm throughout the age range studied. Converging operations strongly indicate that the traditional estimate of the minimum time required for infants to initiate a saccade to a peripheral stimulus may be as much as 100 milliseconds (ms) too long. Moreover, the newly estimated minimum of 133 ms does not appear to change during the 2-12-month period. Reanalysis of the present data and past research reveals that the new, shorter minimum reaction time is unlikely to affect findings based on mean reaction time. However, using the traditional minimum reaction time will inflate estimates of percentage anticipation, especially in infants older than 5 months. Group and individual growth curves are described through quantitative models of four variables: reaction time, standard deviation of reaction time, percentage anticipation, and anticipation latency. Developmental change in reaction time was best described by an asymptotic exponential function, and evidence for a local asymptote during infancy is presented. Variability in reaction time was found to decline with age, independent of mean reaction time, and was best described by a polynomial function with linear and quadratic terms. Anticipation showed little lawful change during any portion of the age span, but latency to anticipate declined linearly throughout the first year. Stability of individual differences was strong between consecutive assessments of mean reaction time. For nonconsecutive assessments, stability was found only for the 6-12-month period. Month-to-month stability was inconsistent for reaction-time variability and weak for both anticipation measures. Analyses of individual differences in growth curves were carried out using random regressions for the polynomial models. The only significant individual difference (in growth curves) was found for reaction-time variability. Parameter estimates from the exponential models for reaction time suggested two or three developmental patterns with different exponential trajectories. This finding indicates that the strong form of the exponential growth hypothesis, which states that processing speed develops at the same rate for all individuals, does not hold for the first year of life. In the concluding chapter, Grices Variable Criterion Model (Grice, 1968) is used to integrate three key findings: regular age changes in mean reaction time and variability but no age change in the minimum reaction time. It is argued that the rate of growth of sensory-detection information is developmentally constant during much of the first year but that age changes occur in the level and spread of the distribution of response threshold values. The unique strengths of the paradigm are discussed, and future directions are suggested for further developing the paradigm itself and for using it as a tool to study broad issues in infant cognition.

Impaired neuropsychological functioning in lead-exposed children.

Neuropsychological functions were assessed in 174 children participating in a longitudinal study of low-level lead exposure. At age 5 1/2 years, children were administered the Working Memory and Planning Battery of the Cambridge Neuropsychological Testing Automated Battery. Measures of sociodemographic characteristics of the family, prenatal and perinatal risk, quality of caregiving and crowding in the home, and maternal and child intelligence were used as covariates to test the hypothesis that children with higher lifetime average blood lead concentrations would perform more poorly on tests of working memory, attentional flexibility, and planning and problem solving. The lifetime average blood lead level in this sample was 7.2 micrograms per deciliter (μg/dL; range: 0-20 μg/dL). Children with greater exposure performed more poorly on tests of executive processes. In both bivariate and multivariate analyses, children with higher lifetime average blood lead concentrations showed impaired performance on the tests of spatial working memory, spatial memory span, intradimensional and extradimensional shifts, and an analog of the Tower of London task. Many of the significant associations remained after controlling for childrens intelligence test scores, in addition to the other covariates. These findings indicate that the effects of pediatric lead exposure are not restricted to global indexes of general intellectual functioning, and executive processes may be at particular risk of lead-induced neurotoxicity.

The Effect of Maternal PTSD Following in Utero Trauma Exposure on Behavior and Temperament in the 9-Month-Old Infant

Abstract:  In view of evidence of in utero glucocorticoid programming, and our prior observation of lower cortisol levels in 9‐month‐old infants of mothers with posttraumatic stress disorder (PTSD) compared to mothers without PTSD, we undertook an examination of the effect of in utero maternal stress, as determined by PTSD symptom severity, and maternal cortisol levels on behavioral outcomes in the infant. Methods: Ninety‐eight pregnant women directly exposed to the World Trade Center (WTC) collapse on 9/11 provided salivary cortisol samples and completed a PTSD symptom questionnaire and a behavior rating scale to measure infant temperament, including distress to limitations, and response to novelty. Results: Mothers who developed PTSD in response to 9/11 had lower morning and evening salivary cortisol levels, compared to mothers who did not develop PTSD. Maternal morning cortisol levels were inversely related to their rating of infant distress and response to novelty (i.e., loud noises, new foods, unfamiliar people). Also, mothers who had PTSD rated their infants as having greater distress to novelty than did mothers without PTSD (t= 2.77, df= 61, P= 0.007). Conclusion: Longitudinal studies are needed to determine how the association between maternal PTSD symptoms and cortisol levels and infant temperament reflect genetic and/or epigenetic mechanisms of intergenerational transmission.

Low-Level Lead Exposure, Executive Functioning, and Learning in Early Childhood

The current paper presents evidence relating low-level lead exposure to impaired executive functioning in young children. Using the Shape School task, we assessed focused attention, attention switching, working memory, and the ability to inhibit automatic responses in a cohort of 170 children. Participants performed the Shape School task at both 48 and 54 months of age; the mean blood lead level was 6.49 µg/dl at 48 months. After controlling for a wide range of sociodemographic, prenatal, and perinatal variables, blood lead level was negatively associated with children’s focused attention while performing the tasks, efficiency at naming colors, and inhibition of automatic responding. In addition, children with higher blood lead levels completed fewer phases of the task and knew fewer color and shape names. There was no association between blood lead and performance on the most difficult tasks, those requiring attention switching or the combination of inhibition and switching. Children’s IQ scores were strongly associated with blood lead and Shape School performance, and when entered as a covariate, only color knowledge and the number of tasks completed remained significant. Results provide only weak support for impaired executive functioning, but the deficits in color knowledge may indicate a primary sensory deficit or difficulty with forming conditional associations, both implicating disruptions in dopamine system function.