Bruce P. Lanphear

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.

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis

Multiple theories of Attention-Deficit/Hyper- activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.

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.

Association of prenatal and childhood blood lead concentrations with criminal arrests in early adulthood

Background Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses. Methods and Findings Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Childrens Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead. Conclusions Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.

Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors

OBJECTIVEnTo examine the joint effects of a dopamine transporter (DAT) polymorphism and maternal prenatal smoking on childhood hyperactivity-impulsivity and inattentiveness.nnnSTUDY DESIGNnA cohort of 161 children was followed prospectively from age 6 months to 60 months. Primary outcomes were the DSM-IV hyperactive-impulsive and inattentive scales of the Conners Parent Rating Scale Revised-Long Version (CPRS R:L). A secondary outcome was the oppositional scale. Predictors included DAT genotype and maternal report of prenatal smoking. Children homozygous for the 480-bp DAT allele (DAT +/+) were compared with all other children (DAT +/- or -/-).nnnRESULTSnIn multivariate analyses, children with both prenatal smoke exposure and the DAT +/+ genotype had significantly elevated hyperactive-impulsive scores (beta, 7.5; SE, 2.9; P<.01) compared with children with no smoke exposure and DAT +/- or -/-. Inattentive scores were not significantly elevated in this group, but oppositional scores were a full standard deviation higher. Neither prenatal smoke exposure alone nor DAT +/+ genotype alone was significantly associated with increased scores.nnnCONCLUSIONSnChild hyperactivity-impulsivity and oppositional behaviors were associated with a DAT polymorphism but only when the child also had exposure to maternal prenatal smoking. This study emphasizes the importance of incorporating environmental cofactors in genetic studies of attention deficit hyperactivity disorder.

Decreased Brain Volume in Adults with Childhood Lead Exposure

Background Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments. Methods and Findings Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation. Conclusions Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to leads effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.

Hepatitis C virus infection in healthcare workers: risk of exposure and infection

OBJECTIVESnTo determine the incidence of hepatitis C virus (HCV) infection among healthcare workers (HCWs) at a university hospital, the proportion of HCWs having non-A, non-B hepatitis (NANBH) who were anti-HCV positive, and the rate of HCV transmission following a HCV-positive needlestick injury.nnnDESIGNnLongitudinal analysis of a dynamic (cohort) population.nnnMEASUREMENTSnFrom 1980 through 1989, HCWs who had clinical NANBH were identified, and from 1987 through 1989, HCWs who reported a blood or body fluid exposure and the patients who were the source of the exposure were screened for antibodies to HCV.nnnSETTINGnA 732-bed, university hospital and outpatient clinics.nnnRESULTSnOver the 10-year period, six cases of occupationally acquired NANBH were observed, for an incidence of 21 cases per 100,000 HCWs per year (standardized incidence ratio, 2.96; 95% confidence interval [CI95], 1.83 to 4.36). Four of the six cases were confirmed to be HCV infection. From 1987 through 1989, 176 (12.7%) of 1,387 patients who were the source of an exposure were anti-HCV positive. Exposures that occurred in the emergency department were more likely to be anti-HCV positive than were exposures from all other locations (relative risk [RR] = 1.7; P = 0.009). Of HCWs who had an HCV-positive needlestick injury and whose serum had been tested for anti-HCV at least 5 months after the exposure, 3 (6.0%) of 50 seroconverted. From 1987 through 1989, the incidence of HCV infection among HCWs was 54 cases per 100,000 HCWs per year.nnnCONCLUSIONnThe incidence of clinical NANBH among HCWs in this study is approximately three times higher than that of non-HCWs. HCWs are at significant risk for exposure to and acquisition of HCV.

Lead-contaminated house dust and urban children's blood lead levels.

OBJECTIVESnThis study assessed the relationship between lead-contaminated house dust and urban childrens blood lead levels.nnnMETHODSnA random-sample survey was used to identify and enroll 205 children, 12 to 31 months of age, who had resided in the same house since at least 6 months of age. Childrens blood and household dust, water, soil, and paint were analyzed for lead, and interviews were conducted to ascertain risk factors for elevated blood lead (> or = 10 micrograms/dL).nnnRESULTSnChildrens mean blood lead level was 7.7 micrograms/dL. In addition to dust lead loading (micrograms of lead per square foot), independent predictors of childrens blood lead were Black race, soil lead levels, ingestion of soil or dirt, lead content and condition of painted surfaces, and water lead levels. For dust lead standards of 5 micrograms/sq ft, 20 micrograms/sq ft, and 40 micrograms/sq ft on noncarpeted floors, the estimated percentages of children having blood lead levels at or above 10 micrograms/dL were 4%, 15%, and 20%, respectively, after adjusting for other significant covariates.nnnCONCLUSIONSnLead-contaminated house dust is a significant contributor to lead intake among urban children who have low-level elevations in blood lead. A substantial proportion of children may have blood lead levels of at least 10 micrograms/dL at dust lead levels considerably lower than current standards.

Assessing the role of influential mentors in the research development of primary care fellows.

Purpose. To assess the association between mentorship and both subsequent research productivity and career development among primary care research fellows. Method. In 1998, using a self-administered questionnaire, the authors surveyed 215 fellows who graduated from 25 National Research Service Award (NRSA) primary care research programs between 1988–1997 to assess quantitative aspects and qualitative domains of their mentorship experience during fellowship training. Results. A total of 139 fellows (65%) responded to mentorship questions a median of four years after their fellowship. Thirty-seven fellows (26.6%) did not have an influential mentor, 42 (30.2%) reported influential but not sustained mentorship, and 60 (43.2%) had influential and sustained mentorship. Individuals with influential mentorship spent more time conducting research (p = .007), published more papers (p = .003), were more likely to be the principal investigator on a grant (p = .008), and more often provided research mentorship to others (72.5% versus 66.7% of those with unsustained mentorship, and 36.4% of those with no influential mentor, p = .008). After controlling for other predictors, influential and sustained mentorship remained an important determinant of career development in research. On qualitative analysis, fellows identified three important domains of mentorship: the relationship between mentor and fellow (such as guidance and support), professional attributes of the mentor (such as reputation), and personal attributes of the mentor (such as availability and caring). Conclusions. Influential and sustained mentorship enhances the research activity of primary care fellows. Research training programs should develop and support their mentors to ensure that they assume this critical role.

Association of environmental toxicants and conduct disorder in U.S. children: NHANES 2001-2004.

Objective The purpose of this study was to examine the association of tobacco smoke and environmental lead exposure with conduct disorder (CD). Methods The National Health and Nutrition Examination Survey (NHANES) 2001–2004 is a nationally representative cross-sectional sample of the noninstitutionalized U.S. population. We examined the association of prenatal tobacco, postnatal tobacco, and environmental lead exposure with CD in children 8–15 years of age (n = 3,081). We measured prenatal tobacco exposure by parent report of cigarette use during pregnancy, and postnatal tobacco using serum cotinine levels. We assessed lead exposure using current blood lead concentration. Parents completed the Diagnostic Interview Schedule for Children to determine whether their children met criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV ) for CD. Results Overall, 2.06% of children met DSM-IV criteria for CD in the past year, equivalent to 560,000 U.S. children 8–15 years of age. After adjustment, prenatal tobacco exposure was associated with increased odds for CD [odds ratio (OR) = 3.00; 95% confidence interval (CI), 1.36–6.63]. Increased blood lead levels (fourth vs. first quartile) and serum cotinine levels (fifth vs. first quintile) were associated with an 8.64-fold (95% CI, 1.87–40.04) and 9.15-fold (95% CI, 1.47–6.90) increased odds of meeting DSM-IV CD criteria. Increasing serum cotinine levels and blood lead levels were also associated with increased prevalence of CD symptoms (symptom count ratio, lead: 1.73; 95% CI, 1.23–2.43; symptom count ratio, cotinine: 1.97; 95% CI, 1.15–3.40). Conclusions These results suggest that prenatal tobacco exposure and environmental lead exposure contribute substantially to CD in U.S. children.