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.

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.

Exposure to perfluoroalkyl substances and women's fertility outcomes in a Singaporean population-based preconception cohort.

OBJECTIVES: Experimental models have demonstrated a link between exposure to perfluoroalkyl substances (PFAS) and decreased fertility and fecundability; however, human studies are scarce. We assessed the associations between preconception plasma PFAS concentrations and fertility outcomes in women. METHODS: In a case-control study nested within the population-based Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO), we measured PFAS in plasma collected in 2015-2017 from 382 women of reproductive age trying to conceive. Using Cox proportional hazards regression (fecundability ratios [FRs]) and logistic regression (odds ratios [ORs]) models, we assessed the associations of individual PFAS with time-to-pregnancy (TTP), and the likelihoods of clinical pregnancy and live birth, respectively, over one year of follow-up, adjusting for analytical batch, age, education, ethnicity, and parity. We used Bayesian weighted quantile sum (BWQS) regression to assess the associations of the PFAS mixture with fertility outcomes. RESULTS: We found a 5-10 % reduction in fecundability per quartile increase of exposure to individual PFAS (FRs [95 % CIs] for clinical pregnancy = 0.90 [0.82, 0.98] for PFDA; 0.88 [0.79, 0.99] for PFOS; 0.95 [0.86, 1.06] for PFOA; 0.92 [0.84, 1.00] for PFHpA). We observed similar decreased odds of clinical pregnancy (ORs [95 % CIs] = 0.74 [0.56, 0.98] for PFDA; 0.76 [0.53, 1.09] for PFOS; 0.83 [0.59, 1.17] for PFOA; 0.92 [0.70, 1.22] for PFHpA) and live birth per quartile increases of individual PFAS and the PFAS mixture (ORs [95 % CIs] = 0.61 [0.37, 1.02] for clinical pregnancy, and 0.66 [0.40, 1.07] for live birth). Within the PFAS mixture, PFDA followed by PFOS, PFOA, and PFHpA were the biggest contributors to these associations. We found no evidence of association for PFHxS, PFNA, and PFHpS and the fertility outcomes examined. CONCLUSIONS: Higher PFAS exposures may be associated with decreased fertility in women. The potential impact of ubiquitous PFAS exposures on infertility mechanisms requires further investigation.

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.

Application of growth modeling to assess the impact of hospital-based phthalate exposure on preterm infant growth parameters during the neonatal intensive care unit hospitalization.

In this study, we use advanced growth modeling techniques and the rich biospecimen and data repositories of the NICU Hospital Exposures and Long-Term Health (NICU-HEALTH) study to assess the impact of NICU-based phthalate exposure on extrauterine growth trajectories between birth and NICU discharge. Repeated holdout weighed quantile sum (WQS) regression was used to assess the effect of phthalate mixtures on the latency to first growth spurt and on the rate of first growth spurt. Further, we assessed sex as an effect modifier of the relationship between a phthalate mixture and both outcomes. Nine phthalate metabolites, mono-ethyl phthalate (MEP), mono-benzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MiBP), mono-(3-carboxypropyl) phthalate (MCPP), mono-2-ethylhexyl phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) were measured in weekly urine specimens from 101 NICU-HEALTH participants between birth and the first growth spurt. Phthalate levels varied by species but not by infant sex, and decreased over the course of the NICU hospitalization as presented in detail in Stroustrup et al., 2018. There was evidence of nonlinearity when assessing the effect of phthalates on latency to first growth spurt. Above a threshold level, a higher phthalate mixture with dominant contributors MCPP, MBzP, and MEP predicted a shorter latency to the first inflection point, or an earlier growth spurt. A higher phthalate mixture with dominant contributors MECPP, MEHHP, and MEOHP was associated with an increased rate of growth. Results of both models were clearly different for boys and girls, consistent with other studies showing the sexually dimorphic impact of early life phthalate exposure. These results suggest that growth curve modeling facilitates evaluation of discrete periods of rapid growth during the NICU hospitalization and exposure to specific phthalates during the NICU hospitalization may both alter the timing of the first growth spurt and result in more rapid growth in a sexually dimorphic manner.

Associations between repeated measures of urinary phthalate metabolites and biomarkers of oxidative stress in a rural agricultural cohort of children with asthma.

Phthalate exposure is widespread, and studies suggest an adverse relationship with asthma morbidity, including some support for oxidative stress as an underlying pathophysiological mechanism. Urinary phthalate metabolites have been associated with biomarkers of oxidative stress, but data are few in children diagnosed with asthma. We used participant data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine longitudinal relationships between phthalates and oxidative stress in a cohort of Latino children with asthma residing in an agricultural community. We used linear mixed-effects models to estimate associations between 11 urinary phthalate metabolites (and one summed measure of di-2-ethylhexyl phthalate (DEHP) metabolites, ∑DEHP) and two urinary biomarkers of oxidative stress: a biomarker of lipid peroxidation via measure of 8-isoprostane and a biomarker of DNA/RNA oxidative damage via combined measure of 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxyguanosine (8-OHG), and 8-hydroxyguanine. Seventy-nine participants provided 281 observations. In covariate-adjusted models, we observed significant positive relationships between all phthalate metabolites and 8-isoprostane, effect sizes ranging from a 9.3 % (95 % CI: 4.2 %-14.7 %) increase in 8-isoprostane for each 100 % increase (i.e., doubling) of mono-(carboxy-isooctyl) phthalate (MCIOP), to a 21.0 % (95 % CI: 14.3 %-28.2 %) increase in 8-isoprostane for each doubling of mono-n-butyl phthalate (MNBP). For each doubling of mono-(carboxy-isononyl) phthalate (MCINP) and mono-ethyl phthalate (MEP), the DNA/RNA oxidative damage biomarker increased by 6.0 % (95 % CI: 0.2 %-12.2 %) and 6.5 % (95 % CI: 1.4 %-11.9 %), respectively. In conclusion, we provide unique data suggesting phthalate exposure is positively associated with oxidative stress in children with asthma. Our repeat measures provide novel identification of a consistent effect of phthalates on oxidative stress in children with asthma via lipid peroxidation. Confirmation in future studies of children with asthma is needed to enhance understanding of the role of phthalates in childhood asthma morbidity.

Prenatal alcohol exposure can be determined from baby teeth: Proof of concept.

BACKGROUND: Prenatal alcohol exposure (PAE), leading to fetal alcohol spectrum disorders (FASD), is a serious public health issue in the United States and globally. Diagnosis of FASD is crucial in obtaining appropriate care, but it is not always possible when PAE cannot be documented. METHODS: Deciduous teeth from a child with known PAE and a child with known absence of PAE were analyzed using liquid chromatography-isotope dilution tandem mass spectrometry (LC-IDMS/MS) in a multiple-reaction monitoring mode for direct markers and LC-high resolution MS in positive and negative mode with hydrophilic interaction liquid chromatography and reverse-phase chromatography, respectively, for indirect markers. RESULTS: Direct markers of PAE (ethyl glucuronide and ethyl sulfate) were detected in prenatal and postnatal dentine from a case tooth but not from a control tooth. Indirect biomarker analysis indicated a dysregulation of amino acids and an increase in cholesterol sulfate in the case compared to the control tooth. CONCLUSIONS: This proof-of-concept study demonstrates for the first time that direct biomarkers of PAE are detectable and measurable in deciduous teeth which begin forming in utero and are typically naturally shed between 5 and 12 years of age. Further examination of these novel biomarkers may allow diagnosis of FASD where documentation of PAE is otherwise unavailable. Furthermore, because teeth grow incrementally, defined growth zones can be sampled allowing for identification of gestational timing of PAE to help better understand mechanisms underlying alcohol's disruption of perinatal development.

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.

Longitudinal measures of phthalate exposure and asthma exacerbation in a rural agricultural cohort of Latino children in Yakima Valley, Washington.

Phthalates are a class of widely used synthetic chemicals found in commonly used materials and products. Epidemiological studies suggest phthalate exposure is associated with asthma outcomes, though most studies have not investigated phthalates as triggers of exacerbations in children diagnosed with asthma. This study used data from the Home Air in Agriculture Pediatric Intervention Trial (HAPI) to examine relationships between phthalate exposure and outcomes related to childhood asthma exacerbation. We used measures of phthalate metabolites and respiratory health measures including fractional exhaled nitric oxide (FENO), the Asthma Control Test (ACT), caregiver report of symptoms, and urinary leukotriene E4 (uLTE4) to estimate longitudinal associations using mixed effects models, adjusted for covariates. For 100% (i.e., doubling) increases in mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-2-ethylhexyl phthalate (MEHP), and mono-ethyl phthalate (MEP), concentrations of FENO increased by 8.7% (95% CI: 0.7-17.3), 7.2% (95% CI: 0.0-14.9), and 6.4% (95% CI: 0.0-13.3), respectively. All phthalate metabolites demonstrated associations with uLTE4, effect sizes ranging from an 8.7% increase in uLTE4 (95% CI: 4.3-12.5) for a 100% increase in MEHP to an 18.1% increase in uLTE4 (95% CI: 13.3-23.1) for a 100% increase in MNBP. In models of caregiver report of symptoms, no phthalate metabolites were significantly associated in primary models. No phthalate metabolites were associated with standardized ACT score. Our results suggest urinary phthalate metabolites are significant predictors of inflammatory biomarkers related to asthma exacerbation in children but not child and caregiver report of airway symptomatology.

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.

Racial/ethnic and neighborhood disparities in metals exposure during pregnancy in the Northeastern United States.

Despite the unequal burden of environmental exposures borne by racially minoritized communities, these groups are often underrepresented in public health research. Here, we examined racial/ethnic disparities in exposure to metals among a multi-ethnic sample of pregnant women. The sample included women enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort (N = 382). Urinary metal concentrations (arsenic [As], barium [Ba], cadmium [Cd], cesium [Cs], chromium [Cr], lead [Pb], antimony [Sb]) were measured during mid-pregnancy and information on individual- and neighborhood-level characteristics was ascertained during an in-person interview and from publicly available databases, respectively. Linear regression was used to examine individual and neighborhood characteristics in relation to metal concentrations. Black/Black-Hispanic women had Cd, Cr, Pb, and Sb levels that were 142.0%, 10.9%, 35.0%, and 32.1% higher than White, non-Hispanic women, respectively. Likewise, White-Hispanic women had corresponding levels that were 141.5%, 108.2%, 59.9%, and 38.3% higher. These same metals were also higher among women residing in areas with higher crime, higher diversity, lower educational attainment, lower household income, and higher poverty. Significant disparities in exposure to metals exist and may be driven by neighborhood-level factors. Exposure to metals for pregnant women can be especially harmful. Understanding exposure inequalities and identifying factors that increase risk can help inform targeted public health interventions.

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.

Effect of Common Consumer Washing Methods on Bisphenol A Release in Tritan Drinking Bottles.

Bisphenol A (BPA)-free plastic products are widely available. Transient BPA release has been reported in Tritan drinking bottles. This study assessed the effectiveness of common consumer washing methods in removing BPA contamination in Tritan bottles using both ELISA and HPLC-MS/MS assays. BPA release was detected in 2 out of 10 kinds of Tritan drinking bottles tested. Average BPA level was 0.493 µg/L in water samples from a type of Tritan kid drinking bottle following 24-hour incubation at room temperature, corresponding to a release rate of 0.015 ng/cm2/h. Of the common consumer cleaning methods identified in an informal survey, dishwashing was the most effective method that significantly reduced, even eliminated BPA release from the tested BPA-positive Tritan bottles, while rinsing with water and handwashing with soap and water were ineffective. The bioactivity of the leached BPA was confirmed using a rodent cardiac myocyte acute exposure model and an invertebrate 7-day exposure model. The BPA release is possibly the result of surface contamination in the manufacturing process. As a case study, our result may be informative for general consumer practice and for better quality control by the manufactures.

Prenatal metal mixtures and sex-specific infant negative affectivity.

Prenatal exposure to metals has been associated with a range of adverse neurocognitive outcomes; however, associations with early behavioral development are less well understood. We examined joint exposure to multiple co-occurring metals in relation to infant negative affect, a stable temperamental trait linked to psychopathology among children and adults. METHODS: Analyses included 308 mother-infant pairs enrolled in the PRISM pregnancy cohort. We measured As, Ba, Cd, Cs, Cr, Pb, and Sb in urine, collected on average during late pregnancy, by ICP-MS. At age 6 months, we assessed negative affect using the Infant Behavior Questionnaire-Revised. We used Weighted Quantile Sum (WQS) regression with repeated holdout validation to estimate the joint association between the metals and global negative affectivity, as well as four subdomains (Fear, Sadness, Distress to Limitations, and Falling Reactivity). We also tested for a sex interaction with estimated stratified weights. RESULTS: In adjusted models, urinary metals were associated with higher scores on the Fear scale (ßWQS = 0.20, 95% confidence interval [CI]: 0.09, 0.30), which captures behavioral inhibition, characterized by startle or distress to sudden changes in the environment and inhibited approach to novelty. We observed a significant sex interaction (95% CI for the cross-product term: -0.19, -0.01), and stratified weights showed girls (61.6%) contributed substantially more to the mixture effect compared with boys (38.4%). Overall, Ba contributed the greatest mixture weight (22.5%), followed by Cs (14.9%) and As (14.6%). CONCLUSIONS: Prenatal exposure to metals was associated with increased infant scores on the temperamental domain of fear, with girls showing particular sensitivity.Key words: Prenatal; Metals; Mixtures; Temperament; Infancy; Negative affect.

Quality assurance and harmonization for targeted biomonitoring measurements of environmental organic chemicals across the Children's Health Exposure Analysis Resource laboratory network.

A consortium of laboratories established under the Children's Health Exposure Analysis Resource (CHEAR) used a multifaceted quality assurance program to promote measurement harmonization for trace organics analyses of human biospecimens that included: (1) participation in external quality assurance (EQA)/proficiency testing (PT) programs; (2) analyses of a urine-based CHEAR common quality control (QC) pool with each analytical batch across all participating laboratories; (3) method validation against NIST Standard Reference Materials® (SRMs); and (4) analyses of blinded duplicates and other project-specific QC samples. The capability of five CHEAR laboratories in organic chemical analysis increased across the 4-year period, and performance in the external PT program improved over time - recent challenges reporting >90% analytes with satisfactory performance. The CHEAR QC pools were analyzed for several classes of organic chemicals including phthalate metabolites and environmental phenols by the participating laboratories with every batch of project samples, which provided a rich source of measurement data for the assessment of intra- and inter-laboratory variance. Within-laboratory and overall variabilities in measurements across laboratories were calculated for target chemicals in urine QC pools; the coefficient of variation (CV) was generally below 25% across batches, studies and laboratories and indicated acceptable analytical imprecision. The suite of organic chemicals analyzed in the CHEAR QC pool was broader than those reported for commercially available reference materials. The accuracy of each of the laboratories' methods was verified through the analysis of several NIST SRMs and was, for example, 97 ± 5.2% for environmental phenols and 95 ± 11% for phthalates. Analysis of blinded duplicate samples showed excellent agreement and reliability of measurements. The intra-class correlation coefficients (ICC) for phthalate metabolites analyzed in various batches across three CHEAR laboratories showed excellent reliability (typically >0.90). Overall, the multifaceted quality assurance protocols followed among the CHEAR laboratories ensured reliable and reproducible data quality for several classes of organic chemicals. Increased participation in external PT programs through inclusion of additional target analytes will further enhance the confidence in data quality.

Evaluating inter-study variability in phthalate and trace element analyses within the Children's Health Exposure Analysis Resource (CHEAR) using multivariate control charts.

BACKGROUND: The Children's Health Exposure Analysis Resource (CHEAR) program allows researchers to expand their research goals by offering the assessment of environmental exposures in their previously collected biospecimens. Samples are analyzed in one of CHEAR's network of six laboratory hubs with the ability to assess a wide array of environmental chemicals. The ability to assess inter-study variability is important for researchers who want to combine datasets across studies and laboratories. OBJECTIVE: Herein we establish a process of evaluating inter-study variability for a given analytic method. METHODS: Common quality control (QC) pools at two concentration levels (A and B) in urine were created within CHEAR for insertion into each batch of samples tested at a rate of three samples of each pool per 100 study samples. We assessed these QC pool results for seven phthalates analyzed for five CHEAR studies by three different lab hubs utilizing multivariate control charts to identify out-of-control runs or sets of samples associated with a given QC sample. We then tested the conditions that would lead to an out-of-control run by simulating outliers in an otherwise "in-control" set of 12 trace elements in blood QC samples (NIST SRM 955c). RESULTS: When phthalates were assessed within study, we identified a single out-of-control run for two of the five studies. Combining QC results across lab hubs, all of the runs from these two studies were now in-control, while multiple runs from two other studies were pushed out-of-control. In our simulation study we found that 3-6 analytes with outlier values (5xSD) within a run would push that run out of control in 65-83% of simulations, respectively. SIGNIFICANCE: We show how acceptable bounds of variability can be established for a given analytic method by evaluating QC materials across studies using multivariate control charts.

Environmental Tobacco Smoke Exposure Among Children by Urinary Biomarkers and Parent Report.

OBJECTIVE: The goal of this study was to describe environmental tobacco smoke (ETS) exposure using urinary biomarkers and its correlation with parent report, among children presenting to emergency room. METHODS: This is a case control study among children aged 3 to 12 years at a tertiary pediatric emergency department in Israel. Children with respiratory (case) or gastrointestinal (control) symptoms were recruited and their accompanying parent completed a short survey. Urine samples were obtained and analyzed for nicotine, cotinine trans-3'-hydroxycotine. Clinical data were extracted from medical records. We compared tobacco exposure using urinary biomarkers, parent report, and Pearson's product-moment correlation, including 95% confidence intervals, between cases and controls. RESULTS: Forty-nine cases with respiratory symptoms and 96 controls with gastrointestinal symptoms were enrolled in the study. Parent-reported ETS exposure in the previous month was higher in the cases compared to control (71.4% vs 57.3%), although the difference was not statistically significant. The mean values of detectable biomarkers did not differ by between cases and controls. However, there was a correlation between urinary biomarkers and reported ETS exposure (0.278-0.460 for various biomarkers) only among cases. CONCLUSIONS: The majority of children in this study had detectable nicotine urinary biomarkers, regardless of their symptoms. However, correlation between parental report and urinary biomarkers was only found among children with symptoms potentially related to ETS. These findings imply that parents of children without respiratory symptoms may underestimate exposure. Efforts to educate parents and caregivers on the risks associated with exposure to ETS should be intensified, regardless of illness.

Pharmacokinetics of bisphenol A in humans following dermal administration.

BACKGROUND: Human exposures to bisphenol A (BPA) are widespread. The current study addresses uncertainties regarding human pharmacokinetics of BPA following dermal exposure. OBJECTIVE: To examine the absorption, distribution, metabolism and excretion of BPA in humans following dermal administration. METHODS: We dermally administered deuterated BPA (d6-BPA) to 10 subjects (6 men and 4 women) at a dose of 100 µg/kg over a 12-hour period and conducted blood and urine analysis from the beginning of dosing through a three- or six-day period. We present time-course serum and urine concentrations of total and unconjugated ("free") d6-BPA and used this information to calculate terminal half-life and area under the curve. RESULTS AND CONCLUSIONS: Detectable serum levels of total d6-BPA were observed at 1.4 h after the start of dosing, and a maximum serum concentration (Cmax) of 3.26 nM was observed. Free d6-BPA was detectable in serum 2.8 h after start of dermal administration, with Cmax of 0.272 nM. Beginning at approximately seven hours and continuing to 12 h (which corresponds to cessation of exposure), the concentration of free and total serum d6-BPA plateaued. The terminal half-lives of total d6-BPA and free d6-BPA in the body were 21.4 ± 9.81 h and 17.6 ± 7.69 h, respectively. Elimination from the body was rate-limited by kinetics in the dermal compartment. Free d6-BPA was a greater percentage of the area under the curve of total serum BPA (8.81%) compared to the 0.56% observed in our previously published oral study. Recovery of total d6-BPA in urine was <2% of the applied dose after six days. Analysis of the area under the curve for dermal and oral administration revealed that 2.2% of the dermal dose became systemically available. These data are in line with prior studies indicating how pharmacokinetics of BPA differ following oral and dermal exposures. Dermal exposure resulted in a longer apparent half-life and higher free:total d6-BPA ratio compared to oral.