Serum concentrations of legacy, alternative, and precursor per- and polyfluoroalkyl substances: a descriptive analysis of adult female participants in the MIREC-ENDO study.

BACKGROUND: Several legacy and emerging per- and polyfluoroalkyl substances (PFAS) have been regulated around the world. There is growing concern over the proliferation of alternative PFAS, as well as PFAS precursors. Biomonitoring data for PFAS are critical for assessing exposure and human health risk. METHODS: We collected serum samples from 289 adult female participants in a 2018-2021 follow-up study of the Maternal-Infant Research on Environmental Chemicals (MIREC) Canadian pregnancy cohort. Samples were analyzed for 40 PFAS using ultra-performance liquid chromatography-tandem mass spectrometry. For those compounds with > 50% detection, as well as the sum of these compounds, we describe serum concentrations and patterns of exposure according to sociodemographic and obstetrical history characteristics. RESULTS: 17 out of 40 PFAS were detected in > 50% of samples with 7 of these detected in > 97% of samples. Median [95th percentile] concentrations (µg/L) were highest for PFOS (1.62 [4.56]), PFOA (0.69 [1.52]), PFNA (0.38 [0.81]), and PFHxS (0.33 [0.92]). Geometric mean concentrations of PFOA and PFHxS were approximately 2-fold lower among those with more children (≥ 3 vs. 1), greater number of children breastfed (≥ 3 vs. ≤ 1), longer lifetime duration of breastfeeding (> 4 years vs. ≤ 9 months), and shorter time since last pregnancy (≤ 4 years vs. > 8 years). We observed similar patterns for PFOS, PFHpS, and the sum of 17 PFAS, though the differences between groups were smaller. Concentrations of PFOA were higher among "White" participants, while concentrations of N-MeFOSE, N-EtFOSE, 7:3 FTCA, and 4:2 FTS were slightly higher among participants reporting a race or ethnicity other than "White". Concentrations of legacy, alternative, and precursor PFAS were generally similar across levels of age, education, household income, body mass index, and menopausal status. CONCLUSIONS: We report the first Canadian biomonitoring data for several alternative and precursor PFAS. Our findings suggest that exposure to PFAS, including several emerging alternatives, may be widespread. Our results are consistent with previous studies showing that pregnancy and breastfeeding are excretion pathways for PFAS.

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.

Restorative dentistry clinical decision-making for hypodontia: peg and missing lateral incisor teeth.

Peg-shaped and missing lateral incisor teeth are common features for patients affected by hypodontia. While improvements in dental appearance may be a strong motivating factor for these patients, providing dental treatment to improve the clinical condition and achieve an acceptable and stable outcome can be complex and lengthy.For patients affected by hypodontia, discussion and consideration of various approaches to their individual treatment are best achieved in a multidisciplinary team environment. This allows debate of options and joint agreement between at least orthodontic and restorative dentistry specialist colleagues, based largely on clinical factors, towards a treatment plan that is acceptable to the patient. As most patients with this lateral incisor form of hypodontia are initially treated as teenagers and young adults, there is also an understanding that treatment outcomes will have lifelong maintenance and resource implications to consider.This paper identifies and discusses the key clinical features that influence the treatment planning process for a patient with either missing or peg lateral incisor teeth. These will often involve consideration of whether to open or close the lateral incisor spaces and whether to restore or replace a peg lateral incisor tooth. The process should be patient-centred, evidence-based, and aim to minimise the lifelong treatment burden, retaining options for future maintenance and retreatment.

Restorative dentistry clinical decision-making for hypodontia: managing missing premolar teeth.

Hypodontia is a relatively common clinical condition and the second premolar tooth is the most common tooth that fails to develop (excluding third molars). For some patients, no treatment is required, as there is little, if any, consequence of the condition. For other patients, the missing teeth are part of a more complex dental presentation, requiring specialist dental management. This paper describes the clinical decision-making process and explores the options for managing this presentation of hypodontia.

The dental technician as a member of the hypodontia multidisciplinary team, with practical considerations for anterior restoration design.

Most patients seeking treatment for hypodontia will require prosthetic replacement of their missing teeth. This will be in the form of dentures, bridges and implant restorations. As these are created by one or more dental technicians who supports the clinical team, a close working relationship between these colleagues is likely to improve the quality of treatment outcome. This interaction will usually occur towards the end of the patient's treatment process, when definitive restorations are prescribed. However, appropriately trained and experienced dental technicians should be involved throughout the patient's treatment process as an integral part of the multidisciplinary team approach to effectively manage these patients.This paper describes the contribution of dental technicians to patient care with particular focus on communication between the restorative dentistry clinical team and the dental technician to improve the quality of anterior restorations. As missing maxillary lateral incisor teeth are a common presentation for this patient group, further technical detail relating to planning resin-bonded bridges for replacement of these teeth is included.

Restorative dentistry clinical decision-making for hypodontia: complex cases.

Hypodontia is a relatively common condition and patients will be seen by both general dental practitioners and specialist dental colleagues. Although hypodontia can be described as mild, moderate and severe, this does not directly correlate with the complexity of treatment required to provide an acceptable outcome. In addition, the complexity of treatment provided by one colleague in the multidisciplinary team may not be the same as for other colleagues.When treatment planning and delivering dental care for these patients, especially those with severe hypodontia, it is useful to recognise the factors that make their care complex and also to follow principles for multidisciplinary treatment planning.

Practical advice for successful clinical treatment with resin-bonded bridges.

Resin-bonded bridges are one of the main options for replacing missing teeth for hypodontia patients. This technique offers several advantages for these patients, who are often young, have unrestored abutment teeth, and have had tooth positions optimised by orthodontic treatment. However, the replacement of missing teeth can be challenging due to tooth positions and anomalies of abutment tooth shape and size.These patients are often young adults at the time of restoration, making the minimally invasive nature and predictable long-term success of resin-bonded bridges advantageous over other treatment methods.This paper in the hypodontia themed issue discusses the importance of case selection and gives practical advice for the design and provision of resin-bonded bridges.

A service evaluation of the multidisciplinary team approach to hypodontia.

Introduction Patients with hypodontia can be seen by a multidisciplinary team clinic (MDT) for treatment planning at the University Dental Hospital of Manchester (UDHM). The MDT consists of orthodontics, restorative dentistry and oral surgery colleagues.Aims and methods A retrospective case-note analysis was conducted on 558 hypodontia patients seen on Manchester Hypodontia Clinic (MHC) between 2016-2022 to assess service utilisation and treatment planning outcomes.Results The average age of patients attending the MHC was 16 (range 8-50). The distribution of mild, moderate and severe hypodontia in the sample was 28%, 37% and 35%, respectively. Most common treatments proposed were fixed appliances, extractions, implants and resin-bonded bridges. Out of 558 patients seen for consultation on the MHC, 365 (65%) were accepted for treatment. The average number of visits for treatment was 15.5 (range: 1-55). The average number of did not attend/was not brought appointments, patient cancellations and hospital cancellations were 0.8, 1.4 and 1.8, respectively.Conclusion Hypodontia patients referred to UDHM are triaged by consultants in orthodontics or restorative dentistry, and if MDT planning is required, they are booked onto the MHC. There are sufficient patients with complex cases of moderate and severe hypodontia to justify a regular MDT hypodontia clinic.

The role of the general dental practitioner in the management of the hypodontia patient.

The general dental practitioner (GDP) is usually the first person to suspect that a young patient is affected by hypodontia. The condition occurs rarely in the primary dentition but is relatively common in the permanent dentition. Between the ages of 7 and 12 years, failure of a permanent tooth to erupt as expected will lead the GDP to initiate and then contribute to the ideal management of the patient's condition. This ranges from reassurance and preventive measures to providing aspects of treatment in a long-term management plan, alongside a multidisciplinary specialist team and thereafter, delivery of life-long dental care.

The genetic basis of hypodontia in dental development.

Dental agenesis is one of the most common developmental anomalies in humans, characterised by the developmental absence of one or more teeth. It can present as an isolated condition (non-syndromic hypodontia) or associated with a syndrome (syndromic hypodontia). This paper aims to review the genetic basis of hypodontia with reference to aetiology, classification and the subsequent clinical features.Significant progress has been made to identify the developmental basis of tooth formation, though there is still a lack of knowledge within the literature of the aetiological basis of inherited tooth loss.Gene anomalies or mutations in WNT10A, MSX1, PAX9, AXIN2 and EDA appear to be most critical during tooth development, leading to various forms of tooth agenesis.

Involving young people and parents in decision-making for hypodontia.

Involving young people and their parents in decisions about their health care is ethically and professionally the right thing to do. Good decision-making relies on informed, value-based deliberation. Providing the right treatment for people with hypodontia is complex, both technically, in terms of the range of options available, and from a communication perspective. Treatment decisions faced by young people with hypodontia can have lifelong implications and the weight of this is felt both by the patient, who may have limited experience of dental treatment and decision-making, and their parents, who act as advocates. It is important that clinicians understand how they can best share the available evidence and their expertise in a way that can be understood and applied. Clinicians also have an important role in facilitating young people to recognise and communicate their own values, expectations, and ultimately, preferences for treatment. This paper outlines the challenges of navigating information sharing and engaging in shared decision-making specific to hypodontia. A scoping review of the literature by the authors was conducted to identify evidence-based advice for discussing uncertainties, risks and increasing engagement in decision-making. This may be useful to both primary and secondary care practitioners involved in decision-making with people with hypodontia.

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.

A descriptive analysis of first trimester urinary concentrations of 14 bisphenol analogues in the MIREC Canadian pregnancy cohort.

BACKGROUND: Concern over the health effects of BPA, particularly for the developing fetus, has led to an increasing use of bisphenol analogues in industrial and consumer products, which may be as hormonally active as BPA. Biomonitoring data for many bisphenol analogues, especially in pregnant populations, are limited. METHODS: We measured concentrations of 14 bisphenol analogues in 1st trimester urine samples (n = 1851) from the Maternal-Infant Research on Environmental Chemicals (MIREC) Canadian pregnancy cohort (2008-2011). We examined patterns of exposure according to sociodemographic and sampling characteristics as well as occupation and frequency of consumption of canned fish within the previous 3 months. RESULTS: BPA was detected in 89% of participants with a specific gravity standardized geometric mean concentration of 0.990 µg/L. Biphenol 4,4' (BP 4,4'), 4,4'-dihydroxydiphenyl ether (DHDPE), and bisphenol E (BPE) were detected in >97% of participants. Bisphenol F (BPF) and bisphenol S (BPS) were detected in >60% of participants. Specific gravity standardized geometric mean concentrations of these 5 compounds ranged from 0.024 to 0.564 µg/L. Nine bisphenol analogues were detected in <9% of participants. Concentrations of BP 4,4', DHDPE, and BPE were higher in younger women and those with higher pre-pregnancy BMI, lower household income, lower education, and among smokers. We found a similar pattern of differences in BPF for age, education, and smoking status while BPS similarly differed across categories of pre-pregnancy BMI. Participants who were unemployed or working in the service industry had higher molar sum of 7 bisphenol analogues than those working in healthcare, education, or an office setting. Canned fish consumption was not related to bisphenol analogue concentrations. CONCLUSION: BP 4,4', DHDPE, BPE, BPF, and BPS were highly detected in 1st trimester urine samples in this large pan-Canadian pregnancy cohort. This suggests widespread exposure to these analogues around 2008-2011 and warrants further investigation into associations with health outcomes.

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.