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Background: East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community., Methods: Children 7-9 years of age from East Liverpool and its surrounding communities, were enrolled (N=106) in the Communities Actively Researching Exposure Study from between March 2013-June 2014. Blood and hair were analyzed for Mn and lead, and serum was analyzed for cotinine. We used linear regression to assess associations between biological measures and IQ subscale scores., Results: Geometric mean blood lead (n=67), blood Mn (n=66), hair Mn (n=98), and serum cotinine (n=69) concentrations were 1.13±1.96μg/dL, 10.06±1.30μg/L, and 360.22±2.17ng/g, 0.76±6.12μg/L respectively. After adjusting for potential confounders, hair Mn was negatively associated with Full Scale IQ., Conclusions: Hair Mn was negatively associated with child IQ scores. Community partners were instrumental in the conception and implementation of this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk., Objectives: The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development., Methods: Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression., Results: Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = -0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (β = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (β = -0.0009; 95% CI: -0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = -0.0013; 95% CI: -0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (β = -0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (β = -0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months., Conclusions: Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood., Citation: Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666-673; http://dx.doi.org/10.1289/ehp.1408577.

Objective: To investigate the relationship between secondhand tobacco smoke (SHS) exposure and neuromotor function in children., Study Design: We studied 404 children aged 7-9 years who were exposed to SHS and other environmental neurotoxicants. Parents reported smoking habits, and serum cotinine levels were measured in children to determine SHS exposure. The Halstead-Reitan Finger Oscillation Test, Purdue Grooved Pegboard Test-Kiddie version, and Bruininks-Oseretsky Test of Motor Proficiency 2-Short Form were used to assess neuromotor function. Multivariable regression models that accounted for potential confounders were used to evaluate the associations., Results: Approximately 50% of the children were exposed to SHS based on serum cotinine measures. Exposure to SHS was significantly associated with motor impairment in children, including diminished visuomotor coordination (P = .01), fine motor integration (P = .01), balance (P = .02), and strength (P = .04) after adjusting for exposures to lead and manganese, age, sex, body mass index, measures of parental cognitive abilities, parental education, and quality of home environment., Conclusion: SHS is a neurotoxicant that may be associated with impaired childhood neuromotor function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb)-exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 microg/L and 0.52 microg/L and post-treatment concentrations were 0.51 microg/L and 0.48 microg/L for placebo and succimer groups, respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable., (2009 Elsevier Inc. All rights reserved.)

Objective: Some children in the United States continue to be exposed to levels of lead that increase their risk for lowered intellectual functioning and behavior problems. It is unclear whether chelation therapy can prevent or reverse the neurodevelopmental sequelae of lead toxicity. The objective of this study was to determine whether chelation therapy with succimer (dimercaptosuccinic acid) in children with referral blood lead levels between 20 and 44 microg/dL (0.96-2.12 micromol/L) at 12 to 33 months of age has neurodevelopmental benefits at age 7 years., Methods: The Treatment of Lead-Exposed Children (TLC) study is a randomized, double-blind, placebo-controlled trial that was conducted between September 1994 and June 2003 in Philadelphia, PA; Newark, NJ; Cincinnati, OH; and Baltimore, MD. Of 1854 referred children who were between the ages of 12 to 33 months and screened for eligibility, 780 were randomized to the active drug and placebo groups stratified by clinical center, body surface area, blood lead level, and language spoken at home. At 7 years of age, 647 subjects remained in the study. Participants were randomly assigned to receive oral succimer or placebo. Up to 3 26-day courses of succimer or placebo therapy were administered depending on response to treatment in those who were given active drug. Eighty-nine percent had finished treatment by 6 months, with all children finishing by 13 months after randomization. All participants received residential lead hazard control measures before treatment. TLC subjects also received a daily multivitamin supplement before and after treatment(s) with succimer or placebo. Scores on standardized neuropsychological measures that tap cognition, behavior, learning and memory, attention, and neuromotor skills were measured., Results: Chelation therapy with succimer lowered average blood lead levels for approximately 6 months but resulted in no benefit in cognitive, behavioral, and neuromotor endpoints., Conclusion: These new follow-up data confirm our previous finding that the TLC regimen of chelation therapy is not associated with neurodevelopmental benefits in children with blood lead levels between 20 and 44 microg/dL (0.96-2.17 micromol/L). These results emphasize the importance of taking environmental measures to prevent exposure to lead. Chelation therapy with succimer cannot be recommended for children with blood lead levels between 20 and 44 microg/dL (0.96-2.12 micromol/L).

The effect of lead exposure on cognitive growth patterns was assessed in a longitudinal study of 196 children. Performances on tests of verbal comprehension and perceptual organization (Vocabulary & Block Design, Wechsler Intelligence Scales for Children) were measured at ages 6.5, 11 and 15 years. Growth curve analyses revealed that the quadratic model best described the relationship between test scores and age. Children with higher lead levels, as measured at age 15 years, demonstrated lower verbal comprehension scores over time and greater decline in their rate of Vocabulary development at age 15 years, as compared to children with lower lead levels. Lead exposure was not significantly associated with growth in perceptual organization test scores. Socioeconomic status and maternal intelligence were statistically significantly associated with growth patterns for both test scores, independent of the effects of lead. The findings suggest that lead negatively impacts the developmental progression of specific cognitive skills from childhood through adolescence.

Background: Polybrominated diphenyl ethers (PBDEs) are persistent chemicals that have been widely used as flame retardants in furniture, carpet padding, car seats, and other consumer products during the past three decades. Objective: We examined whether in utero exposure to PBDEs is associated with child cognitive function and behavior in a U.S. study sample. Methods: In a prospective birth cohort, we measured maternal serum concentrations of BDE‑47 and other PBDE congeners in 309 women at 16 weeks of gestation during 2003–2006 and followed their children in Cincinnati, Ohio. We measured cognitive and motor abilities using the Bayley Scales of Infant Development-II at ages 1, 2, and 3 years; intelligence using the Wechsler Preschool and Primary Scale of Intelligence-III at age 5 years; and children’s behaviors using the Behavioral Assessment System for Children-2 annually at ages 2–5 years. We used linear mixed models or generalized estimating equations with adjustment for potential confounders to estimate associations between these outcomes and log10-transformed PBDE concentrations. Results: The geometric mean of BDE‑47 in maternal serum (20.1 ng/g lipid) was comparable with U.S. adult national reference values. Prenatal BDE‑47 was not significantly associated with Bayley Mental or Psychomotor Development Indices at 1–3 years, but a 10-fold increase in prenatal BDE‑47 was associated with a 4.5-point decrease (95% CI: –8.8, –0.1) in Full-Scale IQ and a 3.3‑point increase (95% CI: 0.3, 6.3) in the hyperactivity score at age 5 years. Conclusions: Prenatal exposure to PBDEs was associated with lower IQ and higher hyperactivity scores in children. [ABSTRACT FROM AUTHOR]

Background: There is increasing concern about the potential effects of traffic-related air pollution (TRAP) on the developing brain. The impact of TRAP exposure on childhood behavior is not fully understood because of limited epidemiologic studies. Objective: We explored the association between early-life exposure to TRAP using a surrogate, elemental carbon attributed to traffic (ECAT), and attention deficit/hyperactivity disorder (ADHD) symptoms at 7 years of age. Methods: From the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort we collected data on exposure to ECAT during infancy and behavioral scores at 7 years of age. Children enrolled in CCAAPS had at least one atopic parent and a birth residence either < 400 m or > 1,500 m from a major highway. Children were followed from infancy through 7 years of age. ECAT exposure during the first year of life was estimated based on measurements from 27 air sampling sites and land use regression modeling. Parents completed the Behavioral Assessment System for Children, 2nd Edition, when the child was 7 years of age. ADHD-related symptoms were assessed using the Hyperactivity, Attention Problems, Aggression, Conduct Problems, and Atypicality subscales. Results: Exposure to the highest tertile of ECAT during the child's first year of life was significantly associated with Hyperactivity T-scores in the "at risk" range at 7 years of age, after adjustment [adjusted odds ratio (aOR) = 1.7; 95% CI: 1.0, 2.7]. Stratification by maternal education revealed a stronger association in children whose mothers had higher education (aOR = 2.3; 95% CI: 1.3, 4.1). Conclusions: ECAT exposure during infancy was associated with higher Hyperactivity scores in chil­dren; this association was limited to children whose mothers had more than a high school education. [ABSTRACT FROM AUTHOR]

Abstract. A total of 53 mother-infant dyads, divided into five diagnostic groups (nonaccidental trauma combined with failure-to-thrive, nonaccidental trauma combined with iron-deficiency anemia, nonaccidental trauma only, neglect only, and normal control subjects) were observed during a feeding session. Qualitative differences were found in the relational characteristics of dyads in which multiple forms of maltreatment existed. Developmental examinations revealed that infants subjected to severe abuse and neglect were significantly retarded in their mental and motor development compared with the remaining index and control groups. The results were interpreted to suggest that relational disturbances are at the core of the problem of infant maltreatment and that on the basis of interactional symptomatology, two broadly different clinical conditions have been identified. [ABSTRACT FROM AUTHOR]

Presents several letters to the editors concerning the effects of lead on child development. Correlation between neonatal blood lead concentration and neurobehavioral outcomes; Complexity of Kaufman assessment battery for children; Advantage of the Kaufman test.

Toxicological studies indicate that poly- and perfluoroalkyl substances (PFAS) may be neurotoxic, but human studies have yet to provide compelling evidence for PFAS' impact on cognitive abilities. To test whether prenatal and childhood PFAS are associated with cognitive abilities at 8 years and whether sex modifies these associations. We included 221 mother-child pairs from the Health Outcomes and Measures of the Environment (HOME) Study, a birth cohort in Cincinnati, OH (USA). We quantified PFAS in maternal serum at 16 ± 3 weeks gestation and in child serum at 3 and 8 years. We used the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) at age 8 years, assessing Full Scale IQ (FSIQ), verbal comprehension, perceptual reasoning, working memory, and processing speed. We used multiple informant models to estimate covariate-adjusted differences in WISC-IV scores by repeated ln-transformed PFAS. Prenatal and childhood perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were not associated with WISC-IV measures. We observed an increase of 4.1-points (95% CI 0.3, 8.0) and 5.7-points (95% CI 1.2, 10.2) in working memory with 1-ln unit increase in prenatal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA), respectively. In addition, PFNA at 3 years was associated with better FSIQ and perceptual reasoning. Child sex modified the relationship between prenatal PFOA and FSIQ; the association was positive in females only. Sex also modified the association between concurrent PFOS and FSIQ, with males having higher scores. We did not observe adverse associations between prenatal and childhood PFAS and cognitive function at age 8 years. • PFOS and PFHxS were not associated with Full Scale IQ (FSIQ) at 8 years. • Prenatal PFOA and PFNA were positively associated with working memory at 8 years. • Child sex modified prenatal PFOA associations, with higher FSIQ scores in females. • We observed higher scores on several WISC scales in males, but not in females. • Findings do not support that PFAS are adversely associated with cognitive function. [ABSTRACT FROM AUTHOR]

Background Exposure to perfluoroalkyl substances (PFASs) may impact children's neurodevelopment. Objective To examine the association of prenatal and early childhood serum PFAS concentrations with children's reading skills at ages 5 and 8 years. Methods We used data from 167 mother-child pairs recruited during pregnancy (2003–2006) in Cincinnati, OH, quantified prenatal serum PFAS concentrations at 16 ± 3 weeks of gestation and childhood sera at ages 3 and 8 years. We assessed children's reading skills using Woodcock-Johnson Tests of Achievement III at age 5 years and Wide Range Achievement Test-4 at age 8 years. We used general linear regression to quantify the covariate-adjusted associations between natural log-transformed PFAS concentrations and reading skills, and used multiple informant model to identify the potential windows of susceptibility. Results Median serum PFASs concentrations were PFOS > PFOA > PFHxS > PFNA in prenatal, 3-year, and 8-year children. The covariate-adjusted general linear regression identified positive associations between serum PFOA, PFOS and PFNA concentrations and children's reading scores at ages 5 and 8 years, but no association between any PFHxS concentration and reading skills. The multiple informant model showed: a) Prenatal PFOA was positively associated with higher children's scores in Reading Composite (β: 4.0, 95% CI: 0.6, 7.4 per a natural log unit increase in exposure) and Sentence Comprehension (β: 4.2, 95% CI: 0.5, 8.0) at age 8 years; b) 3-year PFOA was positively associated with higher children's scores in Brief Reading (β: 7.3, 95% CI: 0.9, 13.8), Letter Word Identification (β: 6.6, 95% CI: 1.1, 12.0), and Passage Comprehension (β: 5.9, 95% CI: 1.5, 10.2) at age 5 years; c) 8-year PFOA was positively associated with higher children's Word Reading scores (β: 5.8, 95% CI: 0.8, 10.7) at age 8 years. Prenatal PFOS and PFNA were positively associated with children's reading abilities at age 5 years, but not at age 8 years; 3-year PFOS and PFNA were positively associated with reading scores at age 5 years. But PFHxS concentrations, at any exposure windows, were not associated with reading skills. Conclusion Prenatal and childhood serum PFOA, PFOS and PFNA concentrations were positively associated with better children's reading skills at ages 5 and 8 years, but no association was found between serum PFHxS and reading skills. [ABSTRACT FROM AUTHOR]

Abstract: The problem described by Dr. Brian Gulson – confounding by unmeasured exposures to pesticides – is only the most recent in a series of potential confounders cited to explain the observed effect of lead on children''s intellectual abilities or behavioral problems. Despite the persistent problem of unmeasured confounders, there are several lines of evidence implicating lead as a toxicant at blood lead levels <10 μg/dL. First, in striking contrast with pesticides, there is considerable evidence from numerous studies linking low-level lead exposure with cognitive deficits and behavioral problems, even after controlling for a variety of potential confounders. Second, the consistency of evidence from diverse cohorts and distinct, if not always directly measured potential confounders — enhances our confidence that the lead effect observed at blood lead levels <10 μg/dL is not attributable to unmeasured confounders. Third, in our reanalysis of the Rochester Lead Study, the inclusion of parent-reported mouthing behaviors and breastfeeding status did not attenuate the effect of lead exposure on children''s intellectual function. Finally, although we can never entirely dismiss unmeasured confounding in observational studies, we can rely on experimental studies of lead-exposed animals to confirm that lead is a toxicant. Thus, while we must remain vigilant for unmeasured or poorly measured confounders, it is crucial to balance the endless search for confounders with the evidence of toxicity and the need to take action to protect public health. The alternative, to perpetually permit children to be exposed to lead and other emerging toxicants, is both absurd and unacceptable. [Copyright &y& Elsevier]

It is unclear whether cadmium (Cd) exposure during fetal brain development is associated with child neurobehavior. To examine the potential associations between Cd exposure during pregnancy and neurobehavior among children. We used data from 276 children in the Health Outcomes and Measures of the Environment (HOME) Study, a well-established prospective pregnancy and birth cohort. We measured maternal urinary Cd concentrations at 26 weeks of gestation. For cognitive function, we assessed Mental Development Index (MDI) and Full-Scale Intelligence Quotient (FSIQ) using the Bayley Scales of Infant Development-II, the Wechsler Preschool and Primary Scales of Intelligence-III, or the Wechsler Intelligence Scales for Children-IV at ages 1, 2, 3, 5, and 8 years. We assessed child behaviors using the Behavior Assessment System for Children-2 at ages 2, 3, 4, 5, and 8 years, yielding four composite measures: Externalizing Problems, Internalizing Problems, Behavioral Symptoms Index, and Adaptive Skills. We used linear mixed models with covariate adjustment to estimate the associations between maternal urinary Cd concentrations and child neurobehavior. We categorized study participants into three groups based on maternal urinary Cd concentrations (Group 1: < limit of detection (LOD), Group 2: 0.06-0.22 μg/g creatinine, Group 3: ＞0.22 μg/g creatinine). In linear mixed models adjusting for maternal and child characteristics, maternal urinary Cd levels were not significantly associated with cognitive function at ages 1, 2, 3, 5, and 8 years or with behavioral composite measures at 2, 3, 4, 5, and 8 years. No significant associations were observed between maternal urinary Cd and cognitive or behavioral measures in children at 1–8 years of age in this study. • Low levels of prenatal cadmium exposure were found in maternal urine • Repeated neurobehavioral assessments were conducted between age 1–8 years • Maternal urinary cadmium was not adversely associated with child cognitive function • Prenatal cadmium exposure was not adversely associated with behavioral measurements [ABSTRACT FROM AUTHOR]