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.

Assessing preconception exposure to environmental chemicals and fecundity: Strategies, challenges, and research priorities.

In 2022, approximately one out of six people globally experienced infertility at some point in their life. Environmental chemicals, particularly those with endocrine disrupting activity, may contribute to impaired fecundity and infertility. We review existing prospective cohort studies of environmental chemicals and fecundity, identify methodological challenges and biases, and outline future research priorities. Studies of preconception environmental chemical exposures and fecundity have occurred in US, Singapore, China and Denmark with recruitment as early as 1982-1986, as recent as 2015-2017 and sample sizes ranging from 99 to 936. Higher exposure to certain chemicals (e.g. heavy metals, perfluoroalkyl substances) was associated with longer time to pregnancy; yet the literature is scarce or nonexistent for many chemicals. Furthermore, prospective studies face challenges and potential biases related to recruiting participants prior to conception, measuring environmental chemicals during critical windows of exposure, and ascertaining when pregnancy occurred. Research priorities include expanding the scope of biomonitoring data collected during the preconception period, continuing to develop and validate analytic methods for self-sampled biospecimens in traditional and novel matrices, collecting data in male partners and investigating etiologic associations according to indicators of marginalization.

Maternal exposure to metals and time-to-pregnancy: The MIREC cohort study.

OBJECTIVE: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility. DESIGN: Pregnancy-based retrospective TTP cohort study. SETTING: Hospitals and clinics from ten cities across Canada. POPULATION: A total of 1784 pregnant women. METHODS: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids. MAIN OUTCOME MEASURES: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months. RESULTS: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles. CONCLUSION: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP.

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.

Prenatal exposure to perfluoroalkyl substances and inflammatory biomarker concentrations.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that induce immunotoxicity in experimental studies; however, epidemiological evidence-particularly during pregnancy-is scarce. We quantified associations between first trimester plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) concentrations and third trimester concentrations of inflammatory biomarkers and determined if these associations were modified by fetal sex. Methods: We analyzed data from 1411 participants, recruited between 2008 and 2011, in the Maternal-Infant Research on Environmental Chemicals study. Our primary outcome was a composite inflammatory index derived by summing the z-scores of eight proinflammatory biomarkers. Using multivariable linear regression models, we quantified associations between each PFAS and the inflammatory index and individual biomarkers. We quantified the effects of the PFAS mixture using weighted quantile sum regression, and evaluated effect modification using product terms and sex-stratified models. Results: Each doubling of PFOA and PFHxS was associated with a 0.38 (95% CI, 0.09, 0.67) and 0.21 (95% CI, 0.01, 0.41) SD increase in the proinflammatory index, respectively. A one-quartile increase in the PFAS mixture was associated with a 0.40 (95% CI, 0.09, 0.71) SD increase in the proinflammatory index. In individual models, we observed positive associations between PFAS and concentrations of monocyte chemoattractant protein-1, macrophage inflammatory protein-1ß, and matrix metalloproteinases-9; however, the magnitude and precision varied according to the specific PFAS. Sex-specific findings were identified in few PFAS-biomarker associations. Conclusions: PFOA, PFOS, and PFHxS, individually and as a mixture, were positively associated with proinflammatory biomarkers during pregnancy.

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.

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.

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.

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.

Heavy metal blood concentrations in association with sociocultural characteristics, anthropometry and anemia among Kenyan adolescents.

OBJECTIVES: To measure heavy metal concentrations among Kenyan youth and quantify associations with sociocultural, demographic, and health factors as well as anthropometry. METHODS: Using data from a study of semi-nomadic pastoralists in Samburu County, Kenya, we measured blood concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in 161 adolescents. We identified sociocultural, demographic and health characteristics associated with each metal and quantified the association between metals and adolescent anthropometry. RESULTS: Median blood concentrations of Pb, Cd, and Hg were 1.82 µg/dL, 0.24 µg/L and 0.16 µg/L, respectively. Place of residence (highlands vs lowlands) was a determinant of metal concentrations. Hg was inversely related to anemia, and metals were not associated with anthropometry. CONCLUSIONS: In this population of Samburu adolescents, median Pb and Cd blood concentrations were higher than other North American or European biomonitoring studies. These findings motivate further investigation into the environmental sources of metals in this community.

Direct LC-MS/MS and indirect GC-MS/MS methods for measuring urinary bisphenol A concentrations are comparable.

BACKGROUND: Bisphenol A (BPA) is typically measured in urine using an indirect method that involves enzymatic deconjugation and extraction. In contrast, the direct method measures free and conjugated BPA concurrently and sums them to estimate urinary BPA concentrations. Statistical comparison of total BPA results using the direct and indirect methods is necessary to accurately interpret biomonitoring data for risk assessments. OBJECTIVES: To compare urinary BPA concentrations estimated from the indirect and direct methods in duplicate first trimester urine samples collected from 1879 pregnant women from the MIREC Study. METHODS: For the indirect method, we measured urinary BPA concentrations using GC-MS/MS. For the direct method, we summed free and conjugated BPA concentrations measured using LC-MS/MS. We evaluated deviation between the two methods using the Bland-Altman analysis in the total sample and stratified (1) by specific gravity and (2) at the limit of quantification (LOQ). RESULTS: Median urinary BPA concentrations for the direct and indirect methods were 0.89 µg BPA equivalents/L and 0.81 µg/L respectively. Concentrations from the direct method were, on average, 8.6% (95% CI: 6.7%, 10.5%) higher than the indirect method in a Bland-Altman analysis. The percent differences between the two methods was 4.0% in urines with specific gravities < 1.02 (n = 1348, 72%) and 20.3% in urine with specific gravity ≥ 1.02. In values below the LOQ (n = 663, 35%), we observed smaller average percent deviation (4.8%) between the two methods but wider limits of agreement. DISCUSSION: Results from this study, based on the largest statistically rigorous comparison of the direct and indirect methods of BPA measurement, contrast previous findings reporting that the indirect method underestimates total BPA exposure. The difference in urinary BPA concentrations we observed with the indirect and direct methods is unlikely to alter the interpretation of health outcome data.

Association between arthritis treatments and ovarian reserve: a prospective study.

RESEARCH QUESTION: How do anti-Müllerian hormone (AMH) concentrations in women with and without arthritis compare? Is there an association between AMH and arthritis drug regimen? DESIGN: In this prospective cohort study, AMH was measured at two time points (T0 and T1) in 129 premenopausal women with arthritis. AMH at T0 was compared with that from a bank of serum samples from 198 premenopausal women without arthritis. Primary outcomes were: (i) diminished ovarian reserve (DOR) (AMH <1.1 ng/ml) and (ii) annual rate of AMH decrease. Univariate, multivariable and Firth logistic regression identified variables associated with annual AMH decrease in excess of the 75th percentile. RESULTS: Median time between T0 and T1 was 1.72 years. At time T0, median age-adjusted AMH in women with arthritis was significantly lower than that of women without arthritis (median 2.21 ng/ml versus 2.78 ng/ml; P = 0.009). Women with arthritis at highest risk for DOR had a history of tubal sterilization or were over the age of 35. Those with highest odds of having an annual AMH decrease in excess of the 75th percentile (over 28% decrease per year) were those: over the age of 35 or who sought care for infertility. Women with arthritis taking methotrexate alone (OR 0.08, 95% CI 0.01-0.67) or methotrexate plus tumour necrosis factor-alpha antagonists (OR 0.13, 95% CI 0.02-0.89) were less likely to be in the highest quartile of annual AMH decrease than women with arthritis not taking medication. CONCLUSIONS: Women with arthritis had lower AMH than healthy controls. Long-term methotrexate use was not associated with an annual AMH decrease.

Urinary phthalates and body mass index in preschool children: The MIREC Child Development Plus study.

Childhood exposure to phthalates, a class of chemicals with known reproductive and developmental effects, has been hypothesized to increase the risk of obesity, but this association is not well understood in preschool children. We examined the association between urinary concentrations of phthalate metabolites and concurrently measured body mass index (BMI) and skinfolds among children between the ages of two and five years. We collected anthropometric measures and biomonitoring data on approximately 200 children enrolled in the Maternal-Infant Research on Environmental Chemicals Child Development Plus study. We measured 22 phthalate metabolites in children's urine and used the 19 metabolites detected in at least 40% of samples. Our primary outcome was BMI z-scores calculated using the World Health Organization growth standards. Skinfold z-scores were secondary outcomes. We used multivariable linear regression to evaluate the association between tertiles of phthalate concentrations and each anthropometric measure. We also used weighted quantile sum regression to identify priority exposures of concern. Our analytic sample included 189 singleton-born children with complete anthropometric data. Children with concentrations of the parent compound di-n-butyl phthalate (∑DnBP) in the third tertile had 0.475 (95% CI: 0.068, 0.883) higher BMI z-scores than those in the lower tertile. ∑DnBP was identified as a priority exposure in the weighted quantile sum regression BMI model. In this population of Canadian preschool aged children, we identified DnBP as a potential chemical of concern in regard to childhood obesity. Future research with serial phthalate measurements and anthropometric measurements in young children will help confirm these findings.