Prenatal Exposure to Air Pollution and Respiratory Distress in Term Newborns: Results from the MIREC Prospective Pregnancy Cohort.

BACKGROUND: Respiratory distress is the leading cause of neonatal morbidity and mortality worldwide, and prenatal exposure to air pollution is associated with adverse long-term respiratory outcomes; however, the impact of prenatal air pollution exposure on neonatal respiratory distress has not been well studied. OBJECTIVES: We examined associations between prenatal exposures to fine particular matter (PM2.5) and nitrogen dioxide (NO2) with respiratory distress and related neonatal outcomes. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a prospective pregnancy cohort (n=2,001) recruited in the first trimester from 10 Canadian cities. Prenatal exposures to PM2.5 (n=1,321) and NO2 (n=1,064) were estimated using land-use regression and satellite-derived models coupled with ground-level monitoring and linked to participants based on residential location at birth. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between air pollution and physician-diagnosed respiratory distress in term neonates in hierarchical logistic regression models adjusting for detailed maternal and infant covariates. RESULTS: Approximately 7% of newborns experienced respiratory distress. Neonates received clinical interventions including oxygen therapy (6%), assisted ventilation (2%), and systemic antibiotics (3%). Two percent received multiple interventions and 4% were admitted to the neonatal intensive care unit (NICU). Median PM2.5 and NO2 concentrations during pregnancy were 8.81 µg/m3 and 18.02 ppb, respectively. Prenatal exposures to air pollution were not associated with physician-diagnosed respiratory distress, oxygen therapy, or NICU admissions. However, PM2.5 exposures were strongly associated with assisted ventilation (OR per 1-µg/m3 increase in PM2.5=1.17; 95% CI: 1.02, 1.35), multiple clinical interventions (OR per 1-µg/m3 increase in PM2.5=1.16; 95% CI: 1.07, 1.26), and systemic antibiotics, (OR per 1-µg/m3 increase in PM2.5=1.12; 95% CI: 1.04, 1.21). These associations were consistent across exposure periods-that is, during prepregnancy, individual trimesters, and total pregnancy-and robust to model specification. NO2 exposure was associated with administration of systemic antibiotics (OR per 1-ppb increase in NO2=1.03; 95% CI: 1.00, 1.06). DISCUSSION: Prenatal exposures to PM2.5 increased the risk of severe respiratory distress among term newborns. These findings support the development and prioritization of public health and prenatal care strategies to increase awareness and minimize prenatal exposures to air pollution. https://doi.org/10.1289/EHP12880.

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.

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.

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.

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.

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.

Individual, Independent, and Joint Associations of Toxic Metals and Manganese on Hypertensive Disorders of Pregnancy: Results from the MIREC Canadian Pregnancy Cohort.

BACKGROUND: Toxic metals, such as lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), may be associated with a higher risk of gestational hypertension and preeclampsia, whereas manganese (Mn) is an essential metal that may be protective. OBJECTIVES: We estimated the individual, independent, and joint associations of Pb, Cd, As, Hg, and Mn on the risk of developing gestational hypertension and preeclampsia in a cohort of Canadian women. METHODS: Metal concentrations were analyzed in first and third trimester maternal blood (n=1,560). We measured blood pressure after 20 wk gestation to diagnose gestational hypertension, whereas proteinuria and other complications defined preeclampsia. We estimated individual and independent (adjusted for coexposure) relative risks (RRs) for each doubling of metal concentrations and examined interactions between toxic metals and Mn. We used quantile g-computation to estimate the joint effect of trimester-specific exposures. RESULTS: Each doubling of third trimester Pb (RR=1.54; 95% CI: 1.06, 2.22) and first trimester blood As (RR=1.25; 95% CI: 1.01, 1.58) was independently associated with a higher risk of developing preeclampsia. First trimester blood As (RR=3.40; 95% CI: 1.40, 8.28) and Mn (RR=0.63; 95% CI: 0.42, 0.94) concentrations were associated with a higher and lower risk, respectively, of developing gestational hypertension. Mn modified the association with As such that the deleterious association with As was stronger at lower concentrations of Mn. First trimester urinary dimethylarsinic acid concentrations were not associated with gestational hypertension (RR=1.31; 95% CI: 0.60, 2.85) or preeclampsia (RR=0.92; 95% CI: 0.68, 1.24). We did not observe overall joint effects for blood metals. DISCUSSION: Our results confirm that even low blood Pb concentrations are a risk factor for preeclampsia. Women with higher blood As concentrations combined with lower Mn in early pregnancy were more likely to develop gestational hypertension. These pregnancy complications impact maternal and neonatal health. Understanding the contribution of toxic metals and Mn is of public health importance. https://doi.org/10.1289/EHP10825.

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.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

BACKGROUND: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 µg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 µg/L. CONCLUSIONS: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Biomonitoring of DEET and DCBA in Canadian children following typical protective insect repellent use.

N,N-diethyl-m-toluamide (DEET) is an ingredient found in many consumer insect repellents and its use is recommended to Canadians by government agencies, including Health Canada, for protection against insect bites including mosquitos and ticks. The majority of research on DEET exposure and toxicokinetics in humans has focused on adult populations with little information from vulnerable populations, including children. We aimed to fill this knowledge gap by examining real-world exposure data for DEET and its metabolite 3-diethylcarbamoyl benzoic acid (DCBA) in a sample population of Canadian children. We conducted a 24-h observational exposure human biomonitoring study at three overnight summer camps in Ontario, Canada through July and August 2019. Participating children aged 7-13 years provided multiple spot urine samples over a 24-h period and completed a journal to document insect repellent use and factors that could influence absorption of DEET. Children were instructed to use insect repellent as they usually would while attending a summer camp. Exposure was quantified using the information from the participant's journal and the change in the mass of their insect repellent containers over the course of the study. A total of 389 urine samples were collected from 124 children. Among participants using insect repellent, urinary levels of DEET were elevated between 2 and 8 h post-application and decreased thereafter but remained qualitatively higher than concentrations in participants who did not use insect repellent on the study day, even at 18-22 h post-application. DCBA was the predominant metabolite of DEET exposure in urine. DCBA was elevated between 8 and 14 h post-application, and declined thereafter, but not to the level observed among those who did not use insect repellent on the study day. Children who used more insect repellent, or used higher concentration insect repellent (10%-30% DEET) excreted higher levels of DEET and DCBA. Excreted DEET and DCBA accounted for 0.001% (median) and 1.3% (median) of the estimated applied DEET, respectively. Children did not reach an undetectable level of DEET or DCBA in urine, even among those not using insect repellent during the study day, indicating a potentially complex multi-route exposure to insect repellents in a real world scenario. This work provides targeted biomonitoring data for children intentionally using DEET-based insect repellents for normal protective use, and will support the risk re-evaluation of DEET by Health Canada.

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.

Perspective: Human Milk Composition and Related Data for National Health and Nutrition Monitoring and Related Research.

National health and nutrition monitoring is an important federal effort in the United States and Canada, and the basis for many of their nutrition and health policies. Understanding of child exposures through human milk (HM) remains out of reach due to lack of current and representative data on HM's composition and intake volume. This article provides an overview of the current national health and nutrition monitoring activities for HM-fed children, HM composition (HMC) and volume data used for exposure assessment, categories of potential measures in HM, and associated variability factors. In this Perspective, we advocate for a framework for collection and reporting of HMC data for national health and nutrition monitoring and programmatic needs, including a shared vision for a publicly available Human Milk Composition Data Repository (HMCD-R) to include essential metadata associated with HMC. HMCD-R can provide a central, integrated platform for researchers and public health officials for compiling, evaluating, and sharing HMC data. The compiled compositional and metadata in HMCD-R would provide pertinent measures of central tendency and variability and allow use of modeling techniques to approximate compositional profiles for subgroups, providing more accurate exposure assessments for purposes of monitoring and surveillance. HMC and related metadata could facilitate understanding the complexity and variability of HM composition, provide crucial data for assessment of infant and maternal nutritional needs, and inform public health policies, food and nutrition programs, and clinical practice guidelines.

Maternal Folate Status and the Relation between Gestational Arsenic Exposure and Child Health Outcomes.

Gestational arsenic exposure adversely impacts child health. Folate-mediated 1-carbon metabolism facilitates urinary excretion of arsenic and may prevent arsenic-related adverse health outcomes. We investigated the potential for maternal folate status to modify associations between gestational arsenic exposure and child health. We used data from 364 mother-child pairs in the MIREC study, a prospective pan-Canadian cohort. During pregnancy, we measured first trimester urinary arsenic concentrations, plasma folate biomarkers, and folic acid supplementation intake. At age 3 years, we evaluated twelve neurodevelopmental and anthropometric features. Using latent profile analysis and multinomial regression, we developed phenotypic profiles of child health, estimated covariate-adjusted associations between arsenic and these phenotypic profiles, and evaluated whether folate status modified these associations. We identified three phenotypic profiles of neurodevelopment and three of anthropometry, ranging from less to more optimal child health. Gestational arsenic was associated with decreased odds of optimal neurodevelopment. Maternal folate status did not modify associations of arsenic with neurodevelopmental phenotypic profiles, but gestational arsenic was associated with increased odds of excess adiposity among those who exceed recommendations for folic acid (>1000 µg/day). However, arsenic exposure was low and folate status was high. Gestational arsenic exposure may adversely impact child neurodevelopment and anthropometry, and maternal folate status may not modify these associations; however, future work should examine these associations in more arsenic-exposed or lower folate-status populations.

Individual and mixture associations of perfluoroalkyl substances on liver function biomarkers in the Canadian Health Measures Survey.

BACKGROUND: Perfluoroalkyl substances can disrupt hepatic metabolism and may be associated with liver function biomarkers. We examined individual and mixture associations of PFAS on liver function biomarkers in a representative sample of Canadian adults. We explored the potential for effect modification by sex and body mass index, as well as by physical activity level which may attenuate the deleterious effect of PFAS on metabolic disorders. METHODS: We analyzed data from participants aged 20-74 from the Canadian Health Measures Survey. We used linear regression to examine associations between plasma concentrations of PFOA, PFOS, PFHxS, PFNA, PFDA, and PFUDA on serum concentrations of aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and total bilirubin. We used quantile g-computation to estimate associations with a PFAS mixture for each simultaneous, one-quartile change in PFAS concentrations. RESULTS: Each doubling of PFOA, PFOS, PFHxS, or PFNA concentrations was associated with higher AST, GGT, and ALP concentrations. Each doubling of PFOA concentrations was associated with 16.5% (95%CI: 10.4, 23.0) higher GGT concentrations among adults not meeting Canada's physical activity guidelines vs. 6.6% (95%CI: -1.6, 15.5) among those meeting these guidelines. Sex and BMI also modified some associations, though to a lesser extent. We did not observe associations between ALT and PFOA (1.2% change; 95%CI: -2.5, 4.9), PFOS (2.2% change; 95%CI: -0.8, 5.3), or PFHxS (1.5% change; 95%CI: -0.4, 3.4). We also did not observe consistent associations for PFDA and PFUDA or with total bilirubin. In quantile g-computation models, each simultaneous one-quartile increase in the PFAS mixture was positively associated with AST (7.5% higher; 95%CI: 4.0, 10.4), GGT (9.7% higher; 95%CI: 1.7, 17.0), and ALP (2.8% higher; 95%CI: 0.5, 5.4). CONCLUSION: Higher plasma concentrations of PFOA, PFOS, PFHxS, and PFNA - both individually and as a mixture - were associated with higher serum concentrations of liver function biomarkers. These results contribute to emerging evidence suggesting that higher levels of physical activity appear to be protective against the hepatotoxic effects of PFOA. This work contributes to a growing body of evidence supporting the hepatotoxic effects of PFAS.

Development of an observational exposure human biomonitoring study to assess Canadian children's DEET exposure during protective use.

Biomonitoring data of N,N-diethyl-meta-toluamide (DEET) in children is scarce and limited to controlled exposure and surveillance studies. We conducted a 24-hour observational exposure and human biomonitoring study designed to estimate use of and exposure to DEET-based insect repellents by Canadian children in an overnight summer camp setting. Here, we present our study design and methodology. In 2019, children between the ages of 7 and 13 took part in the study (n = 126). Children controlled their use of DEET-based insect repellents, and provided an account of their activities at camp that could impact insect repellent absorption. Children provided a total of 389 urine samples throughout the study day, and reported the time that they applied insect repellent, which allowed us to contextualize urinary DEET and metabolite concentrations with respect to the timing of insect repellent application. DEET (2.3%

Biomonitoring of inorganic arsenic species in pregnancy.

Exposure assessment of inorganic arsenic is challenging due to the existence of multiple species, complexity of arsenic metabolism, and variety of exposure sources. Exposure assessment of arsenic during pregnancy is further complicated by the physiological changes that occur to support fetal growth. Given the well-established toxicity of inorganic arsenic at high concentrations, continued research into the potential health effects of low-level exposure on maternal and fetal health is necessary. Our objectives were to review the value of and challenges inherent in measuring inorganic arsenic species in pregnancy and highlight related research priorities. We discussed how the physiological changes of pregnancy influence arsenic metabolism and necessitate the need for pregnancy-specific data. We reviewed the biomonitoring challenges according to common and novel biological matrices and discussed how each matrix differs according to half-life, bioavailability, availability of laboratory methods, and interpretation within pregnancy. Exposure assessment in both established and novel matrices that accounts for the physiological changes of pregnancy and complexity of speciation is a research priority. Standardization of laboratory method for novel matrices will help address these data gaps. Research is particularly lacking in contemporary populations of pregnant women without naturally elevated arsenic drinking water concentrations (i.e. <10 µg/l).

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

Critical Time Windows for Air Pollution Exposure and Birth Weight in a Multicity Canadian Pregnancy Cohort.

BACKGROUND: Maternal prenatal exposure to air pollution has been associated with adverse birth outcomes. However, previous studies focused on a priori time intervals such as trimesters reported inconsistent associations. OBJECTIVES: We investigated time-varying vulnerability of birth weight to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) using flexible time intervals. METHODS: We analyzed 1,300 live, full-term births from Maternal-Infant Research on Environmental Chemicals, a Canadian prospective pregnancy cohort spanning 10 cities (2008-2011). Daily PM2.5 and NO2 concentrations were estimated from ground-level monitoring, satellite models, and land-use regression, and assigned to participants from pre-pregnancy through delivery. We developed a flexible two-stage modeling method-using a Bayesian Metropolis-Hastings algorithm and empirical density threshold-to identify time-dependent vulnerability to air pollution without specifying exposure periods a priori. This approach identified critical windows with varying lengths (2-363 days) and critical windows that fell within, or straddled, predetermined time periods (i.e., trimesters). We adjusted the models for detailed infant and maternal covariates. RESULTS: Critical windows associated with reduced birth weight were identified during mid- to late-pregnancy for both PM2.5 and NO2: -6 g (95% credible interval: -11, -1 g) and -5 g (-10, -0.1 g) per µg/m3 PM2.5 during gestational days 91-139 and 249-272, respectively; and -3 g (-5, -1 g) per ppb NO2 during days 55-145. DISCUSSION: We used a novel, flexible selection method to identify critical windows when maternal exposures to air pollution were associated with decrements in birth weight. Our results suggest that air pollution impacts on fetal development may not be adequately captured by trimester-based analyses.

Early prenatal use of a multivitamin diminishes the risk for inadequate vitamin D status in pregnant women: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study.

BACKGROUND: Reports on the adequacy of vitamin D status of pregnant women are not available in Canada. OBJECTIVES: The objectives of this study were to examine vitamin D status across pregnancy and identify the correlates of vitamin D status of pregnant women in Canada. METHODS: Pregnant women (≥18 years) from 6 provinces (2008-2011) participating in a longitudinal cohort were studied. Sociodemographic data, obstetrical histories, and dietary and supplemental vitamin D intakes were surveyed. Plasma 25-hydroxyvitamin D (25OHD) was measured using an immunoassay standardized to LC-MS/MS from samples collected during the first (n = 1905) and third trimesters (n = 1649) and at delivery (n = 1543). The proportion of women with ≥40 nmol/L of plasma 25OHD (adequate status) was estimated at each time point, and factors related to achieving this cut point were identified using repeated-measures logistic regression. Differences in 25OHD concentrations across trimesters and at delivery were tested a using repeated-measures ANOVA with a post hoc Tukey's test. RESULTS: In the first trimester, 93.4% (95% CI: 92.3%-94.5%) of participants had 25OHD ≥40 nmol/L. The mean plasma 25OHD concentration increased from the first to the third trimester and then declined by delivery (69.8 ± 0.5 nmol/L, 78.6 ± 0.7 nmol/L, and 75.7 ± 0.7 nmol/L, respectively; P < 0.0001). A lack of multivitamin use early in pregnancy reduced the odds of achieving 25OHD ≥40 nmol/L (ORadj = 0.33; 95% CI: 0.25-0.42) across all time points. Factors associated with not using a prenatal multivitamin included multiparity (ORadj = 2.08; 95% CI: 1.42-3.02) and a below-median income (ORadj = 1.39; 95% CI: 1.02-1.89). CONCLUSIONS: The results from this cohort demonstrate the importance of early multivitamin supplement use to achieve an adequate vitamin D status in pregnant women.