Per- and polyfluoroalkyl substances (PFASs) are suspected developmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We examined ...associations of prenatal and childhood PFAS exposure with performance on assessments of cognition in children.
We included mother-child pairs from Project Viva, a longitudinal Boston-area birth cohort enrolled during 1999–2002. We quantified concentrations of eight PFASs, including perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS), in plasma collected from women during pregnancy (median 9.7 weeks gestation) and from children at a visit in mid-childhood (median age 7.7 years). In early childhood (median age 3.2 years) we administered standardized assessments of visual motor skills and vocabulary comprehension, and in mid-childhood we assessed visual motor skills, visual memory, and verbal and non-verbal intelligence. Using multivariable regression, we estimated associations of prenatal and childhood PFAS plasma concentrations with children's cognitive assessment scores, adjusted for relevant covariates including breastfeeding, maternal intelligence, parental education, and household income. Samples sizes ranged from 631 to 971, depending on analysis.
Prenatal PFAS concentrations were associated with both better and worse cognitive performance; children with top quartile prenatal concentrations of some PFASs had better visual motor abilities in early childhood and non-verbal IQ and visual memory in mid-childhood, while children with upper quartile prenatal PFOA and PFOS had lower mid-childhood visual-motor scores. In cross-sectional analyses of mid-childhood PFAS concentrations and cognitive assessments, visual-motor scores on the Wide Range Assessment of Visual Motor Abilities (WRAVMA) (standardized mean = 100, standard deviation = 15) were lower among children with higher PFHxS (fourth quartile (Q4) vs. Q1: −5.0, 95% confidence interval (CI): −9.1, −0.8). Upper quartiles of childhood PFOA and PFOS were also associated with somewhat lower childhood WRAVMA scores, but childhood PFASs were not associated with verbal or non-verbal IQ or visual memory.
We present evidence suggesting associations of prenatal and childhood PFAS exposure with lower childhood visual motor abilities. Other results were inconsistent, with higher prenatal PFASs associated in some cases with better cognitive outcomes.
•Per- and polyfluoroalkyl substances (PFASs) are suspected developmental toxicants.•We examined prenatal and childhood PFAS exposure in relation to child cognition.•Prenatal PFASs were associated with both better and worse cognitive scores.•Childhood PFASs were associated cross-sectionally with lower visual motor abilities.
Gulf War illness (GWI) is a disorder related to military service in the 1991 GW. Prominent symptoms include fatigue, pain and cognitive problems. These symptoms were reported by GW Veterans (GWV) ...immediately after the war and were eventually incorporated into case definitions of GWI. Neuropsychological function in GW veterans has been studied both among deployed GWV and in GWV diagnosed with GWI. Results have been inconsistent between and across GW populations. The purpose of the present investigation was to better characterize neuropsychological function in this veteran population.
Meta-analysis techniques were applied to published studies on neuropsychological performance in GWV to identify domains of dysfunction in deployed vs. non-deployed GW-era veterans and symptomatic vs. non-symptomatic GWVs.
Significantly decreased performance was found in three functional domains: attention and executive function, visuospatial skills and learning/memory.
These findings document the cognitive decrements associated with GW service, validate current GWI case definitions using cognitive criteria, and identify test measures for use in GWI research assessing GWI treatment trial efficacy.
Research on the health effects of chemical mixtures has focused mainly on early life rather than adolescence, a potentially important developmental life stage.
We examined associations of a metal ...mixture with general cognition in a cross-sectional study of adolescents residing near ferromanganese industry, a source of airborne metals emissions.
We measured manganese (Mn), lead (Pb), copper (Cu), and chromium (Cr) in hair, blood, urine, nails, and saliva from 635 Italian adolescents 10-14 years of age. Full-scale, verbal, and performance intelligence quotient (FSIQ, VIQ, PIQ) scores were assessed using the Wechsler Intelligence Scale for Children-III. Multivariable linear regression and Bayesian kernel machine regression (BKMR) were used to estimate associations of the metal mixture with IQ. In secondary analyses, we used BKMR's hierarchical variable selection option to inform biomarker selection for Mn, Cu, and Cr.
Median metal concentrations were as follows: hair Mn,
; hair Cu,
; hair Cr,
; and blood Pb,
. Adjusted models revealed an inverted U-shaped association between hair Cu and VIQ, consistent with Cu as an essential nutrient that is neurotoxic in excess. At low levels of hair Cu (10th percentile,
), higher concentrations (90th percentiles) of the mixture of Mn, Pb, and Cr (
,
, and
, respectively) were associated with a 2.9 (95% CI:
,
)-point decrease in VIQ score, compared with median concentrations of the mixture. There was suggestive evidence of interaction between Mn and Cu. In secondary analyses, saliva Mn, hair Cu, and saliva Cr were selected as the biomarkers most strongly associated with VIQ score.
Higher adolescent levels of Mn, Pb, and Cr were associated with lower IQ scores, especially at low Cu levels. Findings also support further investigation into Cu as both beneficial and toxic for neurobehavioral outcomes. https://doi.org/10.1289/EHP6803.
Veterans of Operation Desert Storm/Desert Shield − the 1991 Gulf War (GW) − are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and ...elsewhere have consistently concluded that approximately 25–32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities.
Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out.
This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008).
We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.
Influences of prenatal and early-life exposures to air pollution on cognition are not well understood.
We examined associations of gestational and childhood exposure to traffic-related pollution with ...childhood cognition.
We studied 1,109 mother-child pairs in Project Viva, a prospective birth cohort study in eastern Massachusetts (USA). In mid-childhood (mean age, 8.0 years), we measured verbal and nonverbal intelligence, visual motor abilities, and visual memory. For periods in late pregnancy and childhood, we estimated spatially and temporally resolved black carbon (BC) and fine particulate matter (PM2.5) exposures, residential proximity to major roadways, and near-residence traffic density. We used linear regression models to examine associations of exposures with cognitive assessment scores, adjusted for potential confounders.
Compared with children living ≥ 200 m from a major roadway at birth, those living < 50 m away had lower nonverbal IQ -7.5 points; 95% confidence interval (CI): -13.1, -1.9, and somewhat lower verbal IQ (-3.8 points; 95% CI: -8.2, 0.6) and visual motor abilities (-5.3 points; 95% CI: -11.0, 0.4). Cross-sectional associations of major roadway proximity and cognition at mid-childhood were weaker. Prenatal and childhood exposure to traffic density and PM2.5 did not appear to be associated with poorer cognitive performance. Third-trimester and childhood BC exposures were associated with lower verbal IQ in minimally adjusted models; but after adjustment for socioeconomic covariates, associations were attenuated or reversed.
Residential proximity to major roadways during gestation and early life may affect cognitive development. Influences of pollutants and socioeconomic conditions on cognition may be difficult to disentangle.
Exposure to environmental metals has been consistently associated with attention and behavioral deficits in children, and these associations may be modified by coexposure to other metals or iron (Fe) ...status. However, few studies have investigated Fe status as a modifier of a metal mixture, particularly with respect to attention-related behaviors.
We used cross-sectional data from the Public Health Impact of Metals Exposure study, which included 707 adolescents (10-14 years of age) from Brescia, Italy. Manganese, chromium, and copper were quantified in hair samples, and lead was quantified in whole blood, using inductively coupled plasma mass spectrometry. Concentrations of Fe status markers (ferritin, hemoglobin, transferrin) were measured using immunoassays or luminescence assays. Attention-related behaviors were assessed using the Conners Rating Scales Self-Report Scale-Long Form, Parent Rating Scales Revised-Short Form, and Teacher Rating Scales Revised-Short Form. We employed Bayesian kernel machine regression to examine associations of the metal mixture with these outcomes and evaluate Fe status as a modifier.
Higher concentrations of the metals and ferritin were jointly associated with worse self-reported attention-related behaviors: metals and ferritin set to their 90th percentiles were associated with 3.0%
; 95% credible interval (CrI):
, 0.06, 4.1% (
; 95% CrI: 0.00, 0.08), and 4.1% (
; 95% CrI: 0.00, 0.08) higher
-scores for self-reported attention deficit/hyperactivity disorder (ADHD) index, inattention, and hyperactivity, respectively, compared with when metals and ferritin were set to their 50th percentiles. These associations were driven by hair manganese, which exhibited nonlinear associations with all self-reported scales. There was no evidence that Fe status modified the neurotoxicity of the metal mixture. The metal mixture was not materially associated with any parent-reported or teacher-reported scale.
The overall metal mixture, driven by manganese, was adversely associated with self-reported attention-related behavior. These findings suggest that exposure to multiple environmental metals impacts adolescent neurodevelopment, which has significant public health implications. https://doi.org/10.1289/EHP12988.
Early life exposure to per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment, but epidemiological findings are inconsistent. In the Project Viva pre-birth cohort, we ...examined associations of prenatal and childhood PFAS plasma concentrations with parent and teacher assessments of children's behavior problems Strengths and Difficulties Questionnaire (SDQ) and executive function abilities Behavior Rating Inventory of Executive Function (BRIEF) at age 6–10 years (sample sizes 485–933). PFAS concentrations in pregnant Project Viva mothers (in 1999–2002) and children at ages 6–10 (in 2007–10) were similar to concentrations at similar time points in women and children in the nationally representative U.S. National Health and Nutrition Examination Survey. We observed no consistent associations of prenatal PFAS concentrations with behavior or executive function. Childhood concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) were associated with higher parent-rated SDQ Total Difficulties scores (mean = 6.7, standard deviation (SD) = 4.9), suggesting greater behavioral problems (top (Q4) versus bottom (Q1) quartile PFOA: 1.5, 95% confidence interval (CI): 0.3, 2.7; PFOS: 1.4, 95% CI: 0.3, 2.5; PFHxS: 1.2, 95% CI: 0.1, 2.3; PFNA: 1.2, 95% CI: 0.1, 2.2; PFDA: 1.1, 95% CI: 0.0, 1.1); teacher-rated SDQ scores did not show associations. Higher childhood PFOS was associated with higher (indicating more problems) parent-rated BRIEF General Executive Composite (GEC) scores (standardized to mean = 50, SD = 10) (Q4 vs. Q1: 2.4, 95% CI: 0.2, 4.6), while teacher BRIEF GEC scores indicated more problems among children with higher PFHxS (Q4 vs. Q1: 3.5, 95% CI: −0.8, 6.3). There were no consistent patterns of sexual dimorphism in associations. In a cohort of U.S. children, we observed cross-sectional associations of childhood PFAS concentrations with greater behavioral and executive function problems, but no consistent associations with prenatal PFAS.
•Per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment.•We assessed early life PFAS and mid-childhood behavior and executive function.•We observed no consistent associations with prenatal PFAS concentrations.•Childhood PFAS were associated with behavioral and executive function problems.•There were no consistent patterns of sexual dimorphism in observed associations.
A cohort of 1022 consecutive singleton births was generated during 1987–1988 in the Faroe Islands, where increased methylmercury exposure occurs from traditional seafood diets that include pilot ...whale meat. The prenatal exposure level was determined from mercury analyses of cord blood, cord tissue, and maternal hair. At age 14 years, 878 of 1010 living cohort members underwent detailed neurobehavioral examination. Eighteen participants with neurological disorders were excluded. Blood and hair samples obtained from the participants were analyzed for mercury. The neuropsychological test battery was designed based on the same criteria as applied at the examination at age 7 years. Multiple regression analysis was carried out and included adjustment for confounders. Indicators of prenatal methylmercury exposure were significantly associated with deficits in finger tapping speed, reaction time on a continued performance task, and cued naming. Postnatal methylmercury exposure had no discernible effect. These findings are similar to those obtained at age 7 years, and the relative contribution of mercury exposure to the predictive power of the multiple regression models was also similar. An analysis of the test score difference between results at 7 and 14 years suggested that mercury-associated deficits had not changed between the two examinations. In structural equation model analyses, the neuropsychological tests were separated into five groups; methylmercury exposure was significantly associated with deficits in motor, attention, and verbal tests. These findings are supported by independent assessment of neurophysiological outcomes. The effects on brain function associated with prenatal methylmercury exposure therefore appear to be multi-focal and permanent.
Metals, including lead (Pb), manganese (Mn), chromium (Cr) and copper (Cu), have been associated with neurodevelopment; iron (Fe) plays a role in the metabolism and neurotoxicity of metals, ...suggesting Fe may mediate metal-neurodevelopment associations. However, no study to date has examined Fe as a mediator of the association between metal mixtures and neurodevelopment.
We assessed Fe status as a mediator of a mixture of Pb, Mn, Cr and Cu in relation to verbal learning and memory in a cohort of Italian adolescents.
We used cross-sectional data from 383 adolescents (10–14 years) in the Public Health Impact of Metals Exposure Study. Metals were quantified in blood (Pb) or hair (Mn, Cr, Cu) using ICP-MS, and three markers of Fe status (blood hemoglobin, serum ferritin and transferrin) were quantified using luminescence assays or immunoassays. Verbal learning and memory were assessed using the California Verbal Learning Test for Children (CVLT-C). We used Bayesian Kernel Machine Regression Causal Mediation Analysis to estimate four mediation effects: the natural direct effect (NDE), natural indirect effect (NIE), controlled direct effect (CDE) and total effect (TE). Beta (β) coefficients and 95 % credible intervals (CIs) were estimated for all effects.
The metal mixture was jointly associated with a greater number of words recalled on the CVLT-C, but these associations were not mediated by Fe status. For example, when ferritin was considered as the mediator, the NIE for long delay free recall was null (β = 0.00; 95 % CI = −0.22, 0.23). Conversely, the NDE (β = 0.23; 95 % CI = 0.01, 0.44) indicated a beneficial association of the mixture with recall that operated independently of Fe status.
An industry-relevant metal mixture was associated with learning and memory, but there was no evidence of mediation by Fe status. Further studies in populations with Fe deficiency and greater variation in metal exposure are warranted.
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•Metals have been linked with neurodevelopment, but less is known about the role of iron (Fe) status.•We examined Fe status as a mediator of associations between a metal mixture and learning and memory.•The mixture was associated with neurodevelopment; there was no evidence of mediation by Fe status.
Manganese (Mn) is an essential element required for growth and development, but higher body burdens have been associated with neurobehavioral decrements in children.
We examined whether prenatal or ...postnatal Mn measured in deciduous teeth was associated with scores on a test of visuospatial learning and memory.
Deciduous teeth were collected from 142 participants (ages 10–14years) residing near varied ferro‑manganese industry in Italy. Mn concentrations were measured in prenatal and postnatal tooth regions by laser ablation inductively coupled plasma mass spectrometry (ICP-MS). The Virtual Radial Arm Maze (VRAM), an animal-human analogue task, was used to assess visuospatial learning and memory. We used generalized additive, linear and zero-inflated Poisson mixed regression models to estimate associations between prenatal or postnatal Mn concentrations and repeated measures of all four VRAM outcomes: time, distance, working and reference memory errors. Effect measure modification by sex was examined in stratified models.
U-shaped associations between prenatal Mn and VRAM outcomes were observed among girls only (pGAMM=0.001 to 0.02 in stratified models). Compared to the mid-tertile of prenatal Mn, girls in the highest tertile took 7.7s 95% CI: −6.1, 21.5 longer to complete the task, traveled 2.3 maze units 0.1, 4.4 farther, and committed more working and reference memory errors (β for count ratio=1.33 1.01, 1.83; 1.10 0.98, 1.24, respectively). This association was not observed among boys. In contrast, for postnatal Mn, no significant associations were found, and patterns were similar for boys and girls.
The prenatal period may be a critical window for the impact of environmental Mn on visuospatial ability and executive function, especially for females.
•Children are vulnerable to Mn toxicity, yet susceptibility factors are understudied.•We measured Mn in teeth to estimate exposure during critical developmental windows.•Complex visuospatial ability was measured using an animal task adapted for humans.•The prenatal period may be important for Mn effects on girls' visuospatial ability.
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