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Abstract Background A growing body of epidemiologic and toxicologic literature indicates that fine airborne particulate matter (PM2.5) pollution is neurotoxic and threatens children’s neurobehavioral development, resulting in reduced cognitive function. Understanding the magnitude of this effect is critical for establishing public health policies that will protect children’s health, preserve human capital, and support societal progress. Objective To quantify the association between ambient PM2.5 air pollution and loss of cognitive function in children, as measured by Intelligence Quotient (IQ) scores, through a systematic literature review and meta-analysis. Methods Following PRISMA guidelines, we conducted a systematic literature search across seven databases: Agricultural and Environmental Science, BIOSIS Citation Index, Embase, GreenFILE, PubMed, Scopus, and Web of Science to identify original scientific studies that investigated the impact of PM2.5 exposure during pre-and postnatal periods on IQ loss during childhood. Using data from studies included for final review, we conducted a meta-analysis, using a random effects model to compute a beta coefficient that quantifies the overall effect of PM2.5 exposure on Full-Scale IQ (FSIQ), Performance IQ (PIQ), and Verbal IQ (VIQ). Findings Of the 1,107 unique publications identified, six studies met the inclusion criteria for final review, representing 4,860 children across three continents (North America, Europe, and Asia). The mean PM2.5 concentration across all studies was 30.4 ± 24.4 µg/m3. Exposure timing ranged from the prenatal period to mid-childhood. Children were an average of 8.9 years old at the time of cognitive testing. We found that each 1 µg/m3 increase in PM2.5 concentration is associated with a -0.27 point change in FSIQ (p

Abstract Background Developmental exposure to particulate matter (PM) air pollution may impair children’s behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children’s behavior. Methods This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. Results We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. Conclusion We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. Trial registration ClinicalTrials.gov: NCT01741051

Abstract Background Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the “exposome.” Mixtures likely have temporal “critical windows” of susceptibility like single agents and measuring them repeatedly might help to define such windows. Common approaches to evaluate the effects of chemical mixtures have focused on their effects at a single time point. Our goal is to expand upon these previous techniques and examine the time-varying critical windows for metal mixtures on subsequent neurobehavior in children. Methods We propose two methods, joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS), to estimate the effects of chemical mixtures measured across multiple time points, while providing data on their critical windows of exposure. We compare the performance of both methods using simulations. We also applied both techniques to assess second and third trimester metal mixture effects in predicting performance in the Rapid Visual Processing (RVP) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessed at 6–9 years in children who are part of the PROGRESS (Programming Research in Obesity, GRowth, Environment and Social Stressors) longitudinal cohort study. The metals, arsenic, cadmium (Cd), cesium, chromium, lead (Pb) and antimony (Sb) were selected based on their toxicological profile. Results In simulations, JWQS and MWQS had over 80% accuracy in classifying exposures as either strongly or weakly contributing to an association. In real data, both JWQS and MWQS consistently found that Pb and Cd exposure jointly predicted longer latency in the RVP and that second trimester exposure better predicted the results than the third trimester. Additionally, both JWQS and MWQS highlighted the strong association Cd and Sb had with lower accuracy in the RVP and that third trimester exposure was a better predictor than second trimester exposure. Conclusions Our results indicate that metal mixtures effects vary across time, have distinct critical windows and that both JWQS and MWQS can determine longitudinal mixture effects including the cumulative contribution of each exposure and critical windows of effect.

Abstract The purpose of this commentary is to consider whether the methods of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) can provide accurate estimates of the impact of developmental neurotoxicant exposures on population health. The discussion focuses on two concerns. First, GBD implicitly largely endorses a “high risk” or “disease” approach to estimating health loss rather than a “population-based” approach. Exposure to many developmental neurotoxicants is highly prevalent but, for most individuals, it does not affect functional health to such an extent that diagnostic criteria for a disease are met. Nevertheless, the impacts are real and can be substantial when viewed in terms of the aggregate impact on a population. Second, in GBD the disability weights used for the most common sequelae of developmental neurotoxicant exposures, based on judgments provided by general population respondents, are not commensurate with the import that these sequelae have for an individual’s lifelong well-being, including their ability to fulfill educational, occupational, and social potential. It would be unfortunate if priorities were set or policy decisions made based on how developmental neurotoxicants compare to other risk factors using the current GBD methods.