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Background: Polychlorinated biphenyls (PCBs), extensively used in various products, prompt ongoing concern despite reduced exposure since the 1970s. This systematic review explores prenatal PCB and hydroxylated metabolites (OH-PCBs) exposure's association with child neurodevelopment. Encompassing cognitive, motor development, behavior, attention, ADHD, and ASD risks, it also evaluates diverse methodological approaches in studies., Methods: PubMed, Embase, PsycINFO, and Web of Science databases were searched through August 23, 2023, by predefined search strings. Peer-reviewed studies published in English were included. The inclusion criteria were: (i) PCBs/OH-PCBs measured directly in maternal and cord blood, placenta or breast milk collected in the perinatal period; (ii) outcomes of cognitive development, motor development, attention, behavior, attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) among children≤18 years old. Quality assessment followed the National Heart, Lung, and Blood Institute's tool., Results: Overall, 87 studies were included in this review. We found evidence for the association between perinatal PCB exposure and adverse cognitive development and attention issues in middle childhood. There appeared to be no or negligible link between perinatal PCB exposure and early childhood motor development or the risk of ADHD/ASD. There was an indication of a sex-specific association with worse cognition and attention scores among boys. Some individual studies suggested a possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There was significant heterogeneity between the studies in exposure markers, exposure assessment timing, outcome assessment, and statistical analysis., Conclusions: Significant methodological, clinical and statistical heterogeneity existed in the included studies. Adverse effects on cognitive development and attention were observed in middle childhood. Little or no apparent link on both motor development and risk of ADHD/ASD was observed in early childhood. Inconclusive evidence prevailed regarding other neurodevelopmental aspects due to limited studies. Future research could further explore sex-specific associations and evaluate associations at lower exposure levels post-PCB ban in the US. It should also consider OH-PCB metabolites, co-pollutants, mixtures, and their potential interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Externalizing disorders, such as attention-deficit/hyperactivity disorder (ADHD), account for the majority of the child/adolescent referrals to mental health services and increase risk for later-life psychopathology. Although the expression of externalizing disorders is more common among males, few studies have addressed how sex modifies associations between metal exposure and adolescent externalizing symptoms. This study aimed to examine sex-specific associations between co-exposure to multiple metals and externalizing symptoms in adolescence and young adulthood. Among 150 adolescents and young adults (55% female, ages: 15-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study in Brescia, Italy, we measured five metals (manganese (Mn), lead (Pb), copper (Cu), chromium (Cr), nickel (Ni)) in four biological matrices (blood, urine, hair, and saliva). Externalizing symptoms were assessed using the Achenbach System of Empirically Based Assessment (ASEBA) Youth Self-Report (YSR) or Adult Self Report (ASR). Using generalized weighted quantile sum (WQS) regression, we investigated the moderating effect of sex (i.e., assigned at birth) on associations between the joint effect of exposure to the metal mixture and externalizing symptoms, adjusting for age and socioeconomic status. We observed that metal mixture exposure was differentially associated with aggressive behavior in males compared to females (β = -0.058, 95% CI [-0.126, -0.009]). In males, exposure was significantly associated with more externalizing problems, and aggressive and intrusive behaviors, driven by Pb, Cu and Cr. In females, exposure was not significantly associated with any externalizing symptoms. These findings suggest that the effect of metal exposure on externalizing symptoms differs in magnitude between the sexes, with males being more vulnerable to increased externalizing symptoms following metal exposure. Furthermore, our findings support the hypothesis that sex-specific vulnerabilities to mixed metal exposure during adolescence/young adulthood may play a role in sex disparities observed in mental health disorders, particularly those characterized by externalizing symptoms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with severe and lifelong impact on mental health and socioeconomic achievements. Environmental factors may play a role in the increasing incidens rates. Previous studies on associations between prenatal and childhood exposure to organophosphate and pyrethroid insecticides and ADHD symptoms have yielded mixed findings., Objectives: To investigate associations between prenatal and childhood exposure to chlorpyrifos and pyrethroids and ADHD symptoms in 5-year-old children from the Odense Child Cohort., Methods: Spot urine samples from pregnant women in gestational week 28 (n = 614) and offspring at 5 years of age (n = 814) were collected and analyzed for the specific metabolite of chlorpyrifos, TCPY (3,5,6-trichloro-2-pyridinol), as well as the generic pyrethroid metabolite, 3-PBA (3-phenoxybenzoic acid). Offspring ADHD symptoms were assessed at age 5 years using the parent reported "ADHD scale" from the "Child Behavior Checklist 1½-5" (n = 1114). Associations between insecticide exposure variables and an ADHD score ≥90th percentile were analyzed using logistic regression for all children and stratified by sex., Results: Most pregnant women had detectable concentrations of 3-PBA (93%) and TCPY (91%) with median concentrations of 0.20 μg/L and 1.62 μg/L, respectively. In children, 3-PBA and TCPY concentrations were detectable in 88% and 82% of the samples, and the median concentrations were 0.17 and 1.16 μg/L. No statistically significant associations were observed between insecticide metabolites and an ADHD score ≥90th percentile at age 5., Conclusion: In this relatively large Danish birth cohort study with mainly low dietary insecticide exposure, we found no statistically significant associations between prenatal or childhood exposure to chlorpyrifos or pyrethroids, and excess ADHD-symptom load, in 5-year-old children. Prospective studies with multiple urine samples across vulnerable windows of neurodevelopment is warranted to improve assessment of safe exposure levels, which is particularly relevant for pyrethroids, since their use is increasing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Health concerns about the potential impact of exposure to fluoride via drinking water (DW) on neuropsychological development include behavioral outcomes such as ADHD., Objective: We aimed to examine the association between prenatal maternal urinary fluoride and symptoms associated with attention-deficit/hyperactivity disorder (ADHD) at the age of 8 and 11 years., Method: Data from 255 to 236 mother-child pairs from the "Infancia y Medio Ambiente" (INMA) birth cohort (Gipuzkoa; Spain) with maternal urinary F adjusted for creatinine (MUFcr) during pregnancy (first and third trimester) and child assessments of ADHD-like symptoms reported by Conners' Rating Scales-Revised at age of 8 and 11 years was available. Clinical approach was also used: cut off criteria (T > 66). Multiple linear regression models were fitted when outcomes were analyzed as continuous, and logistic regression models when the outcomes were analyzed with a categorical clinical approach. Covariates related to maternal characteristics, birth outcomes, childhood, quality of family context and biomarkers of neuro-toxicants were used., Results: No association was found between MUFcr levels during pregnancy and cognitive problems-inattention, hyperactivity or ADHD index score of symptoms at 8 or 11 years. When results were analyzed from the perspective of a clinical approach, at the age of 11 years, there were significant inverse association between MUFcr and being categorized as a cognitive problems-inattention case. ORs were also indicative of a lower risk, although not significant, for ADHD index at age 11. Sensitivity analyses, taking into consideration quality of family context or the levels of other toxicants during pregnancy showed similar results., Conclusions: Higher levels of MUFcr in pregnant women were associated with a lower risk of cognitive problems-inattention at 11 years. These findings are inconsistent with those from previous studies and indicate the need for other population-based studies to confirm or overturn these results., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Exposure to ambient noise and air pollution may affect the manifestation and severity of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). However, evidence is limited, and most studies solely assessed environmental exposures during pregnancy and early childhood., Objective: To examine the longitudinal effects of ambient noise and air pollutants on ASD and ADHD symptom severity during adolescence and early adulthood., Methods: Using a longitudinal design, we included 2750 children between 10 and 12 years old from the TRacking Adolescents' Individual Lives Survey (TRAILS) in the Netherlands, who were assessed in 6 waves from 2001 to 2017. ASD was measured by the Children's Social Behavior Questionnaire and the Adult Social Behavior Questionnaire. ADHD was measured by Child Behavior Checklist and the Adult Behavior Checklist. Ambient noise and air pollution exposures, including Ozone (O 3 ), soot, sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), particulate matter 2.5 (PM 2.5 ), and PM 10 were modeled at the residential level according to standardized protocols. The longitudinal associations between exposures and symptom outcomes were examined using linear mixed models., Results: We found evidence that higher levels of exposure to PM were associated with more severe ASD and ADHD symptoms. This association decreased over time. We did not observe any other consistent associations of noise or other air pollutants with ASD and ADHD severity., Conclusion: The current study provides evidence for the negative impact of PM on ASD and ADHD symptoms. We did not find evidence of the negative health impact of other air pollutants and noise exposures on ASD or ADHD symptoms. Our study adds more evidence on the presence of associations between PM air pollution and neurodevelopmental diseases among adolescents and young adults., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although ozone exposure has neurological toxicity, it remains unclear whether it was associated with an increased risk of attention-deficit/hyperactivity disorders (ADHD) among childhood., Methods: We matched the four-year average ozone concentration with questionnaire data for 35,103 children aged 3-12 years from seven cities in Liaoning, China, 2012-2013. Using mixed-effect logistic regression models, we assessed the association of ozone concentration with multiple ADHD indicators using the Conners Abbreviated Symptom Questionnaire (C-ASQ), including explicit attention-deficit/hyperactivity symptoms (ADHD; score ≥15), attention-deficit/hyperactivity disorder tendencies (ADHD-T; 11 ≤ score ≤14), and attention-deficit/hyperactivity problems (ADHP; score ≥11). Results were also stratified by sociodemongraphics., Results: After adjusting for covariates, we found that each interquartile range (IQR) increase in ozone concentration was associated with an increased risk of ADHD, ADHD-T, and ADHP (P < 0.001) with an odds ratio of 1.12 (95% confidence interval, 1.04-1.21), 1.08 (1.03-1.13), and 1.09 (1.05-1.14), respectively. Additionally, we found greater effect estimates in children who reported longer exercise time (vs those with limited exercise time) with odds ratio of 1.18 (1.07-1.31) vs 1.06 (0.96-1.17) for ADHD, 1.13 (1.06-1.21) vs 1.03 (0.96-1.10) for ADHD-T, and 1.15 (1.08-1.21) vs 1.04 (0.98-1.10) for ADHP. Non-breastfed children were also shown to be more vulnerable to ADHD with an odds ratio of 1.22 (1.09-1.36) compared with 1.06 (0.96-1.16) among the rest., Conclusions: Long-term ozone exposure may be associated with increased ADHD among children. Additional studies are needed to validate our findings and support policies and interventions to address this growing public health concern., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Evidence implicates environmental factors in attention-deficit/hyperactivity disorder (ADHD) risk. Prenatal exposures to polychlorinated biphenyls (PCBs) and the pesticide metabolite p,p'-dichlorodiphenyl dichloroethylene (DDE) have been linked to lower cognitive ability, increased impulsivity, and attention related deficits in the offspring. However, information on the relationship of these exposures to the risk of clinically diagnosed ADHD is limited., Objectives: To determine whether prenatal maternal levels of PCBs or DDE are associated with ADHD diagnosis in the offspring., Methods: The investigation was conducted in the Finnish Prenatal Study of ADHD (FIPS-ADHD), a case-control study nested in a national birth cohort. Cases were born in 1998 or 1999 and diagnosed with ADHD (ICD-9 314x or ICD-10 F90. x) according to the national Care Register for Health Care. Each case was individually matched to a control on sex, date, and place of birth. PCB congeners (PCB 74, 99, 118, 138, 153, 156, 170, 180, 183, 187) and DDE were quantified from archived prenatal maternal sera from 359 matched case-control pairs using gas chromatography - high triple quadrupole mass spectrometry. Maternal total PCBs were quantified as the sum of concentrations of the measured congeners. Associations with ADHD were examined using conditional logistic regression., Results: Maternal PCB or DDE levels greater than the 75th percentiles of the control distributions showed no evidence of association with offspring ADHD (PCBs: adjusted odds ratio (aOR) = 1.01, 95% CI = 0.63, 1.60), p = 0.98; DDE: aOR = 1.13, 95% CI = 0.71, 1.81; p = 0.60). Maternal levels of either pollutant dichotomized at the 90th percentile or considered as a continuous variable also did not show evidence for association with offspring ADHD diagnosis., Discussion: This study did not find evidence for association of maternal prenatal levels of PCBs or DDE with clinical diagnosis of offspring ADHD; however, this does not rule out the possibility of an impact on subclinical phenotypes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Evidence regarding the negative neurodevelopmental effects of compound exposure to petrochemicals remains limited. We aimed to evaluate the association between exposure to petrochemical facilities and generated emissions during early life and the risk of attention-deficit/hyperactivity disorder (ADHD) development in children. We conducted a population-based birth cohort study using the 2004 to 2014 Taiwanese Birth Certificate Database and verified diagnoses of ADHD using the National Health Insurance Database. The level of petrochemical exposure in each participant's residential township was evaluated using the following 3 measurements: distance to the nearest petrochemical industrial plant (PIP), petrochemical exposure probability (accounting for monthly prevailing wind measurements), and monthly benzene concentrations estimated using kriging-based land-use regression models. We applied Cox proportional hazard models to evaluate the association. During the study period, 48,854 out of 1,863,963 children were diagnosed as having ADHD. The results revealed that residents of townships in close proximity to PIPs (hazard ratio [HR] = 1.20, 95% confidence interval [CI]: 1.16-1.23, <3 vs. ≥10 km), highly affected by petrochemical-containing prevailing winds (HR = 1.12, 95% CI: 1.08-1.16, ≥40% vs. <10%), and with high benzene concentrations (HR = 1.26, 95% CI: 1.23-1.29, ≥0.75 vs. <0.55 ppb) were consistently associated with the increased risk of ADHD development in children. The findings of the sensitivity analysis remained robust, particularly for the 2004 to 2009 birth cohort and for models accounting for a longer duration of postnatal exposure. This work provided clear evidence that living near petrochemical plants increases the risk of ADHD development in children. Further studies are warranted to confirm our findings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Prenatal exposure to persistent organic pollutants (POPs), widespread in North America, is associated with increased Attention Deficit/Hyperactivity Disorder (ADHD) symptoms and may be a modifiable risk for ADHD phenotypes. However, the effects of moderate exposure to POPs on task-based inhibitory control performance, related brain function, and ADHD-related symptoms remain unknown, limiting our ability to develop interventions targeting the neural impact of common levels of exposure., Objectives: The goal of this study was to examine the association between prenatal POP exposure and inhibitory control performance, neural correlates of inhibitory control and ADHD-related symptoms., Methods: Prospective data was gathered in an observational study of Canadian mother-child dyads, with moderate exposure to POPs, including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as part of the GESTation and the Environment (GESTE) cohort in Sherbrooke, Quebec, Canada. The sample included 87 eligible children, 46 with maternal plasma samples, functional magnetic resonance imaging (fMRI) data of Simon task performance at 9-11 years, and parental report of clinical symptoms via the Behavioral Assessment System for Children 3 (BASC-3). Simon task performance was probed via drift diffusion modeling, and parameter estimates were related to POP exposure. Simon task-based fMRI data was modeled to examine the difference in incongruent vs congruent trials in regions of interest (ROIs) identified by meta analysis., Results: Of the 46 participants with complete data, 29 were male, and mean age was 10.42 ± 0.55 years. Increased POP exposure was associated with reduced accuracy (e.g. PCB molar sum rate ratio = 0.95; 95% CI [0.90, 0.99]), drift rate (e.g. for PCB molar sum β = -0.42; 95% CI [-0.77, -0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum β = -0.35; 95% CI [-0.69, -0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum β = 2.35; 95%CI [0.17, 4.53]), supporting the possibility that prenatal exposure to POPs is a modifiable risk for ADHD phenotypes., Discussion: We showed that exposure to POPs is related to task-based changes in neural activity in brain regions important for inhibitory control, suggesting a biological mechanism underlying previously documented associations between POPs and neurobehavioral deficits found in ADHD phenotypes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent., Objectives: We investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD)., Methods: This study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach., Results: Odds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]., Conclusion: Prenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Studies of prenatal per- and polyfluoroalkyl substances (PFAS) and attention deficit hyperactivity disorder (ADHD)-related behaviors in children are inconsistent., Objectives: To examine associations between maternal serum PFAS concentrations and child behavior in 241 mother-child dyads within the Health Outcomes and Measures of the Environment (HOME) Study., Methods: We quantified perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA) in maternal serum collected during pregnancy or at delivery. We evaluated a total of 17 outcomes of child behavior using the Behavioral Assessment System for Children-2 (BASC-2) at 5 and 8 years (n = 240) and ADHD diagnostic symptoms and criteria with the Diagnostic Interview Schedule for Children-Young Child (DISC-YC) at 5 years (n = 190). We used linear mixed models and logistic regression with generalized estimating equations to assess associations between PFAS and continuous or dichotomous "at risk" BASC-2 scores; negative binomial regression to calculate incident rate ratios for counts of ADHD symptoms; and Poisson regression with robust standard errors to calculate relative risks of meeting ADHD diagnostic criteria., Results: Each ln-unit increase in PFOS, PFHxS, and PFNA was associated with higher BASC-2 scores and increased odds of "at-risk" scores for externalizing behaviors, including hyperactivity (PFOS: odds ratio [OR] 2.7, 95% confidence interval [CI] 1.2, 5.9; PFHxS: OR 2.5, 95% CI 1.5, 4.3; PFNA: OR 3.2, 95% CI 1.3, 8.0). PFHxS was also associated with internalizing problems (OR 2.0, 95% CI 1.1, 3.4) and somatization (OR 2.2, 95% CI 1.2, 4.0). PFOS and PFNA were significantly associated with 50-80% more DISC-YC symptoms and diagnostic criteria related to hyperactive-impulsive type ADHD. Prenatal PFNA was associated with increased risk of any-type ADHD., Conclusions: Prenatal PFOS and PFNA were consistently associated with measures related to hyperactive-impulsive type ADHD across two validated assessment instruments. PFHxS was associated with increased problems with both externalizing and internalizing behaviors. No associations were noted between PFOA and child neurobehavior., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurobehavioral disorders in childhood globally. Between the two components of ADHD, hyperactivity disorder is more prevalent than inattention during early childhood. Although some investigations have implied a relationship between childhood ADHD and gestational exposure to air pollution, the evidence is limited. The aim of this study was to investigate the association between gestational exposure to air pollution exposure and hyperactivity disorder in childhood in a population-based birth cohort., Methods: The Taiwan Birth Cohort Study started from all deliveries of Taiwan in 2005 by the birth registry, and recruited representative 12% of all mother-infant pairs by two-stage stratified sampling. At age of 8 years in each child, their main caretaker was inquired whether the child had ever received a hyperactivity diagnosis from a physician or other specialist, like special needs educator. Exposure to air pollutants during gestation was estimated through ordinary kriging based on data from air monitoring stations of Environmental Protection Administration, Taiwan. Logistic regression was used to determine adjusted odds ratios (aORs) of hyperactivity disorder in relation to air pollutants., Results: A total of 16,376 mother-infant pairs were included in the final analysis; 374 (2.3%) of the children had received a diagnosis of hyperactivity before 8 years of age. The occurrence of hyperactivity was significantly related to prenatal nitrogen oxide (NO x ), but not to particulate matter 10 μm or less in diameter or sulfur dioxide. Further analysis to separate effects by nitrogen dioxide (NO 2 ) and/or nitric oxide (NO) showed that only NO was significantly related to hyperactivity [aOR per interquartile range (3.14 ppb): 1.26, 95% confidence interval: 1.09-1.46]., Conclusions: In conclusion, our study found childhood hyperactivity disorder to be positively associated with prenatal NO exposure. Further confirmation on potential hazardous effects of NO and investigation on potential mechanisms are warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Previous animal studies have reported that pyrethroids can cause dopamine system abnormalities and attention-deficit/hyperactivity disorder (ADHD) phenotypes. However, epidemiological studies investigating the associations between pyrethroid exposure and ADHD are limited. We aimed to investigate the association between pyrethroid exposure and ADHD-like symptoms among preschool-age children. We used data from 385 children at 4 years of age participating in the Environment and Development of Children (EDC) study. We evaluated pyrethroid exposure through questionnaires and urinary 3-phenoxybenzoic acid (3-PBA) concentrations. We assessed ADHD-like symptoms using the Korean ADHD rating scale (K-ARS). We conducted negative binomial regressions to evaluate the associations between pyrethroid exposure and ADHD-like symptoms. Residential use of insecticide adhesive (β = 0.42, 95% CI: 0.11, 0.74) and insecticide spray (β = 0.33, 95% CI: 0.08, 0.59) was associated with an increase in log-transformed creatinine-adjusted urinary 3-PBA concentrations. Residential insecticide adhesive use was associated with a 51.6% increase in K-ARS scores (95% confidence interval [CI]: 6.3, 116.1) among boys, when compared with non-users. When compared with creatinine-adjusted 3-PBA levels <0.50 μg/g creatinine, creatinine-adjusted 3-PBA levels ≥3.80 μg/g creatinine were associated with a 58% increase in K-ARS scores (95% CI: 0.1, 150.5) among boys. We found associations of residential pyrethroid insecticide use and urinary 3-PBA concentrations with K-ARS scores among preschool-age boys. Since the present study explored cross-sectional associations in preschool-age children, the possibility of reverse causality cannot be dismissed. Further studies implementing a cohort study design are warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Children may be more vulnerable to the combined interactions of chemical and non-chemical stressors from their built, natural, and social environments when compared to adults. Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed childhood neurodevelopmental disorder and is considered a major public health issue, as 75% of childhood cases persist into adulthood. ADHD is characterized by developmentally inappropriate levels of hyperactivity, impulsivity, and inattention, with the neurotransmitter serotonin regulating these symptoms. Monoamine oxidase A (MAOA) aids in serotonin uptake and is often implicated in behavioral and emotional disorders, including ADHD. When children are exposed to cigarette smoke, bisphenol A (BPA), or organophosphate pesticides, MAOA activity is inhibited. Non-chemical stressors, such as traumatic childhood experiences, and lifestyle factors, complicate the relationship between genotype and exposures to chemical stressors. But the co-occurrence among outcomes between exposures to chemical stressors, non-chemical stressors, and the low activity MAOA genotype suggest that mental illness in children may be influenced by multiple interacting factors. In this systematic review, we examine the existing literature that combines exposures to chemical and non-chemical stressors (specifically childhood trauma), MAOA characteristics, and ADHD diagnosis to investigate the interrelationships present. We observe that chemical (lead [Pb], phthalates/plasticizers, persistent organic pollutants, and cigarette smoke) exposure is significantly related to ADHD in children. We also observed that existing literature examining the interaction between MAOA, exposures to chemical stressors, and traumatic experiences and their effect on ADHD outcomes is sparse. We recommend that future studies investigating childhood ADHD include chemical and non-chemical stressors and inherent characteristics to gain a holistic understanding of childhood mental health outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: Polycyclic aromatic hydrocarbons (PAH) are carcinogenic and neurotoxic combustion by-products commonly found in urban air. Exposure to PAH is disproportionately high in low income communities of color who also experience chronic economic stress., Objective: In a prospective cohort study in New York City (NYC) we previously found a significant association between prenatal PAH exposure and Attention Deficit Hyperactivity Disorder (ADHD) behavior problems at age 9. Here, we have evaluated the joint effects of prenatal exposure to PAH and prenatal/childhood material hardship on ADHD behavior problems., Materials and Methods: We enrolled nonsmoking African-American and Dominican pregnant women in New York City between 1998 and 2006 and followed their children through 9 years of age. As a biomarker of prenatal PAH exposure, PAH-DNA adducts were measured in maternal blood at delivery and were dichotomized at the limit of detection (to indicate high vs. low exposure). Maternal material hardship (lack of adequate food, housing, utilities, and clothing) was self-reported prenatally and at multiple time points through child age 9. Latent variable analysis identified four distinct patterns of hardship. ADHD behavior problems were assessed using the Conners Parent Rating Scale- Revised. Analyses adjusted for relevant covariates., Results: Among 351 children in our sample, across all hardship groups, children with high prenatal PAH exposure (high adducts) generally had more symptoms of ADHD (higher scores) compared to those with low PAH exposure. The greatest difference was seen among the children with hardship persisting from pregnancy through childhood. Although the interactions between high PAH exposure and hardship experienced at either period ("persistent" hardship or "any" hardship) were not significant, we observed significant differences in the number of ADHD symptoms between children with high prenatal PAH exposure and either persistent hardship or any hardship compared to the others. These differences were most significant for combined high PAH and persistent hardship: ADHD Index (p < 0.008), DSM-IV Inattentive (p = 0.006), DSM-IV Hyperactive Impulsive problems (p = 0.033), and DSM-IV Index Total (p = 0.009)., Conclusion: The present findings add to existing evidence that co-exposure to socioeconomic disadvantage and air pollution in early life significantly increases the risk of adverse neurodevelopmental outcomes. They suggest the need for multifaceted interventions to protect pregnant mothers and their children., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to clarify the association between organophosphate pesticides (OPs) and attention-deficit/hyperactivity disorder (ADHD) related to oxidative stress and genetic polymorphisms., Methods: This case-control study enrolled 93 children with ADHD and 112 control children in north Taiwan. Six dialkyl phosphate (DAP) metabolites of OPs and oxidative stress biomarkers were analyzed. Polymorphisms of the dopamine receptor D4 gene (DRD4) were identified., Results: Children with ADHD had significantly higher dimethylphosphate (DMP, 236.69nmol/g cre. vs. 186.84nmol/g cre., p value = 0.01) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA, 28.95µg/g cre. vs. 16.55µg/g cre., p value<0.01) concentrations than control children. Children who carried DRD4 GA/AA genotypes (rs752306) were less likely than those who carried the DRD4 GG genotype to have ADHD (odds ratio [OR]: 0.45, 95% CI: 0.24-0.84). The estimated value of the AP (attributable proportion due to interaction) was 0.59 (95% CI: 0.13-1.05), indicating that 59% of ADHD cases in DMP-exposed children with the DRD4 GG genotype were due to the gene-environment interaction. After adjustment for other covariates, children who carried the DRD4 GG genotype, had been exposed to high DMP levels (more than the median), and had high HNE-MA levels had a significantly increased risk for developing ADHD (OR = 11.74, 95% CI: 2.12-65.04)., Conclusion: This study indicated a gene-environment interaction in the risk of ADHD in children. The association between DMP and ADHD in children might relate to the mechanism of lipid peroxidation. Dose-response relationships and the combined effects of OPs, oxidative stress, and genetic polymorphism on ADHD should not be neglected., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Prenatal polybrominated diphenyl ether (PBDE) exposure has been associated with decrements in IQ and increased attention deficit/hyperactivity disorder related behaviors in children; however, data are limited for the role of postnatal exposures., Objectives: We investigated the association between a series of childhood PBDE concentrations and Full-Scale Intelligence Quotient (FSIQ) and externalizing problems at 8 years., Methods: We used data from 208 children in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort. Child serum PBDEs were measured at 1, 2, 3, 5, and 8 years; missing serum PBDE concentrations were estimated via multiple imputation. The Wechsler Intelligence Scales for Children-IV and the Behavior Assessment System for Children-2 was used to assess intelligence and externalizing behavior, respectively, in children at 8 years. We used multiple informant models to estimate associations between repeated lipid-adjusted PBDEs and child neurobehavior and to test for windows of susceptibility., Results: Postnatal exposure to PBDE congeners (- 28, - 47, - 99, - 100, and - 153) at multiple ages was inversely associated with FSIQ at 8 years. For instance, a 10-fold increase in BDE-153 concentrations at 2, 3, 5, and 8 years were all related to lower FSIQ at age 8 (β for 3 years: - 7.7-points, 95% CI - 12.5, - 2.9; β for 8 years: - 5.6-points, 95% CI - 10.8, - 0.4). Multiple PBDE congeners at 8 years were associated with increased hyperactivity and aggressive behaviors at 8 years., Conclusions: Postnatal PBDE exposure was associated with decrements in FSIQ and increases in hyperactivity and aggressive behaviors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Bisphenol A (BPA) has been linked to changes in the dopamine system and development of an Attention-Deficit/Hyperactivity Disorder (ADHD) phenotype in animal models, with differing effects in males compared to females. We examined the association between urinary BPA concentrations and ADHD in a national sample of U.S. children, and whether this association differs by child sex., Methods: We used data from the 2003-2004 National Health and Nutrition Examination Survey, a cross-sectional, nationally representative sample of the U.S., Population: Participants were 8-15 years of age (N=460). Using a diagnostic interview to ascertain the presence of ADHD in the past year, multivariable logistic regression examined the link between concurrent urinary BPA concentrations and ADHD status., Results: Of the 460 participants, 7.1% [95% CI: 4.4-11.3] met Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria for ADHD. Children who had BPA concentrations at or above the median of the sample had higher prevalence of meeting criteria for ADHD (11.2% [95% CI: 6.8-17.8]) than those with BPA concentrations below the median (2.9% [95% CI: 1.1-7.2]). Higher urinary BPA concentrations were associated with ADHD (adjusted odds ratio [aOR]: 5.68 [95% CI: 1.6-19.8] for BPA concentrations above vs. below the median). In sex-stratified analyses, these associations were stronger in boys (aOR=10.9 [95% CI: 1.4-86.0]) than in girls (aOR=2.8 [95% CI: 0.4-21.3]), although the BPA by sex interaction term was not significant (p=0.25)., Conclusion: We found evidence that higher urinary BPA concentrations were associated with ADHD in U.S. children; these associations were stronger in boys than in girls. Considering the widespread use of BPA and growing literature on neurobehavioral effects of BPA in children, further study is warranted to determine if reducing exposure to BPA may represent an important avenue for ADHD prevention., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Existing evidence on the effects of manganese and selenium during fetal life on neurodevelopmental disorders is inadequate. This study aims to investigate the hypothesized relationship between fetal exposure to manganese and selenium and attention deficit hyperactivity disorder (ADHD) diagnosis in childhood. Children born between 1978 and 2000 with ADHD (n=166) were identified at the Department of Child and Adolescent Psychiatry in Malmö, Sweden. Controls from the same region (n=166) were selected from the Medical Birth Register and were matched for year of birth and maternal country of birth. Manganese and selenium were measured in umbilical cord serum. The median cord serum concentrations of manganese were 4.3μg/L in the cases and 4.1μg/L in the controls. The corresponding concentrations of selenium were 47 and 48μg/L. When the exposures were analyzed as continuous variables no associations between cord manganese or selenium concentration and ADHD were observed. However, children with selenium concentrations above the 90th percentile had 2.5 times higher odds (95% confidence interval 1.3-5.1) of having ADHD compared to those with concentrations between the 10th and 90th percentiles. There was no significant interaction between manganese and selenium exposure (p=0.08). This study showed no association between manganese concentrations in umbilical cord serum and ADHD. The association between ADHD diagnoses in children with relatively high cord selenium was unexpected and should be interpreted with caution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Globally, organophosphate (OP) pesticide usage and exposure is widespread. Studies have found that fetuses and infants are more sensitive than adults to environmental toxicants and that prenatal exposure to low levels of OPs has been associated with Attention Deficit Hyperactivity Disorder-Like Phenotypes (ADHD-LP). Paraoxonase 1 (PON1) is an enzyme involved in detoxifying some OPs and its polymorphisms influence enzyme activity and quantity. The objective of this study was to examine whether maternal and/or child PON1 genotypes (PON1R192Q and PON1L55M) were associated with ADHD-LP in a Mexico City, Mexico birth cohort. PON1R192Q and PON1L55M genotypes in mothers (PON1R192Q: N=531; PON1L55M: N=458) and children (PON1R192Q: N=532; PON1L55M: N=478) from blood DNA were determined. We assessed ADHD-LP for children between the ages of 6 and 13 using Conners' Parent Rating Scales-Revised (CRS-R), Conners' Continuous Performance Test (CPT), and the parent scores for Behavior Assessment System for Children-2 (BASC2). Multivariable linear regression models were used to test relationships between ADHD-LP and PON1 polymorphisms. In these models, significant associations were observed with maternal genotypes but not with the child genotypes. A higher DSM IV Hyperactivity/Impulsivity score (β=3.27 points; 95% CI (0.89, 5.65)) and a 2.17 higher score in child DSM IV Total (95% CI (0.05, 4.29)) were observed for maternal PON155MM in comparison to PON155LM+LL. The childattention problems score was 2.27 points higher (95% CI (0.002, 4.53) for maternal PON1192QQ in comparison to PON1192QR+RR. Because maternal PON1 polymorphisms were associated with child ADHD-LP, this may be a viable biomarker of susceptibility for ADHD-LP., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study investigates the association between urinary phthalate metabolite levels and attention deficit disorder (ADD), learning disability (LD), and co-occurrence of ADD and LD in 6-15-year-old children., Methods: We used cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, 2001-2004). Phthalate metabolites with ≥75% detection in urine samples were examined. The study population comprised 1493 children with parent-reported information on ADD or LD diagnosis and phthalate concentrations in urine. Phthalate concentrations were creatinine-adjusted and log10-transformed for analysis. All models controlled for child sex, age, race, household income, blood lead, and maternal smoking during pregnancy., Results: There were 112 ADD cases, 173 LD cases, and 56 ADD and LD cases in the sample. After adjusting for potential confounders, we found increased odds of ADD with increasing urinary concentration of di-2-ethylhexyl phthalates (OR: 2.1; 95% CI: 1.1, 3.9) and high molecular weight phthalates (OR: 2.7; 95% CI: 1.2, 6.1). In addition, dibutyl phthalates (OR: 3.3; 95% CI: 0.9, 12.7) and high molecular weight phthalates (OR: 3.7; 95% CI: 0.9, 14.8) were marginally associated with increased odds of co-occurring ADD and LD. We did not find associations for any phthalate and LD alone. We observed stronger associations between phthalates and ADD and both ADD and LD in girls than boys in some models., Conclusions: We found cross-sectional evidence that certain phthalates are associated with increased odds of ADD and both ADD and LD. Further investigations with longitudinal data are needed to confirm these results., (© 2013 Published by Elsevier Inc.)

Background: There is limited research examining the relationship between lead (Pb) exposure and medically diagnosed attention deficit hyperactivity disorder (ADHD) in children. The role of mercury (Hg) and cadmium (Cd) exposures in ADHD development is even less clear., Objectives: To examine the relationship between Pb, Hg, and Cd and ADHD in children living inside and outside a Lead Investigation Area (LIA) of a former lead refinery in Omaha, NE., Methods: We carried out a case-control study with 71 currently medically diagnosed ADHD cases and 58 controls from a psychiatric clinic and a pediatric clinic inside and outside of the LIA. The participants were matched on age group (5-8, 9-12 years), sex, race (African American or Caucasians and others), and location (inside or outside LIA). We measured whole blood Pb, total Hg, and Cd using inductively coupled plasma mass spectrometry., Results: Inside the LIA, the 27 cases had blood Pb geometric mean (GM) 1.89 µg/dL and the 41 controls had 1.51 µg/dL. Outside the LIA, the 44 cases had blood Pb GM 1.02 µg/dL while the 17 controls had 0.97 µg/dL. After adjustment for matching variables and maternal smoking, socioeconomic status, and environmental tobacco exposure, each natural log unit blood Pb had an odds ratio of 2.52 with 95% confidence interval of 1.07-5.92. Stratification by the LIA indicated similar point estimate but wider CIs. No associations were observed for Hg or Cd., Conclusions: Postnatal Pb exposure may be associated with higher risk of clinical ADHD, but not the postnatal exposure to Hg or Cd., (© 2013 Published by Elsevier Inc.)