Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Urinary concentrations and determinants of glyphosate and glufosinate in pregnant Canadian participants in the MIREC study.

BACKGROUND: Glyphosate is the most widely applied herbicide in agriculture. Glufosinate is a broad spectrum herbicide used to manage glyphosate-resistant weeds. Despite the widespread use of these herbicides, biomonitoring data - which inform risk assessment and management - are sparse. OBJECTIVES: To identify determinants of urinary concentrations of these herbicides and their metabolites in pregnancy. METHODS: We measured urinary concentrations of glyphosate, glufosinate, and their primary metabolites aminomethylphosphonic acid (AMPA) and 3-methylphosphinicopropionic acid (3-MPPA) in a single spot urine specimen collected during the first trimester of pregnancy from the Maternal-Infant Research on Environmental Chemicals (MIREC) study. MIREC recruited about 2000 pregnant women from 10 Canadian cities between 2008 and 2011. We used UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) with sensitive limits of detection to quantify analyte concentrations. We examined urinary concentrations according to maternal sociodemographics, sample collection characteristics, reported pesticide use, and consumption of fruits, vegetables, legumes, and grain products. We used ANOVA models with specific gravity-standardized chemical concentrations as the dependent variable to determine associations with maternal and sample determinants. RESULTS: Among women with biobanked urine samples (n = 1829-1854), 74% and 72% had detectable concentrations of glyphosate and AMPA, respectively. In contrast, one and six percent of women had detectable concentrations of glufosinate and 3-MPPA, respectively. The specific gravity-standardized geometric mean (95% CI) concentrations of glyphosate and AMPA were 0.112 (0.099-0.127) µg/L and 0.159 (0.147-0.172) µg/L, respectively. We observed a dose-response relationship between consumption of whole grain bread and higher urinary glyphosate concentrations. Season of urine collection and self-reported pesticide use were not associated with increased concentrations of any analyte. CONCLUSIONS: We detected glyphosate and AMPA in the majority of pregnant women from this predominantly urban Canadian cohort. Diet was a probable route of exposure.

Prenatal and concurrent blood mercury concentrations and associations with IQ in canadian preschool children.

BACKGROUND: Prenatal and childhood mercury (Hg) exposures have been associated with negative impacts on child neurodevelopment. It is unclear if associations persist at the low Hg exposures typical in Western countries. OBJECTIVE: To examine associations between prenatal/childhood blood Hg concentrations and child IQ in Canadian male and female children while considering the potential modifying role of prenatal fish consumption. METHODS: We analyzed data from the Maternal-Infant Research on Environmental Chemicals study. Hg was measured in first trimester (n = 527), cord (n = 430), and child (at 3-4 years of age, n = 355) blood and examined sex-stratified associations between blood Hg and children's Full Scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), and General Language Composite (GLC) scores (assessed with WPPSI-III). Prenatal Hg analyses were further stratified by prenatal fish consumption (low: 0-2, moderate: 3-7, or high: ≥8 times/month). RESULTS: Higher cord blood Hg concentrations were associated with lower PIQ (ß = -3.27; 95%CI: 6.44, -0.09) in male children with the lowest prenatal fish consumption. Progressively stronger positive associations were observed with PIQ in male children for moderate (ß = 1.08; 95%CI: 0.10, 2.26) and high (ß = 3.07; 95%CI: 1.95, 4.19) prenatal fish consumption. Cord blood Hg concentrations were positively associated with female children's FSIQ (ß = 1.29; 95% CI: 0.77, 1.81) and PIQ (ß = 2.01; 95% CI: 1.19, 2.83); however, when stratified only in the highest fish consumption subgroup. Among female children, higher child blood Hg concentrations were associated with an approximately 1-point increase in FSIQ, VIQ, and GLC. CONCLUSIONS: Prenatal exposure to low levels of Hg was associated with lower PIQ scores in male children with low prenatal fish intake. Positive associations between cord and child blood Hg concentrations and IQ were primarily observed in female children and may be due to beneficial effects of prenatal fish intake.

Organophosphate pesticides exposure during fetal development and IQ scores in 3 and 4-year old Canadian children.

BACKGROUND: Organophosphate pesticides are widely used in agriculture and for other purposes, leading to ubiquitous exposure in human populations. Some studies reported cognitive deficits in children exposed prenatally to organophosphate pesticides, but findings from recent studies were inconsistent. Furthermore, recent biomonitoring studies suggest exposure levels have decreased. Hence, the risks from current prenatal exposure to organophosphate pesticides for child neurodevelopment are uncertain. Furthermore, sex-differences also remain to be better documented in relation to potential neurodevelopmental effects. OBJECTIVE: To examine the association between prenatal exposure to organophosphate pesticides and IQ scores among boys and girls living in several major Canadian cities. METHODS: We used data from the MIREC cohort (Maternal-Infant Research on Environmental Chemicals). Women were recruited in 2008-2011 from 10 Canadian cities during their first trimester of pregnancy, and urine spot samples were collected for measurement of three dimethyl alkyl phosphate (DMAP) and three diethyl alkyl phosphate (DEAP) metabolites. When children were 3-4 years of age, we used the Wechsler Preschool and Primary Scales of Intelligence-III (WPPSI-III) to assess cognitive ability of children from 6 out of the 10 cities (Halifax, Hamilton, Kingston, Montreal, Toronto, and Vancouver). We analysed the association between maternal exposure to organophosphate pesticides (DMAP and DEAP urinary metabolites) and children's IQ scores with generalized estimating equations (GEEs) to take into account the clustered-data resulting from the six study sites. All analyses were sex-stratified (n = 296 boys and 311 girls). RESULTS: The participants were predominantly well-educated, white women, with a relatively high household income. Children had a mean age of 3.4 years at the moment of IQ assessment (range, 3.0-4.1 years). In girls, there was no association between IQ scores and DEAPs or DMAPs. Higher concentrations of DEAPs were significantly associated with poorer Verbal IQ scores (for a 10-fold increase in concentrations, -6.28; 95% CIs, -12.13, -0.43) in boys. The association for Performance IQ in boys also indicated poorer scores with higher DEAP concentrations, but the confidence intervals included the null value (-4.05; 95% CIs, -10.19, 2.10). The relation between DMAPs and IQ scores in boys was also negative, but association estimates were small and not significant. CONCLUSION: Urinary metabolites of organophosphate pesticides were not associated with IQ in girls, but we observed that higher maternal urinary DEAPs were associated with poorer Verbal IQ in boys. However, exposure misclassification may be an issue as only one urine sample per woman was analysed. The present study contributes to the accumulating evidence linking exposure to organophosphate pesticides during fetal development with poorer cognitive function in children, bringing data on the risks in a context of low exposure levels encountered in primarily urban populations from Canada.

Blood metal levels and early childhood anthropometric measures in a cohort of Canadian children.

Fetal exposure to some toxic metals has been associated with reduced fetal growth, but the impact of contemporary, low-level metals on anthropometric measures in childhood is not well understood. Our primary objective was to quantify associations between childhood levels of toxic metals and concurrently measured body mass index (BMI) in a population of Canadian preschool-aged children. We collected biomonitoring data and anthropometric measures on 480 children between the ages of two and five years in the Maternal-Infant Research on Environmental Chemicals (MIREC) Child Development Plus study. Concentrations of four toxic metals (lead, arsenic, cadmium, and mercury) were measured in whole blood collected from pregnant women and their children. Blood levels of key essential elements were also measured in children. Children's weight, height, and BMI z-scores were calculated using the World Health Organization growth standards. We used a series of linear regression models, adjusted for potential parental confounders, concurrently measured metals and elements, and prenatal blood metal levels, to evaluate associations between tertiles of each toxic metal and anthropometric measures. We tested for effect modification by sex. Of the 480 children, 449 (94%) were singleton births and had complete biomonitoring and anthropometric data. The majority of children had detectable concentrations of metals. In the adjusted models, girls with blood lead concentrations in the highest tertile (>0.82 µg/dL) had, on average, 0.26 (95% Cl: -0.55, 0.03) lower BMI z-scores than those in the referent category. In contrast, boys with lead levels in the highest tertile had, on average, 0.14 higher BMI z-scores (95% Cl: -0.14, 0.41) (p-value heterogeneity = 0.04). In this population of Canadian preschool-aged children with low-level blood lead concentrations, we observed effect modification by sex in the association between Pb and BMI but no statistically significant associations in the sex-specific strata. Child blood levels of As, Cd, and Hg were not associated with childhood BMI, weight, or height in boys or girls.

Associations between maternal triclosan concentrations in early pregnancy and gestational diabetes mellitus, impaired glucose tolerance, gestational weight gain and fetal markers of metabolic function.

BACKGROUND: Triclosan is a phenolic biocide used in a multitude of consumer products and in health care settings. It is widely detected in the American and Canadian populations and has been shown in animal models to act as an endocrine disrupting agent. However, there has been little examination to date of the effects of triclosan exposure in pregnancy on perinatal metabolic outcomes in human populations. METHODS: Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a Canadian pregnancy cohort, we measured associations of first-trimester urinary triclosan concentrations with total gestational weight gain, gestational diabetes mellitus and impaired glucose tolerance in pregnancy, and fetal markers of metabolic function. Leptin and adiponectin were measured in plasma from umbilical cord blood samples in term neonates and categorized into low (< 10th percentile), intermediate (10th-90th percentile) and high (> 90th percentile) levels. Triclosan concentrations were grouped into quartiles and associations with study outcomes were examined using logistic regression models with adjustment for maternal age, race/ethnicity, pre-pregnancy BMI, education and urinary specific gravity. Restricted cubic spline analysis was performed to help assess linearity and shape of any dose-response relationships. All analyses for leptin and adiponectin levels were performed on the entire cohort as well as stratified by fetal sex. RESULTS: Triclosan measures were available for 1795 MIREC participants with a live born singleton birth. Regression analyses showed a non-significant inverse association between triclosan concentrations and leptin levels above the 90th percentile that was restricted to female fetuses (OR for highest quartile of triclosan compared to lowest quartile = 0.4 (95% CI 0.2-1.1), p-value for trend across quartiles = 0.02). Triclosan concentrations in the second quartile were associated with elevated odds of adiponectin below the 10th percentile in male fetuses (OR for Q2 compared to Q1 = 2.5, 95% CI 1.1-5.9, p-value for trend across quartiles = 0.93). No significant linear associations between triclosan concentrations and leptin or adiponectin levels in overall or sex-specific analyses were observed from restricted cubic spline analyses. No significant associations were observed in adjusted analyses between triclosan concentrations and gestational diabetes mellitus, impaired glucose tolerance or gestational weight gain. CONCLUSIONS: This study does not support an association between triclosan concentrations in pregnancy and fetal metabolic markers, glucose disorders of pregnancy, or excessive gestational weight gain.

Maternal Concentrations of Perfluoroalkyl Substances and Fetal Markers of Metabolic Function and Birth Weight.

Perfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals that have been widely used in the production of common household and consumer goods for their nonflammable, lipophobic, and hydrophobic properties. Inverse associations between maternal or umbilical cord blood concentrations of perfluorooctanoic acid and perfluorooctanesulfonate and birth weight have been identified. This literature has primarily examined each PFAS individually without consideration of the potential influence of correlated exposures. Further, the association between PFAS exposures and indicators of metabolic function (i.e., leptin and adiponectin) has received limited attention. We examined associations between first-trimester maternal plasma PFAS concentrations and birth weight and cord blood concentrations of leptin and adiponectin using data on 1,705 mother-infant pairs from the Maternal Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada birth cohort study that recruited women between 2008 and 2011. Bayesian hierarchical models were used to quantify associations and calculate credible intervals. Maternal perfluorooctanoic acid concentrations were inversely associated with birth weight z score, though the null value was included in all credible intervals (log10 ß = −0.10, 95% credible interval: −0.34, 0.13). All associations between maternal PFAS concentrations and cord blood adipocytokine concentrations were of small magnitude and centered around the null value. Follow-up in a cohort of children is required to determine how the observed associations manifest in childhood.

Air Pollution Exposure During Pregnancy and Fetal Markers of Metabolic function: The MIREC Study.

Previous evidence suggests that exposure to outdoor air pollution during pregnancy could alter fetal metabolic function, which could increase the risk of obesity in childhood. However, to our knowledge, no epidemiologic study has investigated the association between prenatal exposure to air pollution and indicators of fetal metabolic function. We investigated the association between maternal exposure to nitrogen dioxide and fine particulate matter (aerodynamic diameter ≤2.5 µm) and umbilical cord blood leptin and adiponectin levels with mixed-effects linear regression models among 1,257 mother-infant pairs from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, conducted in Canada (2008-2011). We observed that an interquartile-range increase in average exposure to fine particulate matter (3.2 µg/m(3)) during pregnancy was associated with an 11% (95% confidence interval: 4, 17) increase in adiponectin levels. We also observed 13% (95% confidence interval: 6, 20) higher adiponectin levels per interquartile-range increase in average exposure to nitrogen dioxide (13.6 parts per billion) during pregnancy. Significant associations were seen between air pollution markers and cord blood leptin levels in models that adjusted for birth weight z score but not in models that did not adjust for birth weight z score. The roles of prenatal exposure to air pollution and fetal metabolic function in the potential development of childhood obesity should be further explored.

Exposure to organophosphorus and organochlorine pesticides, perfluoroalkyl substances, and polychlorinated biphenyls in pregnancy and the association with impaired glucose tolerance and gestational diabetes mellitus: The MIREC Study.

BACKGROUND: Studies report increases in rates of gestational diabetes mellitus (GDM) over recent decades. Environmental chemicals may increase the risk of diabetes through impacts on glucose metabolism, mitochondrial dysfunction, and endocrine-disrupting mechanisms including effects on pancreatic ß-cell function and adiponectin release. OBJECTIVES: To determine the associations between pesticides, perfluoroalkyl substances (PFASs) and polychlorinated biphenyls (PCBs) measured in early pregnancy and impaired glucose tolerance (IGT) and GDM in a Canadian birth cohort. METHODS: Women enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study were included if they had a singleton delivery and did not have pre-existing diabetes. Exposure variables included three organophosphorus (OP) pesticide metabolites detected in first-trimester urine samples, as well as three organochlorine (OC) pesticides, three PFASs, and four PCBs in first-trimester blood samples. Gestational IGT and GDM were assessed by chart review in accordance with published guidelines. Adjusted logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI) for the association between quartiles of environmental chemicals and both gestational IGT and GDM. RESULTS: Of the 2001 women recruited into the MIREC cohort, 1274 met the inclusion criteria and had outcome and biomonitoring data available. Significantly lower odds of GDM were observed in the third and fourth quartiles of dimethylphosphate (DMP) and in the fourth quartile of dimethylthiophosphate (DMTP) in adjusted analyses (DMP Q3: OR=0.2, 95% CI=0.1-0.7; DMP Q4: OR=0.3, 95% CI=0.1-0.8; DMTP: OR=0.3, 95% CI=0.1-0.9). Significantly elevated odds of gestational IGT was observed in the second quartile of perfluorohexane sulfonate (PFHxS) (OR=3.5, 95% CI=1.4-8.9). No evidence of associations with GDM or IGT during pregnancy was observed for PCBs or OC pesticides. CONCLUSIONS: We did not find consistent evidence for any positive associations between the chemicals we examined and GDM or IGT during pregnancy. We observed statistical evidence of inverse relationships between urine concentrations of DMP and DMTP with GDM. We cannot rule out the influence of residual confounding due to unmeasured protective factors, such as nutritional benefits from fruit and vegetable consumption, also associated with pesticide exposure, on the observed inverse associations between maternal OP pesticide metabolites and GDM. These findings require further investigation.

Maternal blood metal levels and fetal markers of metabolic function.

Exposure to metals commonly found in the environment has been hypothesized to be associated with measures of fetal growth but the epidemiological literature is limited. The Maternal-Infant Research on Environmental Chemicals (MIREC) study recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. Our objective was to assess the association between prenatal exposure to metals (lead, arsenic, cadmium, and mercury) and fetal metabolic function. Average maternal metal concentrations in 1st and 3rd trimester blood samples were used to represent prenatal metals exposure. Leptin and adiponectin were measured in 1363 cord blood samples and served as markers of fetal metabolic function. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between metals and both high (≥ 90%) and low (≤ 10%) fetal adiponectin and leptin levels. Leptin levels were significantly higher in female infants compared to males. A significant relationship between maternal blood cadmium and odds of high leptin was observed among males but not females in adjusted models. When adjusting for birth weight z-score, lead was associated with an increased odd of high leptin. No other significant associations were found at the top or bottom 10th percentile in either leptin or adiponectin models. This study supports the proposition that maternal levels of cadmium influence cord blood adipokine levels in a sex-dependent manner. Further investigation is required to confirm these findings and to determine how such findings at birth will translate into childhood anthropometric measures.

Sex- and age-differences in blood manganese levels in the U.S. general population: national health and nutrition examination survey 2011-2012.

BACKGROUND: Manganese is an essential element, but excessive manganese exposure has neurotoxic effects. OBJECTIVE: To examine blood manganese levels in the general population with respect to sex, age, race/ethnicity, pregnancy and menauposal status, as well as levels of trace elements in blood. METHODS: We used data from the National Health and Nutrition Examination Survey, a national survey of U.S. residents (n = 7720 participants, ages 1 to 80 years). General linear models and generalized additive models were used to examine the association between blood manganese concentration and participants' characterisics, accounting for the complex survey design. RESULTS: Blood manganese levels ranged from 1.6 to 62.5 µg/L, with arithmetic means of 10.6 and 9.2 µg/L for women and men, respectively. The following characteristics were significantly associated with higher blood manganese levels: female sex, younger age, Asian origin, and being pregnant. In addition, there were non-linear relationships between blood manganese levels and cadmium, iron, lead, and mercury levels. CONCLUSION: The higher blood manganese levels observed among females suggest sex-related metabolic differences in the regulation of manganese, and elevated levels among pregnant women suggest an important role of manganese in reproduction. The present study supports the need to take into consideration age- and sex-related differences in blood manganese levels, as well as pregnancy status when examining manganese essentiality or toxicity.

A birth cohort study to investigate the association between prenatal phthalate and bisphenol A exposures and fetal markers of metabolic dysfunction.

BACKGROUND: Obesity and type-2 diabetes are on the rise and in utero exposure to environmental contaminants is a suspected contributing factor. Our objective was to examine associations between prenatal exposure to potential endocrine disrupting chemicals and markers of fetal metabolic dysfunction. METHODS: The Maternal-Infant Research on Environmental Chemicals Study (MIREC) recruited 2001 women during the first trimester of pregnancy from 10 Canadian sites. First trimester maternal urine was measured for 11 phthalate metabolites and bisphenol A (BPA). Leptin and adioponectin measured in 1,363 available umbilical cord blood samples served as markers of metabolic function. Restricted cubic spline curves were used to assess the relationship between continuous measures of phthalate and BPA levels and cord blood adipokines. Polytomous logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between phthalates and BPA and both high (≥90th percentile) and low (≤10th percentile) fetal adiponectin and leptin, adjusting for confounding factors. Analyses were conducted for all subjects, overall, and separately by fetal sex. RESULTS: Leptin was significantly higher in female than male infants. We observed an inverse, non-linear relationship between BPA and adiponectin among males in the restricted cubic spline and linear regression analysis. Mono-(3-carboxypropyl) (MCPP) was associated with increased odds of high leptin among males in the polytomous logistic regression models (4th quartile OR = 3.5 95% CI: 1.1-11.6). CONCLUSION: Our findings contribute to the growing body of evidence examining the influence of early life exposure on metabolic regulation and function. Associations between maternal exposure to chemicals and markers of metabolic function appear to be potentially sex specific. However, further investigation is required to determine whether in utero and childhood exposure to BPA and phthalates are associated with metabolic dysfunctions later in life.

Using in vitro data to derive acceptable exposure levels: A case study on PBDE developmental neurotoxicity.

BACKGROUND: Current acceptable chemical exposure levels (e.g., tolerable daily intake) are mainly based on animal experiments, which are costly, time-consuming, considered non-ethical by many, and may poorly predict adverse outcomes in humans. OBJECTIVE: To evaluate a method using human in vitro data and biological modeling to calculate an acceptable exposure level through a case study on 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity (DNT). METHODS: We reviewed the literature on in vitro assays studying BDE-47-induced DNT. Using the most sensitive endpoint, we derived a point of departure using a mass-balance in vitro disposition model and benchmark dose modeling for a 5% response (BMC05) in cells. We subsequently used a pharmacokinetic model of gestation and lactation to estimate administered equivalent doses leading to four different metrics of child brain concentration (i.e., average prenatal, average postnatal, average overall, and maximum concentration) equal to the point of departure. The administered equivalent doses were translated into tolerable daily intakes using uncertainty factors. Finally, we calculated biomonitoring equivalents for maternal serum and compared them to published epidemiological studies of DNT. RESULTS: We calculated a BMC05 of 164 µg/kg of cells for BDE-47 induced alteration of differentiation in neural progenitor cells. We estimated administered equivalent doses of 0.925-3.767 µg/kg/day in mothers, and tolerable daily intakes of 0.009-0.038 µg/kg/day (composite uncertainty factor: 100). The lowest derived biomonitoring equivalent was 19.75 ng/g lipids, which was consistent with reported median (0.9-23 ng/g lipids) and geometric mean (7.02-26.9 ng/g lipids) maternal serum concentrations from epidemiological studies. CONCLUSION: This case study supports using in vitro data and biological modeling as a viable alternative to animal testing to derive acceptable exposure levels.

Density and proximity of oil and gas wells and concentrations of trace elements in urine, hair, nails and tap water samples from pregnant individuals living in Northeastern British Columbia.

BACKGROUND: Oil and gas exploitation can release several contaminants in the environment, including trace elements, with potentially deleterious effects on exposed pregnant individuals and their developing fetus. Currently, there is limited data on pregnant individuals' exposure to contaminants associated with oil and gas activity. OBJECTIVES: We aimed to 1)measure concentrations of trace elements in biological and tap water samples collected from pregnant individuals participating in the EXPERIVA study; 2)compare with reference populations and health-based guidance values; 3)assess correlations across matrices; and 4)evaluate associations with the density/proximity of oil and gas wells. METHODS: We collected tap water, hair, nails, and repeated urine samples from 85pregnant individuals, and measured concentrations of 21trace elements. We calculated oil and gas well density/proximity (Inverse Distance Weighting [IDW]) for 4buffer sizes (2.5 km, 5 km, 10 km, no buffer). We performed Spearman's rank correlation analyses to assess the correlations across elements and matrices. We used multiple linear regression models to evaluate the associations between IDWs and concentrations. RESULTS: Some study participants had urinary trace element concentrations exceeding the 95th percentile of reference values; 75% of participants for V, 29% for Co, 22% for Ba, and 20% for Mn. For a given trace element, correlation coefficients ranged from -0.23 to 0.65 across matrices; correlations with tap water concentrations were strongest for hair, followed by nails, and urine. Positive (e.g., Cu, Cr, Sr, U, Ga, Ba, Al, Cd) and negative (e.g., Fe) associations were observed between IDW metrics and the concentrations of certain trace elements in water, hair, and nails. SIGNIFICANCE: Our results suggest that pregnant individuals living in an area of oil and gas activity may be more exposed to certain trace elements (e.g., Mn, Sr, Co, Ba) than the general population. Association with density/proximity of wells remains unclear.

A cohort study of the multipollutant effects of PM2.5, NO2, and O3 on C-reactive protein levels during pregnancy.

Background: PM2.5, NO2, and O3 contribute to the development of adverse pregnancy complications. While studies have investigated the independent effects of these exposures, literature on their combined effects is limited. Our objective was to study the multipollutant effects of PM2.5, NO2, and O3 on maternal systemic C-reactive protein (CRP) levels. Methods: We used data from 1170 pregnant women enrolled in the Maternal-Infant Research on Environmental Chemicals Study (MIREC) study in Canada. Air pollution exposures were assigned to each participant based on residential location. CRP was measured in third-trimester blood samples. We fit multipollutant linear regression models and evaluated the effects of air pollutant mixtures (14-day averages) using repeated-holdout Weighted Quantile Sum (WQS) regression and by calculating the Air Quality Health Index (AQHI). Results: In multipollutant models adjusting for NO2, O3, and green space, each interquartile range (IQR) increase in 14-day average PM2.5 (IQR: 6.9 µg/m3) was associated with 27.1% (95% confidence interval [CI] = 6.2, 50.7) higher CRP. In air pollution mixture models adjusting for green space, each IQR increase in AQHI was associated with 37.7% (95% CI = 13.9, 66.5) higher CRP; and an IQR increase in the WQS index was associated with 78.6% (95% CI = 29.7, 146.0) higher CRP. Conclusion: PM2.5 has the strongest relationship of the individual pollutants examined with maternal blood CRP concentrations. Mixtures incorporating all three pollutants, assessed using the AQHI and WQS index, showed stronger relationships with CRP compared with individual pollutants and illustrate the importance of conducting multipollutant analyses.

Computerized Cognitive Test Batteries for Children and Adolescents-A Scoping Review of Tools For Lab- and Web-Based Settings From 2000 to 2021.

OBJECTIVE: Cognitive functioning is essential to well-being. Since cognitive difficulties are common in many disorders, their early identification is critical, notably during childhood and adolescence. This scoping review aims to provide a comprehensive literature overview of computerized cognitive test batteries (CCTB) that have been developed and used in children and adolescents over the past 22 years and to evaluate their psychometric properties. METHOD: Among 3192 records identified from three databases (PubMed, PsycNET, and Web of Science) between 2000 and 2021, 564 peer-reviewed articles conducted in children and adolescents aged 3 to 18 years met inclusion criteria. Twenty main CCTBs were identified and further reviewed following PRISMA guidelines. Relevant study details (sample information, topic, location, setting, norms, and psychometrics) were extracted, as well as administration and instrument characteristics for the main CCTBs. RESULTS: Findings suggest that CCTB use varies according to age, location, and topic, with eight tools accounting for 85% of studies, and the Cambridge Neuropsychological Test Automated Battery (CANTAB) being most frequently used. Few instruments were applied in web-based settings or include social cognition tasks. Only 13% of studies reported psychometric properties. CONCLUSIONS: Over the past two decades, a high number of computerized cognitive batteries have been developed. Among these, more validation studies are needed, particularly across diverse cultural contexts. This review offers a comprehensive synthesis of CCTBs to aid both researchers and clinicians to conduct cognitive assessments in children in either a lab- or web-based setting.

Measurement of 24 phthalate metabolites in 1st trimester urine samples: The MIREC study.

Phthalates are non-persistent chemicals measured as metabolites in urine. Over time, new metabolites have been identified. In the original Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008-2011), we measured 11 phthalate metabolites in first trimester urine samples. The goal of the present study was to develop a method to measure new metabolites, to increase the sensitivity for some previously measured metabolites, and to measure these new metabolites in biobanked urine samples from MIREC participants. Using Ultra Performance Liquid Chromatography with a tandem mass spectrometer, we developed a method to measure 24 metabolites from 10 different parent phthalates. Chromatographic interpretation of some of the di-iso-decyl phthalate metabolites (mono-(2-propyl-6oxoheptyl) phthalate (MOiDP), mono-(2,7-methyl-7-carboxyheptyl) phthalate (MCiNP), mono-(2-propyl-6-hydroxy-heptyl) phthalate (MHiDP)) and di-iso-nonyl phthalate metabolites (mono(oxo-isononyl) phthalate (MOiNP), mono(carboxy-isooctyl) phthalate (MCiOP), mono(hydroxy-isononyl) phthalate (MHiNP) and mono-isononyl phthalate (MiNP)) was challenging as these are complex isomeric mixtures. To validate and confirm our quantitation peaks, an assay using a high-resolution detection technique was developed on a Quadrupole Time-of-Flight (QToF) system. This system has a mass resolution of at least 0.005 amu, compared to 0.5 amu for the MS/MS detector. Using the QToF system, the distinction between an isomer and possible interference was achieved with the use of the exact mass. In about 1800 MIREC samples, mono-cyclo-hexyl phthalate (MCHP), mono-(7-carboxy-n-heptyl) phthalate (MCHpP), mono-iso-decyl phthalate (MiDP), and mono-n-octyl phthalate (MnOP) were rarely detected, while detection of MMP was improved. MCiOP, MiNP and MCiNP had to be reported semi-quantitatively. Given the complexity of isomeric mixtures of some phthalates, researchers must be careful in their determination of the analytes and the approach used in their quantification when generating biomonitoring data. This study produced biomonitoring data for a large population of pregnant people that can be used in risk assessment of phthalates. Future work will examine associations with birth and child outcomes.

Childhood exposure to pyrethroids and neurodevelopment in Canadian preschoolers.

BACKGROUND: Pyrethroid insecticides are used both residentially and agriculturally and their toxicity targets the nervous system of insects. They might also interfere with development and function of the human brain. A few epidemiological studies suggest that exposure to pyrethroids may be associated with neurobehavioral problems in children but there is little data on potential associations with cognitive outcomes. Furthermore, many studies showed that the neurotoxic effects of several pesticides are modified by sex, hence, considerations of potential sex-differences are important to investigate. OBJECTIVE: To study the cross-sectional association between urinary levels of pyrethroid metabolites and neurodevelopment, including neurobehavioral and cognitive outcomes, in preschool-age children, and to examine whether sex might modify these associations. METHODS: We used data from a follow-up examination of the Maternal-Infant Research on Environmental Chemicals (MIREC), the MIREC Child Development study (MIREC-CD Plus) on children at age 3-4 years living in 6 Canadian cities. For each participant, we collected a urine sample for measurements of pyrethroids metabolites (cis-DBCA, cis-DCCA, trans-DCCA, 3-PBA, 4-F-3-PBA). We assessed neurodevelopment with the Wechsler Primary and Preschool Scale of Intelligence-III (WPPSI-III) and two scales of the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P). Parents reported children's behavior using the Behavior Assessment System for Children-2 (BASC-2) and the Social Responsiveness Scale-2 (SRS-2). We examined associations between children's urinary pyrethroid metabolite concentrations and neurodevelopmental scores with multiple linear regression models, adjusting for confounders, in boys and girls separately. RESULTS: The study included 179 children (mean age: 3.2 y, range 2.8-4.0). The detection frequencies were high for most pyrethroid metabolites (83-100%), but lower for 4-F-3-PBA (36%). Higher concentrations of cis-DBCA were significantly associated with lower verbal, performance and full-scale IQ scores in boys (e.g., for a 2-fold increase in cis-DBCA, ß = -2.0; 95% CI: -3.4, -0.6 for full-scale IQ). In girls, the only metabolite associated with cognitive scores was 3-PBA, which was associated with lower verbal IQ scores (ß = -1.3, 95% CI: -2.6, -0.1). For neurobehavioral outcomes in boys, there were associations between poorer BASC-2 Adaptive Skills scores with higher concentrations of cis-DCCA (ß = -1.6, 95% CI: -2.3, -0.9), trans-DCCA (ß = -1.5, 95% CI: -2.2, -0.8), 3-PBA (ß = -1.7, 95% CI: -2.5, -0.9), and sum of pyrethroid metabolites (ß = -1.8, 95% CI: -2.6, -0.9). In girls, we observed a significant association between higher concentration of cis-DCCA and better BASC-2 Adaptive Skills score (ß = 1.0; 95% CI, 0.2, 1.8), but not with other urinary pyrethroids metabolites. Scores on the SRS-2 and BRIEF-P were not associated with pyrethroid metabolites. CONCLUSION: There were associations between some pyrethroid pesticide metabolites and indicators of neurodevelopmental disorder, especially among boys. These associations are in agreement with previous studies and could suggest that exposure to pyrethroid pesticides represents a risk of potential toxicity for the cognitive development of children, and a risk for behavioral development. However, the cross-sectional nature of this study limits causal inferences.

Descriptive analysis of organophosphate ester metabolites in a pan-Canadian pregnancy cohort.

Organophosphate esters (OPEs) are widely used in numerous consumer products for their flame retardant and plasticizing properties. Despite potential widespread exposure, biomonitoring data during critical windows of development are scarce and limited to the most widely studied metabolites. We quantified urinary concentrations of multiple OPE metabolites in a vulnerable Canadian population. Using data and biobanked specimens from the Maternal-Infant Research on Environmental Chemicals (MIREC) study (2008-2011), we measured first trimester urinary concentrations of 15 OPE metabolites as well as one flame retardant metabolite and quantified associations with sociodemographic and sample collection characteristics in 1865 pregnant participants. We applied 2 different analytical methods to quantify OPEs, one using UItra-Performance Liquid Chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and the other using Atmospheric Pressure Gas Chromatography coupled to mass spectrometry (APGC-MS/MS) with sensitive limits of detection (0.008-0.1 µg/L). We modelled associations between sociodemographic and sample collection characteristics and specific gravity-standardized chemical concentrations. Six OPE metabolites were detected in the majority (68.1-97.4 %) of participants. Bis-(2-chloroethyl) hydrogen phosphate had the highest detection rate (97.4 %). Diphenyl phosphate had the highest geometric mean concentration (0.657 µg/L). Metabolites of tricresyl phosphate were detected in few participants. Associations between sociodemographic characteristics varied according to each OPE metabolite. Pre-pregnancy body mass index tended to be positively associated with OPE metabolite concentrations whereas age tended to be inversely associated with OPE concentrations. OPE concentrations were, on average, higher in urine samples collected in the summer than other seasons the winter. We present the largest biomonitoring study of OPE metabolites in pregnant people to date. These findings demonstrate widespread exposure to OPEs and their metabolites and identify subpopulations who may experience heightened exposure.

Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort.

BACKGROUND: Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce. OBJECTIVE: To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex. METHODS: We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics. RESULTS: Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10-2.50), 4.97 (3.20-6.20) and 1.09 (0.67-1.60) µg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = -2.80, 95% CI: -4.92, -0.68; PFOS: B = -2.64, 95% CI: -4.77, -0.52; PFHxS: B = -2.92, 95% CI: -4.72, -1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = -3.16, 95% CI: -4.90, -1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: -0.99, 2.26). No significant associations were found for EF in either males or females. CONCLUSIONS: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.