Associations between per- and poly-fluoroalkyl substance (PFAS) exposure and immune responses among women in the California Teachers study: A cross-sectional evaluation.

INTRODUCTION: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that have been linked to a number of health outcomes, including those related to immune dysfunction. However, there are limited numbers of epidemiological-based studies that directly examine the association between PFAS exposure and immune responses. METHODS: In this cross-sectional study nested in the California Teachers Study cohort, we measured nine PFAS analytes in serum. Of the 9 analytes, we further evaluated four (PFHxS [perfluorohexane sulfonate], PFNA [perfluorononanoic acid], PFOA [perfluorooctanoic acid], PFOS [perfluorooctanesulfonic acid]) that had detection levels of > 80 %, in relation to 16 systemic inflammatory/immune markers and corresponding immune pathways (Th1 [pro-inflammatory/macrophage activation], B-cell activation, and T-cell activation). Study participants (n = 722) were female, completed a questionnaire regarding various health measures and behaviors, and donated a blood sample between 2013-2016. The association between PFAS analytes and individual immune markers and pathways were evaluated by calculating odds ratios (OR) and 95 % confidence intervals (CI) in a logistic regression model. PFAS analytes were evaluated both as a dichotomous exposure (above or below the respective median) and as a continuous variable (per 1 unit increase [ng/mL]). RESULTS: The prevalence of detecting any PFAS analyte rose with increasing age, with the highest PFAS prevalence observed among those aged 75 + years and the lowest PFAS prevalence observed among those aged 40-49 years (study participant age range: 40-95 years). Significant associations with BAFF (B-cell activating factor) levels above the median were observed among participants with elevated (defined as above the median) levels of PFHxS (OR=1.53), PFOA (OR=1.43), and PFOS (OR=1.40). Similarly, there were statistically significant associations between elevated levels of PFHxS and TNFRII (tumor necrosis factor receptor 2) levels (OR=1.78) and IL2Rα (interleukin 2 receptor subunit alpha) levels (OR=1.48). We also observed significant inverse associations between elevated PFNA and sCD14 (soluble cluster of differentiation 14) (OR=0.73). No significant associations were observed between elevated PFNA and any immune marker. Evaluation of PFAS exposures as continuous exposures in association with dichotomized cytokines were generally consistent with the dichotomized associations. CONCLUSIONS: PFAS exposure was associated with altered levels of circulating inflammatory/immune markers; the associations were specific to PFAS analyte and immune marker. If validated, our results may suggest potential immune mechanisms underlying associations between the different PFAS analytes and adverse health outcomes.

Surfactant Coformulants in Glyphosate-Based Herbicides: Current Gaps, and Paths Forward in Human Biomonitoring.

Polyethoxylated tallow amine (POEA) surfactants in glyphosate formulations are understudied. They may constitute greater health risks than glyphosate itself. Lack of validated biomarkers of exposure and metabolism, as well as analytical methods for measuring POEA, limit the study of a formulation's toxicity and associated risk.

A cross-validation based approach for estimating specific gravity in elementary-school aged children using a nonlinear model.

Environmental research often relies on urinary biomarkers which require dilution correction to accurately measure exposures. Specific gravity (SG) and creatinine (UCr) are commonly measured urinary dilution factors. Epidemiologic studies may assess only one of these measures, making it difficult to pool studies that may otherwise be able to be combined. Participants from the National Health and Nutrition Examination Survey 2007-2008 cycle were used to perform k-fold validation of a nonlinear model estimating SG from UCr. The final estimated model was applied to participants from the School Inner-City Asthma Intervention Study, who submitted urinary samples to the Children's Health Exposure Analysis Resource. Model performance was evaluated using calibration metrics to determine how closely the average estimated SG was to the measured SG. Additional models, with interaction terms for age, sex, body mass index, race/ethnicity, relative time of day when sample was collected, log transformed 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and asthma status were estimated and assessed for improvement. The association between monobenzyl phthalate (MBZP) and asthma symptom days, controlling for measured UCr, measured SG, and each estimated SG were compared to assess validity of the estimated SG. The model estimating SG from UCr alone, resulted in a beta estimate of 1.10 (95% CI: 1.01, 1.19), indicating agreement between model-predicted SG and measured SG. Inclusion of age and sex in the model improved estimation (ß = 1.06, 95% CI: 0.98, 1.15). The full model accounting for all interaction terms with UCr resulted in the best agreement (ß = 1.01, 95% CI: 0.93,1.09). Associations between MBZP and asthma symptoms days, controlling for each estimated SG, were within the range of effect estimates when controlling for measured SG and measured UCr (Rate ratios = 1.28-1.34). Our nonlinear modeling provides opportunities to estimate SG in studies that measure UCr or vice versa, enabling data pooling despite differences in urine dilution factors.

Cross-sectional associations of maternal PFAS exposure on SARS-CoV-2 IgG antibody levels during pregnancy.

BACKGROUND: Perfluoroalkylated substances (PFAS) are man-made, persistent organic compounds with immune-modulating potentials. Given that pregnancy itself represents an altered state of immunity, PFAS exposure-related immunotoxicity is an important environmental factor to consider in SARS-CoV-2 infection during pregnancy as it may further affect humoral immune responses. AIM: To investigate the relationship between maternal plasma PFAS concentrations and SARS-CoV-2 antibody levels in a NYC-based pregnancy cohort. METHODS: Maternal plasma was collected from 72 SARS-CoV-2 IgG + participants of the Generation C Study, a birth cohort established at the beginning of the COVID-19 pandemic in New York City. Maternal SARS-CoV-2 anti-spike IgG antibody levels were measured using ELISA. A panel of 16 PFAS congeners were measured in maternal plasma using a targeted UHPLC-MS/MS-based assay. Spearman correlations and linear regressions were employed to explore associations between maternal IgG antibody levels and plasma PFAS concentrations. Weighted quantile sum (WQS) regression was also used to evaluate mixture effects of PFAS. Models were adjusted for maternal age, gestational age at which SARS-CoV-2 IgG titer was measured, COVID-19 vaccination status prior to IgG titer measurement, maternal race/ethnicity, parity, type of insurance and pre-pregnancy BMI. RESULTS: Our study population is ethnically diverse with an average maternal age of 32 years. Of the 16 PFAS congeners measured, nine were detected in more than 60% samples. Importantly, all nine congeners were negatively correlated with SARS-CoV-2 anti-spike IgG antibody levels; n-PFOA and PFHxS, PFHpS, and PFHxA reached statistical significance (p < 0.05) in multivariable analyses. When we examined the mixture effects using WQS, a quartile increase in the PFAS mixture-index was significantly associated with lower maternal IgG antibody titers (beta [95% CI] = -0.35 [-0.52, -0.17]). PFHxA was the top contributor to the overall mixture effect. CONCLUSIONS: Our study results support the notion that PFAS, including short-chain emerging PFAS, act as immunosuppressants during pregnancy. Whether such compromised immune activity leads to downstream health effects, such as the severity of COVID-19 symptoms, adverse obstetric outcomes or neonatal immune responses remains to be investigated.

Validated single urinary assay designed for exposomic multi-class biomarkers of common environmental exposures.

Epidemiological studies often call for analytical methods that use a small biospecimen volume to quantify trace level exposures to environmental chemical mixtures. Currently, as many as 150 polar metabolites of environmental chemicals have been found in urine. Therefore, we developed a multi-class method for quantitation of biomarkers in urine. A single sample preparation followed by three LC injections was optimized in a proof-of-approach for a multi-class method. The assay was validated to quantify 50 biomarkers of exposure in urine, belonging to 7 chemical classes and 16 sub-classes. The classes represent metabolites of 12 personal care and consumer product chemicals (PCPs), 5 polycyclic aromatic hydrocarbons (PAHs), 5 organophosphate flame retardants (OPFRs), 18 pesticides, 5 volatile organic compounds (VOCs), 4 tobacco alkaloids, and 1 drug of abuse. Human urine (0.2 mL) was spiked with isotope-labeled internal standards, enzymatically deconjugated, extracted by solid-phase extraction, and analyzed using high-performance liquid chromatography-tandem mass spectrometry. The methanol eluate from the cleanup was split in half and the first half analyzed for PCPs, PAH, and OPFR on a Betasil C18 column; and pesticides and VOC on a Hypersil Gold AQ column. The second half was analyzed for tobacco smoke metabolites and a drug of abuse on a Synergi Polar RP column. Limits of detection ranged from 0.01 to 1.0 ng/mL of urine, with the majority ≤0.5 ng/mL (42/50). Analytical precision, estimated as relative standard deviation of intra- and inter-batch uncertainty, variabilities, was <20%. Extraction recoveries ranged from 83 to 109%. Results from the optimized multi-class method were qualified in formal international proficiency testing programs. Further method customization options were explored and method expansion was demonstrated by inclusion of up to 101 analytes of endo- and exogenous chemicals. This exposome-scale assay is being used for population studies with savings of assay costs and biospecimens, providing both quantitative results and the discovery of unexpected exposures.

Metal mixtures are associated with increased anxiety during pregnancy.

BACKGROUND: Exposure to low-dose toxic metals in the environment is ubiquitous. Several murine studies have shown metals induce anxiety-like behaviors, and mechanistic research supports that metals disrupt neurotransmitter signaling systems implicated in the pathophysiology of anxiety. In this study, we extend prior research by examining joint exposure to six metals in relation to maternal anxiety symptoms during pregnancy. METHODS: The sample includes 380 participants enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. Spot urine was collected during pregnancy (mean ± standard deviation: 31.1 ± 6.1 weeks), and concentrations of six metals (barium [Ba], cadmium [Cd], chromium [Cr], cesium [Cs], lead [Pb], antimony [Sb]) were measured by Inductively Coupled Plasma - Mass Spectrometry. Trait anxiety symptoms were measured during pregnancy using a short version of the Spielberger State Trait Anxiety Inventory (STAI-T) and information on covariates was collected by questionnaire. We used weighted quantile sum (WQS) regression as the primary modeling approach to examine metals, treated as a mixture, in relation to higher (≥20) vs. lower anxiety symptoms while adjusting for urinary creatinine and key sociodemographic variables. RESULTS: The sample is socioeconomically and racially/ethnically diverse. Urinary metal concentrations were log-normally distributed and 25% of the sample had an STAI-T score ≥20. Joint exposure to metals was associated with elevated anxiety symptoms (ORWQS = 1.56, 95% CI: 1.24, 1.96); Cd (61.8%), Cr (14.7%), and Cs (12.7%) contributed the greatest weight to the mixture effect. CONCLUSION: Exposure to metals in the environment may be associated with anxiety symptoms during pregnancy. This is a public health concern, as anxiety disorders are highly prevalent and associated with significant co-morbidities, especially during pregnancy when both the mother and developing fetus are susceptible to adverse health outcomes.

Randomized trial of a portable HEPA air cleaner intervention to reduce asthma morbidity among Latino children in an agricultural community.

BACKGROUND: Data on pediatric asthma morbidity and effective environmental interventions in U.S. agricultural settings are few. We evaluated the effectiveness of HEPA air cleaners on asthma morbidity among a cohort of rural Latino children. METHODS: Seventy-five children with poorly controlled asthma and living in non-smoking homes were randomly assigned to asthma education alone or along with HEPA air cleaners placed in their sleeping area and home living room. The Asthma Control Test (ACT) score, asthma symptoms in prior 2 weeks, unplanned clinical utilization, creatinine-adjusted urinary leukotriene E4 (uLTE4 [ng/mg]), and additional secondary outcomes were evaluated at baseline, six, and 12 months. Group differences were assessed using multivariable-adjusted generalized estimating equations. Incident rate ratios of ever experiencing the metrics of poorer asthma health during follow-up (suboptimal asthma management) were estimated using Poisson regression models in secondary analysis. RESULTS: Mean child age was 9.2 and 8.6 years in intervention and control groups, respectively, and two-thirds of participants were male. Primary analysis of repeated measures of ACT score did not differ between groups (HEPA group mean change compared to controls 10% [95% CI: - 12-39%]). A suggestion of greater decrease in uLTE4 (ng/mg creatinine) was observed (- 10% [95% CI: - 20 -1%]). Secondary analysis showed children with HEPAs were less likely to have an ACT score meeting a clinically defined cutoff for poorly controlled asthma using repeated measures (IRR: 0.45 [95% CI: 0.21-0.97]). In Poisson models, intervention participants had reduced risk of ever meeting this cutoff (IRR: 0.43 [95% CI: 0.21-0.89]), ever having symptoms in the past 2 weeks (IRR: 0.71 [95% CI: 0.52-0.98]), and lower risk of any unplanned clinical utilization (IRR: 0.35 [95% CI: 0.13-0.94]) compared to control participants. DISCUSSION: The HAPI study showed generally improved outcomes among children in the HEPA air cleaner group. However, primary analyses did not meet statistical significance and many outcomes were subjective (self-report) in this unblinded study, so findings must be interpreted cautiously. HEPA air cleaners may provide additional benefit for child asthma health where traditional asthmagens (traffic, tobacco smoke) are not prominent factors, but larger studies with more statistical power and blinded designs are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04919915 . Date of retrospective registration: May 19, 2021.

Prenatal toxic metal mixture exposure and newborn telomere length: Modification by maternal antioxidant intake.

BACKGROUND: Telomere length (TL) predicts the onset of cellular senescence and correlates with longevity and age-related disease risk. While telomeres erode throughout life, adults display fixed ranking and tracking of TL, supporting the importance of the early environment in determining inter-individual variability across the life course. Given their guanine-rich structure, telomeres are highly susceptible to oxidative stress (OS). We examined maternal metal exposure, which can induce OS, in relation to newborn TL. We also considered the modifying role of maternal antioxidant intake. METHODS: Analyses included 100 mother-newborn pairs enrolled in the Boston and New York City-based PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. We measured As, Ba, Cd, Ni, and Pb in maternal late-pregnancy urine by ICP-MS and quantified relative leukocyte TL (rLTL) in cord blood using qPCR. We used Weighted Quantile Sum (WQS) regression to estimate the metal mixture - rLTL association and conducted repeated holdout validation to improve the stability of estimates across data partitions. We examined models stratified by high (>median) versus low (≤median) maternal antioxidant intake, estimated from Block98 Food Frequency Questionnaires. We considered urinary creatinine, week of urine collection, maternal age, and race/ethnicity as covariates. RESULTS: In adjusted models, urinary metals were inversely associated with newborn rLTL (ßWQS = -0.50, 95% CI: -0.78, -0.21). The top metals contributing to the negative association included Ba (weight: 35.4%), Cd (24.5%) and Pb (26.9%). In models stratified by antioxidant intake, the significant inverse association between metals and rLTL remained only among mothers with low antioxidant intake (low: ßWQS = -0.92, 95% CI: -1.53, -0.30; high: ßWQS = -0.03, 95% CI: -0.58, 0.52). Results were similar in unadjusted models. CONCLUSIONS: Relative LTL was shorter among newborns of mothers with higher exposure to metals during pregnancy. Higher maternal antioxidant intake may mitigate the negative influence of metals on newborn rLTL.

Mass defect filtering for suspect screening of halogenated environmental chemicals: A case study of chlorinated organophosphate flame retardants.

RATIONALE: Organophosphate flame retardants (OPFRs) are a class of flame retardants widely found in environmental and biological matrices that have been extensively studied due to their adverse health effects in humans. OPFRs are loosely bound chemicals that can detach from treated products and be released into indoor and outdoor environments, where they have the potential to further undergo transformation and degradation processes, in particular the chlorinated OPFRs (Cl-PFRs). Their detection remains a moving target for analysts, and traditional targeted mass spectrometry methods are suitable only for those compounds with authentic standards. METHODS: Mass defect filter (MDF) is a strategy to filter molecular features using thresholds applied to the mass defect value of a target ion or molecular feature of interest. We have developed an MDF strategy for the detection and tentative identification of twelve potential Cl-PFR transformation products in a study mixture of six known Cl-PFRs using MS/MS data acquired on a high-resolution mass spectrometer. Most compounds in the Cl-PFRs family share a ClO4 P group as a core structure, of which modification results in a significant shift in the exact masses of the resulting compounds but show only a minimal shift in their mass defects. Subsequently, the MDF strategy was employed to tentatively identify Cl-PFRs retrospectively in six human urine samples that had previously been analyzed. RESULTS: MDF in combination with product ion filtering for the characteristic [H2 O3 P]+ and [H4 O4 P]+ ions and neutral loss filtering for the characteristic Cn H2n-x Clx group resulted in revealing suspects and homologues in the Cl-PFRs family. Furthermore, the MDF of the product ions detected additional Cl-PFR-related compounds that differed significantly in the exact masses of both precursor and product ions but had minimal shift in the mass defects of product ions. The mass defect of one or more common product ions helped to detect a few Cl-PFR analogs that had not been identified by MDF of the core structure precursor ion. CONCLUSIONS: MDF helped to detect some Cl-PFRs present in lower concentrations, which went undetected without data filters. MDF also helped to detect chromatographic peaks for Cl-PFR homologues that are likely structural analogs that resulted from impurities and/or derivatives and transformation products. The methodology was applied to demonstrate and tentatively detect known and suspect Cl-PFRs in human urine samples retrospectively.

The tooth exposome in children's health research.

PURPOSE OF REVIEW: The exposome concept proposes a comprehensive assessment of environmental exposures from the prenatal period onwards. However, determining exposure timing, especially over the prenatal period, is a major challenge in environmental epidemiologic studies. RECENT FINDINGS: For decades, teeth have been used to estimate long-term cumulative exposure to metals. Recently developed high-dimensional analytical methods, which combine sophisticated histological and chemical analysis to precisely sample tooth layers that correspond to specific life stages, have the potential to reconstruct the exposome in the second and third trimesters of prenatal development and during early childhood. SUMMARY: A retrospective temporal exposomic approach that precisely measures exposure intensity 'and timing' during prenatal and early childhood development would substantially aid epidemiologic investigations, particularly case-control studies of rare health outcomes.

Tooth matrix analysis for biomonitoring of organic chemical exposure: Current status, challenges, and opportunities.

Epidemiological evidence supports associations between prenatal exposure to environmental organic chemicals and childhood health impairments. Unlike the common choice of biological matrices such as urine and blood that can be limited by short half-lives for some chemicals, teeth provide a stable repository for chemicals with half-life in the order of decades. Given the potential of the tooth bio-matrix to study long-term exposures to environmental organic chemicals in human biomonitoring programs, it is important to be aware of possible pitfalls and potential opportunities to improve on the current analytical method for tooth organics analysis. We critically review previous results of studies of this topic. The major drawbacks and challenges in currently practiced concepts and analytical methods in utilizing tooth bio-matrix are (i) no consideration of external (from outer surface) or internal contamination (from micro-odontoblast processes), (ii) the misleading assumption that whole ground teeth represent prenatal exposures (latest formed dentine is lipid rich and therefore would absorb and accumulate more organic chemicals), (iii) reverse causality in exposure assessment due to whole ground teeth, and (iv) teeth are a precious bio-matrix and grinding them raises ethical concerns about appropriate use of a very limited resource in exposure biology and epidemiology studies. These can be overcome by addressing the important limitations and possible improvements with the analytical approach associated at each of the following steps: (i) tooth sample preparation to retain exposure timing, (ii) organics extraction and pre-concentration to detect ultra-trace levels of analytes, (iii) chromatography separation, (iv) mass spectrometric detection to detect multi-class organics simultaneously, and (v) method validation, especially to exclude chance findings. To highlight the proposed improvements we present findings from a pilot study that utilizes tooth matrix biomarkers to obtain trimester-specific exposure information for a range of organic chemicals.

Passive exposures of children to volatile trihalomethanes during domestic cleaning activities of their parents.

Domestic cleaning has been proposed as a determinant of trihalomethanes (THMs) exposure in adult females. We hypothesized that parental housekeeping activities could influence children's passive exposures to THMs from their mere physical presence during domestic cleaning. In a recent cross-sectional study (n = 382) in Cyprus [41 children (< 18 y) and 341 adults (≥ 18 y)], we identified 29 children who met the study's inclusion criteria. Linear regression models were applied to understand the association between children sociodemographic variables, their individual practices influencing ingestion and noningestion exposures to ΣTHMs, and their urinary THMs levels. Among the children-specific variables, age alone showed a statistically significant inverse association with their creatinine-adjusted urinary ΣTHMs (rS = -0.59, p < 0.001). A positive correlation was observed between urinary ΣTHMs (ng g(-1)) of children and matched-mothers (rS = 0.52, p = 0.014), but this was not the case for their matched-fathers (rS = 0.39, p = 0.112). Time spent daily by the matched-mothers for domestic mopping, toilet and other cleaning activities using chlorine-based cleaning products was associated with their children's urinary THMs levels (rS = 0.56, p = 0.007). This trend was not observed between children and their matched-fathers urinary ΣTHMs levels, because of minimum amount of time spent by the latter in performing domestic cleaning. The proportion of variance of creatinine-unadjusted and adjusted urinary ΣTHMs levels in children that was explained by the matched-mothers covariates was 76% and 74% (p < 0.001), respectively. A physiologically-based pharmacokinetic model adequately predicted urinary chloroform excretion estimates, being consistent with the corresponding measured levels. Our findings highlighted the influence of mothers' domestic cleaning activities towards enhancing passive THMs exposures of their children. The duration of such activities could be further tested as a valid indicator of children's THMs body burden.

Association between urinary levels of bisphenol A and its monochlorinated derivative and obesity.

Population-based studies suggest the association between exposures to bisphenol A (BPA) and obesity. However, no human studies are available that link exposures to chlorinated derivatives of BPA with obesity biomarkers. The objective of this exploratory post hoc analysis of our cross-sectional study's dataset was to evaluate the association between urinary levels of BPA and monochlorinated BPA (mono-ClBPA) with body mass index (BMI) in a random sample of 223 adults (≥18 years) from the general population in Cyprus. Univariate analysis and multiple logistic regressions were performed for descriptive statistics and estimating odds ratio (OR) of above normal BMI, respectively. We observed a relatively weak positive association between urinary mono-ClBPA and BMI, such as (i) 76 ng g(-1) in participants with above normal BMI (≥25 kg m(-2)) versus 55 ng g(-1) in those with normal BMI (<25 kg m(-2)) (P for mean difference = 0.053) and (ii) higher percentage of participants with above normal BMI in the high urinary mono-ClBPA tertile (63% in tertile 3 and 57% in tertile 2 versus 50% in tertile 1, P for trend = 0.056). Similar tests of association between urinary BPA and BMI showed null outcome. A dichotomously-classified group analysis showed an increased odds ratio (OR) for higher BMI in the group with high creatinine-adjusted urinary levels of BPA and mono-ClBPA when compared with the participants group with low levels for both compounds [logistic model adjusted for gender and health status as potential confounders; adjusted OR (95% CI): 2.34 (1.10, 5.10), P = 0.027]. Measurements of both BPA and its trace chlorinated derivative in human matrices may be warranted for a comprehensive exposure assessment towards improving our understanding of their obesogenic effects.

Preliminary evidence of the association between monochlorinated bisphenol A exposure and type II diabetes mellitus: A pilot study.

Evidence for the association of bisphenol A (BPA) with type II diabetes mellitus (T2DM) has been inconsistent in human studies. In-vitro and animal studies indicate that chlorinated BPA derivatives aggravate BPA health effects via higher estrogenic activity and alteration of membrane-initiating signaling pathways. We evaluated the association between urinary monochlorinated BPA (mono-ClBPA) concentrations and the incidence of T2DM. In our cross-sectional study, we identified 20 adult participants (≥18 yr) who reported having T2DM (doctor-diagnosed) and 131 adults with normal health. First morning void urine samples were analyzed for total BPA and mono-ClBPA. Detection limits of the analytical method were 95 ng L(-1) for BPA and 32 ng L(-1) for mono-ClBPA. Multivariable logistic regression analyses and additive Bayesian network modeling were performed. After adjusting for age, gender, BMI, urinary total BPA and other confounders, the odds of having T2DM was 3.29 times higher (95% confidence interval, CI: 1.10, 11.4; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA levels (n = 151); this relation did not hold for total BPA. The globally optimum Bayesian model corroborated the results of the logistic regression by expressing mono-ClBPA in the pathway of T2DM, and not for total BPA. An age-matched sensitivity analysis confirmed the increase in OR of T2DM by 3.04 times (95% CI: 1.10, 11.0; P < 0.05) per unit increase in log-transformed and creatinine-adjusted urinary mono-ClBPA concentration (n = 68). The urinary monochlorinated BPA derivative was significantly associated with T2DM, whereas the parent compound (total BPA) was not. Caution should be applied in interpreting these findings, as this is the first study to report this association and the sample size of participants with T2DM is small. Additional research with a larger sample size coupled with relevant toxicological studies is warranted.

Spatial and seasonal variability of urinary trihalomethanes concentrations in urban settings.

A complex network of sources and routes of exposure to disinfection by-products (DBP), such as trihalomethanes (THM) has been driving the wide variability of daily THM intake estimates in environmental epidemiological studies. We hypothesized that the spatiotemporal variability of THM exposures could be differentially expressed with their urinary levels among residents whose households are geographically clustered in district-metered areas (DMA) receiving the same tap water. Each DMA holds unique drinking-water pipe network characteristics, such as pipe length, number of pipe leaking incidences, number of water meters by district, average minimum night flow and average daily demand. The present study assessed the spatial and seasonal variability in urinary THM levels among residents (n=310) of geocoded households belonging to two urban DMA of Nicosia, Cyprus, with contrasting water network properties. First morning urine voids were collected once in summer and then in winter. Results showed that the mean sum of the four urinary THM analytes (TTHM) was significantly higher during summer for residents of both areas. Linear mixed effects models adjusted for age, season and gender, illustrated spatially-resolved differences in creatinine-adjusted urinary chloroform and TTHM levels between the two studied areas, corroborated by differences observed in their pipe network characteristics. Additional research is warranted to shed light on the contribution of spatially-resolved and geographically-clustered environmental exposures coupled with internal biomarker of exposure measurements towards better understanding of health disparities within urban centers.

Incorporating potable water sources and use habits into surveys that improve surrogate exposure estimates for water contaminants: the case of bisphenol A.

Human biomonitoring studies for water contaminants are often accompanied by surveys relying solely on total drinking water consumption rates, thus, failing to account for specific water sources (bottled and tap water) and use habits, such as water used for preparing cold/hot beverages (coffee, tea, juice, etc.). Despite the extensive use of bisphenol A (BPA) in polycarbonate (PC)-based water contact materials, rarely do BPA biomonitoring studies focus on various PC water uses and sources. Better resolved water consumption rates could reduce the uncertainty associated with surrogate daily BPA intake estimates using fine-tuned surveys. This approach provided a proof of concept on inclusion of water consumption from various sources and uses into estimates of daily intake for water contaminants like BPA found in water-contact materials. The next steps would be in quantifying the extent of improvement in exposure assessment that adds value to refined survey designs.

Co-occurrence profiles of trace elements in potable water systems: a case study.

Potable water samples (N = 74) from 19 zip code locations in a region of Greece were profiled for 13 trace elements composition using inductively coupled plasma mass spectrometry. The primary objective was to monitor the drinking water quality, while the primary focus was to find novel associations in trace elements occurrence that may further shed light on common links in their occurrence and fate in the pipe scales and corrosion products observed in urban drinking water distribution systems. Except for arsenic at two locations and in six samples, rest of the analyzed elements was below maximum contaminant levels, for which regulatory values are available. Further, we attempted to hierarchically cluster trace elements based on their covariances resulting in two groups; one with arsenic, antimony, zinc, cadmium, and copper and the second with the rest of the elements. The grouping trends were partially explained by elements' similar chemical activities in water, underscoring their potential for co-accumulation and co-mobilization phenomena from pipe scales into finished water. Profiling patterns of trace elements in finished water could be indicative of their load on pipe scales and corrosion products, with a corresponding risk of episodic contaminant release. Speculation was made on the role of disinfectants and disinfection byproducts in mobilizing chemically similar trace elements of human health interest from pipe scales to tap water. It is warranted that further studies may eventually prove useful to water regulators from incorporating the acquired knowledge in the drinking water safety plans.

Urinary biomarkers of environmental exposures and asthma morbidity in a school inner city asthma study.

BACKGROUND: The burden of pediatric asthma and other allergic diseases is not evenly distributed among United States populations. OBJECTIVE: To determine whether urinary biomarkers are associated with asthma morbidity, and if associations vary by child race, ethnicity and sex. METHODS: This study includes n = 152 children with physician-diagnosed asthma who participated in the School Inner-City Asthma Intervention Study (SICAS-2). Metabolites of phenol, paraben, polycyclic aromatic hydrocarbons, and phthalate analytes were analyzed from urine samples collected at baseline. Asthma symptom days over the past 2 weeks were dichotomized to no asthma symptom days or any asthma symptom days. Cross-sectional regression models were adjusted for age, sex, number of colds, household income, prescription control, race and ethnicity, body mass index (BMI) percentile, and smoke exposure. Weighted quantile sum regression was used to analyze each chemical class and a total mixture effect, controlling for the same covariates. Analyses were conducted with the assistance of the National Institute of Environmental Health Sciences Children's Health Exposure Analysis Resource (CHEAR). RESULTS: Participants were mostly Hispanic/Latino and low income with an average age of 7.83 years and the average maximum asthma symptom days over the past two weeks of 2.13 (standard deviation: 3.56). The maximum concentrations indicate extreme values for several chemicals, including bisphenol-3, 2,5-dichlorophenol, propyl and methyl parabens, triclosan, methyl paraben and cotinine. We found a significant interaction effect and differing contributions of analytes for children with allergen sensitivity versus those that did not. For stratified analyses assessing effect modification by child race and ethnicity, weighted quantile sum interaction models showed reduced odds of asthma symptoms to a greater magnitude in children of other races and ethnicities compared to Black, Non-Hispanic children. CONCLUSIONS: Preliminary analyses of the association between environmental chemical exposure and asthma symptoms among inner-city children revealed an inverse association, which may be due to personal care and medication use and can be understood further in future analyses. Beneficial effects were detected for most of the chemicals.

Metabolism-Disrupting Chemical Mixtures during Pregnancy, Folic Acid Supplementation, and Liver Injury in Mother-Child Pairs.

Background and Aims: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver injury and effect modification by folic acid (FA) supplementation in mother-child pairs. Methods: We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. We defined liver injury as elevated liver enzymes in children, and using established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver injury outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. Results: In children, many MDC-mixtures were associated with liver injury outcomes. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations ( p -interactions<0.05). In mothers, only the LMWP-mixture was associated with liver injury [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day ( p -interactions<0.05). Conclusions: Pregnancy MDC exposures may increase liver injury risk, particularly in children. These associations may be attenuated by higher FA supplementation and maternal cobalt levels.

Phthalate exposure in the neonatal intensive care unit is associated with development of bronchopulmonary dysplasia.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a serious yet common morbidity of preterm birth. Although prior work suggests a possible role for phthalate exposure in the development of BPD, no study has rigorously evaluated this. Our objective was to determine whether hospital-based phthalate exposure is associated with the development of BPD and to identify developmental windows sensitive to exposure. STUDY DESIGN: This is a prospective multicenter cohort study of 360 preterm infants born at 23-33 weeks gestation participating in the Developmental Impact of NICU Exposures (DINE) cohort. 939 urine specimens collected during the NICU stay were analyzed for biomarkers of phthalate exposure by liquid chromatography with tandem mass spectrometry. The modified Shennan definition was used to diagnose bronchopulmonary dysplasia. Reverse distributed-lag modeling identified developmental windows sensitive to specific phthalate exposure, controlling for relevant covariates including sex and respiratory support. RESULTS: Thirty-five percent of participants were diagnosed with BPD. Exposure to specific phthalate mixtures at susceptible points in preterm infant development are associated with later diagnosis of BPD in models adjusted for use of respiratory support. The weighted influence of specific phthalate metabolites in the mixtures varied by sex. Metabolites of di(2-ethylhexyl) phthalate, a phthalate previously linked to neonatal respiratory support equipment, drove this association, particularly among female infants, at 26- to 30-weeks post-menstrual age. CONCLUSIONS: This is the largest and only multi-site study of NICU-based phthalate exposure and clinical impact yet reported. In well-constructed models accounting for infant sex and respiratory support, we found a significant positive association between ultimate diagnosis of BPD and prior exposure to phthalate mixtures with DEHP predominance at 26- to 30-weeks PMA or 34-36-weeks PMA. This information is critically important as it identifies a previously unrecognized and modifiable contributing factor to BPD.