Evaluation of VTE, MACE, and Serious Infections Among Patients with RA Treated with Baricitinib Compared to TNFi: A Multi-Database Study of Patients in Routine Care Using Disease Registries and Claims Databases.

INTRODUCTION: The aim of this work is to evaluate baricitinib safety with respect to venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection relative to tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA from 14 real-world data sources (three disease registries, eight commercial and three government health insurance claims databases) in the United States (n = 9), Europe (n = 3), and Japan (n = 2) were analyzed using a new user active comparator design. Propensity score matching (1:1) controlled for potential confounding. Meta-analysis of incidence rate ratios (IRR) and incidence rate differences (IRD) for each outcome, from each data source was executed using modified Poisson regression and Cochran-Mantel-Haenszel analysis. RESULTS: Of 9013 eligible baricitinib-treated patients, 7606 were propensity score-matched with TNFi-treated patients, contributing 5879 and 6512 person-years of baricitinib and TNFi exposure, respectively. Across data sources, 97 patients (56 baricitinib) experienced VTE during follow-up, 93 experienced MACE (54 baricitinib), and 321 experienced serious infection (176 baricitinib). Overall IRRs comparing baricitinib with TNFi treatment were 1.51 (95% CI 1.10, 2.08) for VTE, 1.54 (95% CI 0.93, 2.54) for MACE, and 1.36 (95% CI 0.86, 2.13) for serious infection. IRDs for VTE, MACE, and serious infection, respectively, were 0.26 (95% CI -0.04, 0.57), 0.22 (95% CI -0.07, 0.52), and 0.57 (95% CI -0.07, 1.21) per 100 person-years greater for baricitinib than TNFi. CONCLUSIONS: Overall results suggest increased risk of VTE with baricitinib versus TNFi, with consistent point estimates from the two largest data sources. A numerically greater risk was observed for MACE and serious infection when comparing baricitinib versus TNFi, with different point estimates from the two largest data sources. Findings from this study and their impact on clinical practice should be considered in context of limitations and other evidence regarding the safety and efficacy of baricitinib and other Janus kinase inhibitors. TRIAL REGISTRATION: EU PAS Register ( http://encepp.eu ), identifier #32271.

Waxing activity as a potential source of exposure to per- and polyfluoroalkyl substances (PFAS) and other environmental contaminants among the US ski and snowboard community.

BACKGROUND: Skiers and snowboarders apply waxes and solvents to their equipment to enhance glide across the snow. Waxing results in exposures to per- and polyfluoroalkyl substances (PFAS) and particulate matter, which have been associated with adverse health effects among professional wax technicians in Scandinavia. However, little is known about exposure among people who participate at other levels of sport, including recreationally, in other regions. OBJECTIVE: We sought to characterize wax-related exposures among US skiers and snowboarders who participate across numerous levels of sport to expand scientific understanding of environmental health risks among this population. METHODS: We used an anonymous electronic survey to evaluate wax-related exposures among US cross-country and downhill skiers and snowboarders. Specifically, we assessed (Fang et al., 2020): duration of time involved with each sport in any role (Freberg et al., 2013), intensity of wax-related exposures based on time spent in waxing areas, wax use, and wax type (Rogowski et al., 2007), frequency of fluorinated wax application, and (Freberg et al., 2010) use of exposure interventions. RESULTS: Participants tended to be long-term winter sports enthusiasts (e.g., median downhill skiing duration: 31 years). Nearly all (92%) participants personally applied some wax to their skis/snowboards and most applied waxes containing PFAS (67%) and solvents (62%). Ski professionals waxed the most pairs of skis with fluorinated waxes annually (median (IQR): 20 (1, 100)), though individuals participating recreationally also applied fluorinated waxes regularly. Exposure interventions were not widely used. SIGNIFICANCE: Waxing activities may pose significant risk of exposure to PFAS and other environmental contaminants among the US ski and snowboard community. Efforts are needed to reduce these exposures through changes to wax use patterns and broader adoption of exposure reduction strategies.

Inter-method reliability of silicone exposome wristbands and urinary biomarker assays in a pregnancy cohort.

Silicone wristbands act as passive environmental samplers capable of detecting and measuring concentrations of a variety of chemicals. They offer a noninvasive method to collect complex exposure data in large-scale epidemiological studies. We evaluated the inter-method reliability of silicone wristbands and urinary biomarkers in the New Hampshire Birth Cohort Study. A subset of study participants (n = 96) provided a urine sample and wore a silicone wristband for 7 days at approximately 12 gestational weeks. Women were instructed to wear the wristbands during all their normal activities. Concentrations of urinary compounds and metabolites in the urine and parent compounds in wristbands were compared. High detection rates were observed for triphenyl phosphate (76.0%) and benzophenone (78.1%) in wristbands, although the distribution of corresponding urinary concentrations of chemicals did not differ according to whether chemicals were detected or not detected in wristbands. While detected among only 8.3% of wristbands, median urinary triclosan concentrations were higher among those with triclosan detected in wristbands (9.04 ng/mL) than without (0.16 ng/mL). For most chemicals slight to fair agreement was observed across exposure assessment methods, potentially due to low rates of detection in the wristbands for chemicals where observed urinary concentrations were relatively low as compared to background concentrations in the general population. Our findings support the growing body of research in support of deploying silicone wristbands as an important exposure assessment tool.

Chemical exposures assessed via silicone wristbands and endogenous plasma metabolomics during pregnancy.

BACKGROUND: Metabolomics is a promising method to investigate physiological effects of chemical exposures during pregnancy, with the potential to clarify toxicological mechanisms, suggest sensitive endpoints, and identify novel biomarkers of exposures. OBJECTIVE: Investigate the influence of chemical exposures on the maternal plasma metabolome during pregnancy. METHODS: Data were obtained from participants (n = 177) in the New Hampshire Birth Cohort Study, a prospective pregnancy cohort. Chemical exposures were assessed via silicone wristbands worn for one week at ~13 gestational weeks. Metabolomic features were assessed in plasma samples obtained at ~24-28 gestational weeks via the Biocrates AbsoluteIDQ® p180 kit and nuclear magnetic resonance (NMR) spectroscopy. Associations between chemical exposures and plasma metabolomics were investigated using multivariate modeling. RESULTS: Chemical exposures predicted 11 (of 226) and 23 (of 125) metabolomic features in Biocrates and NMR, respectively. The joint chemical exposures did not significantly predict pathway enrichment, though some individual chemicals were associated with certain amino acids and related metabolic pathways. For example, N,N-diethyl-m-toluamide was associated with the amino acids glycine, L-glutamic acid, L-asparagine, and L-aspartic acid and enrichment of the ammonia recycling pathway. SIGNIFICANCE: This study contributes evidence to the potential effects of chemical exposures during pregnancy upon the endogenous maternal plasma metabolome.

Association of Cesarean Delivery and Formula Supplementation with the Stool Metabolome of 6-Week-Old Infants.

Cesarean delivery and formula feeding have both been implicated as important factors associated with perturbations to the infant gut microbiome. To investigate the functional metabolic response of the infant gut microbial milieu to these factors, we profiled the stool metabolomes of 121 infants from a US pregnancy cohort study at approximately 6 weeks of life and evaluated associations with delivery mode and feeding method. Multivariate analysis of six-week stool metabolomic profiles indicated discrimination by both delivery mode and diet. For diet, exclusively breast-fed infants exhibited metabolomic profiles that were distinct from both exclusively formula-fed and combination-fed infants, which were relatively more similar to each other in metabolomic profile. We also identified individual metabolites that were important for differentiating delivery mode groups and feeding groups and metabolic pathways related to delivery mode and feeding type. We conclude based on previous work and this current study that the microbial communities colonizing the gastrointestinal tracts of infants are not only taxonomically, but also functionally distinct when compared according to delivery mode and feeding groups. Further, different sets of metabolites and metabolic pathways define delivery mode and diet metabotypes.

Use of Exposomic Methods Incorporating Sensors in Environmental Epidemiology.

PURPOSE OF REVIEW: The exposome is a recently coined concept that comprises the totality of nongenetic factors that affect human health. It is recognized as a major conceptual advancement in environmental epidemiology, and there is increased demand for technologies that capture the spatial, temporal, and chemical variability of exposures across individuals (i.e., "exposomic sensors"). We review a selection of these tools, highlighting their strengths and limitations with regard to epidemiological research. RECENT FINDINGS: Wearable passive samplers are emerging as promising exposomic sensors for individuals. In conjunction with targeted and untargeted assays, these sensors enable the measurement of complex multipollutant mixtures, which can include both known and previously unknown environmental contaminants. Because of their minimally burdensome and noninvasive nature, they are deployable among sensitive populations, such as seniors, pregnant women, and children. The integration of exposomic data captured by these sensors with other omic data (e.g., transcriptomic and metabolomic) presents exciting opportunities for investigating disease risk factors. For example, the linkage of exposomic sensor data with other omic data may indicate perturbation by multipollutant mixtures at multiple physiological levels, which would strengthen evidence of their effects and potentially indicate targets for interventions. However, there remain considerable theoretical and methodological challenges that must be overcome to realize the potential promise of omic integration. Through continued investment and improvement in exposomic sensor technologies, it may be possible to refine their application and reduce their outstanding limitations to advance the fields of exposure science and epidemiology.

Periconceptional and prenatal exposure to metal mixtures in relation to behavioral development at 3 years of age.

BACKGROUND: Behavioral effects of prenatal exposure to mixtures of essential and toxic metals are incompletely understood. METHODS: We investigated neurodevelopmental effects of prenatal metal exposures in the New Hampshire Birth Cohort Study, a prospective birth cohort. We measured metals (As, Cu, Mn, Pb, Se, Zn) in maternal prenatal and postnatal toenails and infant toenails, reflecting exposures during periconception and early pregnancy, mid pregnancy, and late pregnancy and early neonatal life, respectively. Mothers completed the Social Responsiveness Scale, 2nd ed. (SRS-2) and the Behavior Assessment System for Children, 2nd ed. (BASC-2) to assess their child's neurobehavior at 3 years. We used mean field variational Bayes for lagged kernel machine regression to investigate associations of toenail metal concentrations with SRS-2 Total Scores and BASC-2 composite scores (SRS-2: n = 371; BASC-2: n = 318). RESULTS: Infant toenail Mn was associated with poorer performance on multiple BASC-2 composite scores. Maternal postnatal toenail As was associated with worse scores on the BASC-2 Internalizing Problems and Behavioral Symptoms Index. Associations with Mn were generally stronger in males, and associations with As were generally stronger in females. Other metals, including Pb, were weakly or inconsistently associated with BASC-2 outcomes, and there were no strong associations of individual metals and SRS-2 Total Scores. We observed suggestive evidence of interaction between As and Se for SRS-2 Total Scores and BASC-2 Adaptive Skills, though overall evidence of interactions between metals was weak. CONCLUSION: Our results support the hypothesis that exposure to Mn and As in mid to late pregnancy may be neurodevelopmentally harmful.

Assessment of Multipollutant Exposures During Pregnancy Using Silicone Wristbands.

Silicone wristbands can assess multipollutant exposures in a non-invasive and minimally burdensome manner, which may be suitable for use among pregnant women. We investigated silicone wristbands as passive environmental samplers in the New Hampshire Birth Cohort Study, a prospective pregnancy cohort. We used wristbands to assess exposure to a broad range of organic chemicals, identified multipollutant exposure profiles using self-organizing maps (SOMs), and assessed temporal consistency and determinants of exposures during pregnancy. Participants (n = 255) wore wristbands for 1 week at 12 gestational weeks. Of 1,530 chemicals assayed, 199 were detected in at least one wristband and 16 were detected in >60% of wristbands. A median of 23 (range: 12,37) chemicals were detected in each wristband, and chemicals in commerce and personal care products were most frequently detected. A subset of participants (n=20) wore a second wristband at 24 gestational weeks, and concentrations of frequently detected chemicals were moderately correlated between time points (median intraclass correlation: 0.22; range: 0.00,0.69). Women with higher educational attainment had fewer chemicals detected in their wristbands and the total number of chemicals detected varied seasonally. Triphenyl phosphate concentrations were positively associated with nail polish use, and benzophenone concentrations were highest in summer. No clear associations were observed with other a priori relations, including certain behaviors, season, and socioeconomic factors. SOM analyses revealed 12 profiles, ranging from 2 to 149 participants, captured multipollutant exposure profiles observed in this cohort. The most common profile (n = 149) indicated that 58% of participants experienced relatively low exposures to frequently detected chemicals. Less common (n ≥ 10) and rare (n < 10) profiles were characterized by low to moderate exposures to most chemicals and very high and/or very low exposure to a subset of chemicals. Certain covariates varied across SOM profile membership; for example, relative to women in the most common profile who had low exposures to most chemicals, women in the profile with elevated exposure to galaxolide and benzyl benzoate were younger, more likely to be single, and more likely to report nail polish use. Our study illustrates the utility of silicone wristbands for measurement of multipollutant exposures in sensitive populations, including pregnant women.

Maternal serum perfluoroalkyl substance mixtures and thyroid hormone concentrations in maternal and cord sera: The HOME Study.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous. Previous studies have found associations between PFAS and thyroid hormones in maternal and cord sera, but the results are inconsistent. To further address this research question, we used mixture modeling to assess the associations with individual PFAS, interactions among PFAS chemicals, and the overall mixture. METHODS: We collected data through the Health Outcomes and Measures of the Environment (HOME) Study, a prospective cohort study that between 2003 and 2006 enrolled 468 pregnant women and their children in the greater Cincinnati, Ohio region. We assessed the associations of maternal serum PFAS concentrations measured during pregnancy with maternal (n = 185) and cord (n = 256) sera thyroid stimulating hormone (TSH), total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), and free triiodothyronine (FT3) using two mixture modeling approaches (Bayesian kernel machine regression (BKMR) and quantile g-computation) and multivariable linear regression. Additional models considered thyroid autoantibodies, other non-PFAS chemicals, and iodine deficiency as potential confounders or effect measure modifiers. RESULTS: PFAS, considered individually or as mixtures, were generally not associated with any thyroid hormones. A doubling of perfluorooctanesulfonic acid (PFOS) had a positive association with cord serum TSH in BKMR models but the 95% Credible Interval included the null (ß = 0.09; 95% CrI: -0.08, 0.27). Using BKMR and multivariable models, we found that among children born to mothers with higher thyroid peroxidase antibody (TPOAb), perfluorooctanoic acid (PFOA), PFOS, and perfluorohexanesulfonic acid (PFHxS) were associated with decreased cord FT4 suggesting modification by maternal TPOAb status. CONCLUSIONS: These findings suggest that maternal serum PFAS concentrations measured in the second trimester of pregnancy are not strongly associated with thyroid hormones in maternal and cord sera. Further analyses using robust mixture models in other cohorts are required to corroborate these findings.

Maternal, cord, and three-year-old child serum thyroid hormone concentrations in the Health Outcomes and Measures of the Environment study.

PURPOSE: Maternal thyroid function during pregnancy may influence offspring thyroid function, though relations between maternal and child thyroid function are incompletely understood. We sought to characterize relations between maternal, cord and child thyroid hormone concentrations in a population of mother-child pairs with largely normal thyroid function. METHODS: In a prospective birth cohort, we measured thyroid hormone concentrations in 203 mothers at 16 gestational weeks, 273 newborns and 159 children at 3 years among participants in the Health Outcomes and Measures of the Environment (HOME) Study. We used multivariable linear regression to estimate associations of maternal thyroid hormones during pregnancy with cord serum thyroid hormones and also estimated associations of maternal and cord thyroid hormones with child thyroid-stimulating hormone (TSH). RESULTS: Each doubling of maternal TSH was associated with a 16.4% increase of newborn TSH (95% CI: 3.9%, 30.5%), and each doubling of newborn TSH concentrations was associated with a 10.4% increase in child TSH concentrations at 3 years (95% CI: 0.1%, 21.7%). An interquartile range increase in cord FT4 concentrations was associated with an 11.7% decrease in child TSH concentrations at 3 years (95% CI: -20.2%, -2.3%). CONCLUSIONS: We observed relationships between maternal, newborn and child thyroid hormone concentrations in the HOME Study. Our study contributes to understandings of interindividual variability in thyroid function among mother-child pairs, which may inform future efforts to identify risk factors for thyroid disorders or thyroid-related health outcomes.

Prenatal exposure to metal mixture and sex-specific birth outcomes in the New Hampshire Birth Cohort Study.

BACKGROUND: In utero exposure to individual metals may impact fetal growth, though little is known about the effects of exposure to metal mixtures. Therefore, we investigated joint effects of in utero exposure to a mixture of As (arsenic), Mn (manganese), and Pb (lead) on newborn outcomes in a United States population. METHODS: Concentrations of As, Mn, and Pb were determined in maternal postpartum toenail samples, a biomarker of in utero exposure, from 989 maternal-infant pairs (492 females and 497 males). Newborns' anthropometric characteristics, including head circumference, length, and weight, were obtained from medical records. The joint effects of the three metals were modeled using Bayesian kernel machine regression and linear regression. Both sex-combined and sex-stratified statistical analyses were performed. RESULTS: We observed an inverted-U-shape association between maternal toenail Mn concentrations and newborn head circumference, particularly among female infants. Concentrations of Pb were related to reduced head circumference, weight, and length, especially among females at lower concentrations of the other metals. Overall, toenail As concentrations were related to reduced head circumference, especially among males, and an increase in birth length and weight among females. We found little evidence of As interactions with other metals within the mixture. CONCLUSIONS: Our findings suggest that in utero metal mixture exposures may influence birth outcomes, and that such relations may differ by infant sex.

Organophosphate Esters: Are These Flame Retardants and Plasticizers Affecting Children's Health?

PURPOSE OF REVIEW: Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and are consequently prevalent in the environment and frequently detected in human biomonitoring studies. Exposure during pregnancy is of particular concern as OPEs have recently been detected in placental tissues, suggesting they may be transferred to the developing infant. Also, studies have now shown that children typically experience higher exposure to several OPEs compared with adults, indicating they may be disproportionately impacted by these compounds. This review summarizes the current literature on reproductive and child health outcomes of OPE exposures and highlights areas for future research. RECENT FINDINGS: Experimental animal studies demonstrate potential for OPEs to adversely impact health, and a limited number of epidemiologic studies conducted in adult cohorts suggest that OPEs may interfere with the endocrine system. Neurodevelopment is perhaps the most well studied of children's health endpoints, and several studies indicate that prenatal and early life OPE exposures impact both cognitive and behavioral development. Associations have also been reported with reproductive outcomes (e.g., fertilization and pregnancy loss) and with the timing of parturition and preterm birth. Cross-sectional studies also demonstrate associations between OPEs and respiratory health outcomes, allergic disease, and measures of adiposity. An expanding body of research demonstrates that OPEs are associated with adverse reproductive health and birth outcomes, asthma and allergic disease, early growth and adiposity, and neurodevelopment. Still, additional research is urgently needed to elucidate the full impact of OPEs on children's health.

Prenatal exposure to organophosphate esters and behavioral development in young children in the Pregnancy, Infection, and Nutrition Study.

Organophosphate esters (OPEs) are commonly used as plasticizers and flame retardants in consumer products, and exposure is relatively ubiquitous in most populations studied. This may be of concern as some OPEs may be neurotoxic, endocrine-disrupting, and interfere with behavioral development; however, observational evidence is limited. We used data from the Pregnancy, Infection, and Nutrition Study, a prospective birth cohort study, to investigate associations between maternal OPE metabolite concentrations during pregnancy and behavioral development in offspring. Women provided a urine sample during pregnancy that was analyzed for concentrations of OPE metabolites, including diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). Offspring's behavioral development was assessed by the Behavioral Assessment System for Children (2nd Edition) (BASC-2) at approximately 36 months. Linear regression was used to estimate associations between tertiles in specific gravity-corrected OPE metabolite concentrations and children's scores on the BASC-2, adjusted for maternal age, maternal BMI, maternal race, maternal education, familial income, maternal depression, quality of the home environment, and sex. Higher BDCIPP concentrations were associated with higher scores on the Behavioral Symptoms Index (1st vs. 3rd tertile: ß = 3.03; 95% CI = 0.40, 5.67) and Externalizing Problems (1st vs. 3rd tertile: ß = 2.49; 95% CI: -0.12, 5.10) composites. Among BASC-2 scales, BDCIPP was most strongly associated with Withdrawal, Attention Problems, Depression, Hyperactivity, and Aggression. DPHP concentrations were also associated with higher scores on the Externalizing Problems and Behavioral Symptoms Index composites, but not as strongly as BDCIPP. Conversely, higher concentrations of ip-PPP were associated with fewer adverse behavioral symptoms, including an inverse association with the Internalizing Problems composite (1st vs. 3rd tertile: ß = -3.74; 95% CI = -6.75, -0.74) and constituent scales. BCIPHIPP was not strongly associated with any measured behavioral outcomes. Our results suggest that greater maternal exposure to tris(1,3-dichloro-2-propyl phosphate) (TDCIPP, parent compound of BDCIPP) and, to a lesser degree, triphenyl phosphate (TPHP, parent compound of DPHP) during pregnancy is associated with adverse behavioral development in children. Our study contributes to the growing body of evidence pertaining to adverse developmental effects of prenatal OPE exposure and highlights the need for further research to characterize risks associated with this ubiquitous family of chemicals.

Prenatal exposure to organophosphate esters and cognitive development in young children in the Pregnancy, Infection, and Nutrition Study.

Organophosphate esters (OPEs) are a class of chemicals commonly used as flame retardants and plasticizers. OPEs are applied to a wide variety of consumer products and have a propensity to leach from these products. Consequently, OPEs are ubiquitous contaminants in many human environments and human exposure is pervasive. Accumulating evidence suggests that OPEs are capable of interfering with childhood cognitive development through both neurologic- and endocrine-mediated mechanisms. However, observational evidence of cognitive effects is limited. We used data collected in the third phase of the Pregnancy, Infection, and Nutrition Study to investigate cognitive effects of prenatal exposure to OPEs. In a spot prenatal maternal urine sample, we measured the following OPE metabolites: diphenyl phosphate (DPHP), bis(1,3-dichloro-2-propyl phosphate) (BDCIPP), isopropyl-phenyl phenyl phosphate (ip-PPP), and 1-hydroxyl-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP). We assessed children's language and multi-faceted and overall cognitive development between two and three years of age using the MacArthur-Bates Communicative Development Inventories (MB-CDI) and the Mullen Scales of Early Learning (MSEL). We used linear regression to estimate the change in children's scores on these developmental assessments per interquartile range (IQR) increase in log-transformed, specific-gravity-corrected prenatal OPE metabolite concentrations, adjusted for maternal age, education, income, race/ethnicity, BMI, and child's sex. A total of 149 children had both OPE metabolite measurements and MB-CDI scores, and 227 children had both OPE metabolite measurements and MSEL scores. We observed that higher concentrations of ip-PPP (ng/ml) were associated with lower scores on the MSEL Cognitive Composite Score (ß = -2.61; 95% CI: -5.69, 0.46), and separately on two of the four MSEL Scales that comprise the Cognitive Composite, specifically the Fine Motor Scale (ß = -3.08; 95% CI: -5.26, -0.91) and the Expressive Language Scale (ß = -1.21; 95% CI: -2.91, 0.49). We similarly observed that prenatal ip-PPP concentrations were inversely associated with age-standardized scores on the MB-CDI Vocabulary assessment (ß = -1.19; 95% CI: -2.53, 0.16). Other OPE metabolites were not strongly associated with performance on either assessment. Our results suggest that isopropylated triarylphosphate isomers, the presumed parent compounds of ip-PPP, may adversely impact cognitive development, including fine motor skills and early language abilities. Our study contributes to the growing body of observational evidence that suggests prenatal exposure to OPEs may adversely affect cognitive development.

Statistical Approaches for Estimating Sex-Specific Effects in Endocrine Disruptors Research.

BACKGROUND: When a biologic mechanism of interest is anticipated to operate differentially according to sex, as is often the case in endocrine disruptors research, investigators routinely estimate sex-specific associations. Less attention has been given to potential sexual heterogeneity of confounder associations with outcomes. When relationships of covariates with outcomes differ according to sex, commonly applied statistical approaches for estimating sex-specific endocrine disruptor effects may produce divergent estimates. OBJECTIVES: We discuss underlying assumptions and evaluate the performance of two traditional approaches for estimating sex-specific effects, stratification and product terms, and introduce a simple modeling alternative: an augmented product term approach. METHODS: We describe the impact of assumptions regarding sexual heterogeneity of confounder relationships on estimates of sex-specific effects of the exposure of interest for three approaches: stratification, traditional product terms, and augmented product terms. Using simulated and applied examples, we demonstrate properties of each approach under a range of scenarios. RESULTS: In simulations, sex-specific exposure effects estimated using the traditional product term approach were biased when confounders had sex-dependent associations with the outcome. Sex-specific estimates from stratification and the augmented product term approach were unbiased but less precise. In the applied example, the three approaches yielded similar estimates, but resulted in some meaningful differences in conclusions based on statistical significance. CONCLUSIONS: Investigators should consider sexual heterogeneity of confounder associations when choosing an analytic approach to estimate sex-specific effects of endocrine disruptors on health. In the presence of sex-dependent confounding, our augmented product term approach may be advantageous over stratification when there is prior knowledge available to fit reduced models or when investigators seek an automated test for effect measure modification. https://doi.org/10.1289/EHP334.

Associations between blood BTEXS concentrations and hematologic parameters among adult residents of the U.S. Gulf States.

BACKGROUND: Studies of workers exposed to benzene at average air concentrations below one part per million suggest that benzene, a known hematotoxin, causes hematopoietic damage even at low exposure levels. However, evidence of such effects outside of occupational settings and for other volatile organic compounds (VOCs) is limited. OBJECTIVE: To investigate associations between ambient exposures to five VOCs, including benzene, and hematologic parameters among adult residents of the U.S. Gulf Coast. MATERIALS AND METHODS: Blood concentrations of selected VOCs were measured in a sample of adult participants in the Gulf Long-term Follow-up Study (GuLF STUDY) during 2012 and 2013. Complete blood counts with differentials were also performed on a subset of participants (n=406). We used these data together with detailed questionnaire data to estimate adjusted associations between blood BTEXS (benzene, toluene, ethylbenzene, o-xylene, m/p-xylene, and styrene) concentrations and hematologic parameters using generalized linear models. RESULTS: We observed inverse associations between blood benzene concentrations and hemoglobin concentration and mean corpuscular hemoglobin concentration, and a positive association with red cell distribution width among tobacco smoke-unexposed participants (n=146). Among tobacco smoke-exposed participants (n=247), we observed positive associations between blood VOC concentrations and several hematologic parameters, including increased white blood cell and platelet counts, suggestive of hematopoietic stimulation typically associated with tobacco smoke exposure. Most associations were stronger for benzene than for the other VOCs. CONCLUSIONS: Our results suggest that ambient exposure to BTEXS, particularly benzene, may be associated with hematologic effects, including decreased hemoglobin concentration, mean corpuscular hemoglobin concentration, and increased red cell distribution width.

Prenatal phthalate biomarker concentrations and performance on the Bayley Scales of Infant Development-II in a population of young urban children.

INTRODUCTION: Evidence suggests prenatal phthalate exposures may have neurodevelopmental consequences. Our objective was to investigate prenatal exposure to phthalates and cognitive development in a cohort of young urban children. MATERIALS AND METHODS: We recruited pregnant women in New York City from 1998 to 2002 and measured concentrations of nine phthalate metabolites in urine collected in late pregnancy. We administered a neurodevelopmental screening instrument, the Bayley Scales of Infant Development II (BSID-II), to children who returned for follow-up at approximately 24 months (n=276). We estimated associations between phthalate metabolite concentrations in maternal urine and BSID-II indices (Mental Development Index (MDI), Psychomotor Development Index (PDI)). RESULTS: We observed no associations between phthalate metabolite concentrations and performance on the MDI or PDI in boys and girls combined. We did, however, observe evidence of effect measure modification by sex. We observed several negative associations between metabolite concentrations and both MDI and PDI scores among girls, suggesting poorer performance across multiple metabolites, with estimates equal to a 2-3 point decrease in score per ln-unit increase in creatinine-standardized metabolite concentration. Conversely, we observed multiple weakly positive associations among boys, equal to a 1-2 point increase in score per ln-unit increase in metabolite concentration. The strongest associations were for the metabolites mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate, and mono(3-carboxylpropyl) phthalate (MCPP). CONCLUSIONS: Girls of mothers with higher urinary concentrations of MCPP and metabolites of dibutyl phthalates had lower MDI scores on the BSID-II. These same biomarker concentrations were often associated with improved scores among boys. We observed similar results for MnBP, MCPP, and MBzP on the PDI. Given the prevalence of phthalate exposures in reproductive aged women, the implications of potential neurotoxicity warrant further investigation.