Long-term exposure to ambient particulate matter and stroke etiology: Results from the Women's Health Initiative.

BACKGROUND: Ambient particulate matter (PM) air pollution is a leading cause of global disability and accounts for an annual 2.9 million deaths globally. PM is established as an important risk factor for cardiovascular disease, however the evidence supporting a link specifically between long-term exposure to ambient PM and incident stroke is less clear. We sought to evaluate the association of long-term exposure to different size fractions of ambient PM with incident stroke (overall and by etiologic subtypes) and cerebrovascular deaths within the Women's Health Initiative, a large prospective study of older women in the US. METHODS: We studied 155,410 postmenopausal women without previous cerebrovascular disease enrolled into the study between 1993 and 1998, with follow-up through 2010. We assessed geocoded participant address-specific concentrations of ambient PM (fine [PM2.5], respirable [PM10] and coarse [PM10-2.5]), as well as nitrogen dioxide [NO2] using spatiotemporal models. We classified hospitalization events into ischemic, hemorrhagic, or other/unclassified stroke. Cerebrovascular mortality was defined as death from any stroke etiology. We used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for individual and neighborhood-level characteristics. RESULTS: During a median follow-up time of 15 years, participants experienced 4,556 cerebrovascular events. The hazard ratio for all cerebrovascular events was 2.14 (95% CI: 1.87, 2.44) comparing the top versus bottom quartiles of PM2.5. Similarly, there was a statistically significant increase in events comparing the top versus bottom quartiles of PM10 and NO2 (HR: 1.17; 95% CI: 1.03, 1.33 and HR:1.26; 95% CI: 1.12, 1.42). The strength of association did not vary substantially by stroke etiology. There was little evidence of an association between PMcoarse and incident cerebrovascular events. CONCLUSIONS: Long-term exposure to fine (PM2.5) and respirable (PM10) particulate matter as well as NO2 was associated with a significant increase of cerebrovascular events among postmenopausal women. Strength of the associations were consistent by stroke etiology.

Long-term aircraft noise exposure and risk of hypertension in postmenopausal women.

BACKGROUND: Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive. OBJECTIVES: We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S. METHODS: Day-night average (DNL) and night equivalent sound levels (Lnight) were modeled for 90 U.S. airports from 1995 to 2010 in 5-year intervals using the Aviation Environmental Design Tool and linked to participant geocoded addresses from 1993 to 2010. Participants with modeled exposures ≥45 A-weighted decibels (dB [A]) were considered exposed, and those outside of 45 dB(A) who also did not live in close proximity to unmodeled airports were considered unexposed. Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg or inventoried/self-reported antihypertensive medication use. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) for incident hypertension when exposed to DNL or Lnight ≥45 versus <45 dB(A), controlling for sociodemographic, behavioral, and environmental/contextual factors. RESULTS/DISCUSSION: There were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing Lnight exposure at risk of hypertension. In adjusted models, DNL and Lnight ≥45 db(A) were associated with HRs of 1.00 (95% confidence interval [CI]: 0.93, 1.08) and 1.06 (95%CI: 0.91, 1.24), respectively. There was no evidence supporting a positive exposure-response relationship, and findings were robust in sensitivity analyses. Indications of elevated risk were seen among certain subgroups, such as those living in areas with lower population density (HRinteraction: 0.84; 95%CI: 0.72, 0.98) or nitrogen dioxide concentrations (HRinteraction: 0.82; 95%CI: 0.71, 0.95), which may indicate lower ambient/road traffic noise. Our findings do not suggest a relationship between aircraft noise and incident hypertension among older women in the U.S., though associations in lower ambient noise settings merit further investigation.

Socioeconomic impact of treatment with biological disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis.

OBJECTIVES: We evaluate the socioeconomic impact of treatment with biological and targeted synthetic disease-modifying antirheumatic drugs in Japanese patients with rheumatoid arthritis. METHODS: We analysed data retrospectively from the prospective observational CorEvitas RA Japan Registry (March 2016-February 2020). Patients were categorised into paid workers (PWs) and home workers (HWs) and further based on drug classes. We assessed medication persistence, treatment outcomes, health care resource utilisation, and socioeconomic impact over 12 months, including direct (drugs and health care resource utilisation) and indirect (loss of productivity) costs. RESULTS: Overall, 187 PWs and 114 HWs were identified. Over 12 months, medication persistence was high, treatment outcomes improved, and outpatient visits reduced in both groups. Following treatment initiation, direct costs increased, whereas indirect (loss of productivity) costs decreased in both groups. The unadjusted socioeconomic impact [Japanese yen (JPY)] increased across all drug classes in PWs (range: 29,700-151,700) and HWs (range: -28,700 to 83,000). Adjusted change in monthly socioeconomic impact was JPY 29,700-138,900 for PWs and JPY -28,000 to 92,800 for HWs. CONCLUSIONS: In this study of Japanese patients with rheumatoid arthritis, the socioeconomic burden increased across patient groups and drug classes. The decrease in indirect (loss of productivity) costs partially offset the increase in direct costs.

Urinary Cadmium and Incident Heart Failure: A Case-Cohort Analysis Among Never-Smokers in Denmark.

BACKGROUND: Epidemiologic studies suggest cadmium exposure is associated with cardiovascular disease risk, including heart failure. However, prior findings may be influenced by tobacco smoking, a dominant source of cadmium exposure and risk factor for heart failure. The present study leverages up to 20 years of follow-up in the Danish Diet, Cancer and Health cohort to examine the relationship between urinary cadmium and incident heart failure among people who never smoked. METHODS: Between 1993 and 1997, 19,394 never-smoking participants (ages 50-64 years) enrolled and provided a urine sample. From this sample, we randomly selected a subcohort of 600 men and 600 women and identified 958 incident heart failure cases occurring between baseline and 2015. Using a case-cohort approach, we estimated adjusted hazard ratios (aHR) for heart failure in Cox proportional hazards models with age as the time scale. RESULTS: Participants had relatively low concentrations of urinary cadmium, as expected for never smokers (median = 0.20; 25th, 75th = 0.13, 0.32 µg cadmium/g creatinine). In adjusted models, we found that higher urinary cadmium was associated with a higher rate of incident heart failure overall (aHR = 1.1 per interquartile range difference [95% CI = 1.0, 1.2). In sex-stratified analyses, the association seemed restricted to men (aHR = 1.5 [95% CI = 1.2, 1.9]). CONCLUSIONS: In this cohort of people who never smoked tobacco, environmental cadmium was positively associated with incident heart failure, especially among men.

Gestational perfluoroalkyl substance exposure and body mass index trajectories over the first 12 years of life.

BACKGROUND/OBJECTIVES: Gestational exposure to perfluoroalkyl substances (PFAS), a ubiquitous class of persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disease. However, it is unclear if gestational PFAS exposure is associated with adiposity trajectories related to adult obesity and cardiometabolic health. SUBJECTS/METHODS: We measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid, and perfluorohexanesulfonic acid (PFHxS) concentrations in maternal serum collected between 16 weeks gestation and delivery in a cohort of 345 mother-child pairs in Cincinnati, OH (enrolled 2003-06). From age 4 weeks to 12 years, we measured weight and length or height up to eight times and calculated child body mass index (BMI) (1865 repeated measures). Using covariate-adjusted linear mixed models and splines to account for repeated BMI measures and nonlinear BMI patterns, respectively, we estimated the age/magnitude of infancy BMI zenith (~1 year) and childhood BMI nadir (~5 years), BMI accrual from 8 to 12 years, and BMI at age 12 years by PFAS terciles. RESULTS: BMI trajectories varied by PFOA concentrations (age × PFOA interaction p value = 0.03). Children born to women with higher PFOA concentrations had lower infancy and early childhood BMI, earlier BMI nadir, accelerating BMI gains in mid-childhood and adolescence, and higher BMI at age 12 years. Some of these associations were non-monotonic. PFOS and PFHxS were not associated with alterations in BMI trajectories, but were monotonically associated with lower BMI across infancy, childhood, and adolescence. Compared to children in the first PFOS tercile, those in the second (ß: -0.83; 95% confidence interval (CI): -2.11, 0.51 kg/m2), and third (ß: -1.41; 95% CI: -2.65, -0.14 kg/m2) had lower BMI at age 12 years. CONCLUSIONS: These results suggest that gestational PFOA exposure may be associated with BMI trajectories related to adult obesity and cardiometabolic disease, while PFOS and PFHxS exposure is associated with lower BMI in the first 12 years of life.

Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight.

BACKGROUND: A growing body of evidence links maternal exposure to particulate matter <2.5 µM in diameter (PM2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM2.5 exposure prior to and during pregnancy and infant birthweight. METHODS: We evaluated PM2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. RESULTS: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM2.5 exposure levels averaged across the identified growth restriction window. CONCLUSION: Our findings suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.

DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study.

BACKGROUND: Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). METHODS: We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. RESULTS: Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q < 0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q < 0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. CONCLUSION: We found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

Firefighter occupation is associated with increased risk for laryngeal and hypopharyngeal squamous cell carcinoma among men from the Greater Boston area.

OBJECTIVE: Firefighters are exposed to a wide variety of carcinogens during the line of duty, including several associated with head and neck cancer. Existing studies assessing head and neck cancer risk with firefighting have predominately included occupational cohorts or registry data, which are limited by inability to adjust for smoking and alcohol consumption-major risk factors for head and neck cancer. Our objective was to assess the risk of head and neck cancer among men with an occupational history as a firefighter. METHODS: This work was conducted using male subjects from a large population-based case-control study of head and neck cancer from the greater Boston area using self-reported occupational history (718 cases and 905 controls). RESULTS: An occupational history as a firefighter was reported for 11 cases and 14 controls. Although no significant association was observed overall, we observed substantial increased risk for hypopharyngeal and laryngeal squamous cell carcinoma among professional municipal firefighters who had a light or no smoking history (OR=8.06, 95% CI 1.74 to 37.41), with significantly increasing risk per decade as a firefighter (OR=2.10, 95% CI 1.06 to 4.14). CONCLUSION: Professional municipal firefighters may be at increased risk for hypopharyngeal and laryngeal squamous cell carcinoma due to carcinogenic exposures encountered during the line of duty.

Ambient air pollution during pregnancy and risk of gestational diabetes in New York City.

BACKGROUND: Emerging evidence suggests a potential association between ambient air pollution and risk of gestational diabetes mellitus (GDM), but results have been inconsistent. Accordingly, we assessed the associations between ambient fine particulate matter (PM2.5) and nitrogen dioxide (NO2) levels with risk of GDM. METHODS: Using linked data from birth certificates, hospital discharge diagnoses, and air pollution estimates informed by the New York City Community Air Survey, we fit conditional logistic regression models to evaluate the association between residential levels of PM2.5 and NO2 with risk of GDM among 256,372 singleton live births of non-smoking mothers in New York City born 2008-2010, adjusting for sociodemographic factors and stratified on zip code of maternal address. RESULTS: GDM was identified in 17,065 women, yielding a risk of GDM in the study sample of 67 per 1000 deliveries. In single pollutant models, 1st and 2nd trimester PM2.5 was associated with a lower and higher risk of GDM, respectively. In models mutually adjusting for PM2.5 levels in both trimesters, GDM was associated with PM2.5 levels in the 2nd trimester (OR: 1.06, 95% CI: 1.02, 1.10 per interquartile range increase in PM2.5), but not the 1st trimester (OR: 0.99, 95% CI: 0.96, 1.02). Conversely, GDM was associated with NO2 during the 1st trimester (OR: 1.05, 95% CI: 1.01, 1.09), but not the 2nd trimester (OR: 1.02, 95% CI: 0.98, 1.06). The positive associations between pollutants and GDM were robust to different model specifications. PM2.5 in the 2nd trimester was more strongly associated with GDM among mothers who were aged <35 years and not Medicaid recipients. NO2 in the 1st trimester was more strongly associated with GDM among overweight and parous women. CONCLUSIONS: In this large cohort of singleton births in New York City, NO2 in the 1st trimester and PM2.5 in the 2nd trimester were associated with higher odds of GDM, while 1st trimester PM2.5 was weakly and inconsistently associated with lower odds of GDM.

Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to Agent Orange.

BACKGROUND: Exposure to the herbicide Agent Orange during the Vietnam War was widespread and is associated with numerous adverse health outcomes. A continuing concern of veterans is the possibility that exposure to the dioxin-containing herbicide might induce adverse reproductive outcomes. We sought to assess whether exposure to Agent Orange in Vietnam was associated with changes in DNA methylation in sperm in a subset of Vietnam veterans who participated in the Air Force Health Study (AFHS). METHODS: We studied 37 members of the AFHS chosen to have no, low, medium or high exposure to Agent Orange, based upon serum dioxin levels obtained during a series of examinations. DNA from stored semen was extracted and DNA methylation assessed on the Illumina 450 K platform. RESULTS: Initial epigenome-wide analysis returned no loci that survived control for false discovery. However, the TEAD3 gene had four different CpG sites that showed loss of DNA methylation associated with dioxin exposure. Analysis assessing regional DNA methylation changes revealed 36 gene regions, including the region of the imprinted gene H19 to have altered DNA methylation associated with high exposure compared to the low exposure group. Additional comparison of our data with sperm DNA methylation data from Russian boys exposed to dioxin found an additional 5 loci that were altered in both studies and exhibited a consistent direction of association. CONCLUSIONS: Studying a small number of sperm samples from veterans enrolled in the AFHS, we did not find evidence of significant epigenome-wide alterations associated with exposure to Agent Orange. However, additional analysis showed that the H19 gene region is altered in the sperm of Agent Orange-exposed Ranch Hand veterans. Our study also replicated several findings of a prior study of dioxin-exposed Russian boys. These results provide additional candidate loci for further investigation and may have implications for the reproductive health of dioxin-exposed individuals.

Projected Changes in Temperature-related Morbidity and Mortality in Southern New England.

BACKGROUND: Climate change is expected to result in more heat-related, but potentially fewer cold-related, emergency department visits and deaths. The net effect of projected changes in temperature on morbidity and mortality remains incompletely understood. We estimated the change in temperature-related morbidity and mortality at two sites in southern New England, United States, through the end of the 21st century. METHODS: We used distributed lag Poisson regression models to estimate the present-day associations between daily mean temperature and all-cause emergency department visits and deaths in Rhode Island and in Boston, Massachusetts. We estimated the change in temperature-related visits and deaths in 2045-2054 and 2085-2094 (relative to 2001-2010) under two greenhouse gas emissions scenarios (RCP4.5 and RCP8.5) using downscaled projections from an ensemble of over 40 climate models, assuming all other factors remain constant. RESULTS: We observed U-shaped relationships between temperature and morbidity and mortality in Rhode Island, with minima at 10.9°C and 22.5°C, respectively. We estimated that, if this population were exposed to the future temperatures projected under RCP8.5 for 2085-2094, there would be 5,976 (95% eCI = 1,630, 11,379) more emergency department visits but 218 (95% eCI = -551, 43) fewer deaths annually. Results were similar in Boston and similar but less pronounced in the 2050s and under RCP4.5. CONCLUSIONS: We estimated that in the absence of further adaptation, if the current southern New England population were exposed to the higher temperatures projected for future decades, temperature-related emergency department visits would increase but temperature-related deaths would not.

Prenatal exposure to perfluoroalkyl substances and adipocytokines: the HOME Study.

OBJECTIVE: Gestational perfluoroalkyl substances exposure has been associated with decreased birthweight. We determined if gestational perfluoroalkyl substances exposure was associated with fetal metabolic markers using data from the HOME Study, a prospective birth cohort of pregnant women and their children in Cincinnati, Ohio. METHODS: Maternal serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid, and perfluorohexane sulfonic acid were quantified. We measured neonatal adipocytokine (leptin and adiponectin) concentrations in umbilical cord serum, and estimated percent differences with a 2-fold increase in maternal perfluoroalkyl substances concentrations among 230 mother-infant pairs. RESULTS: Median maternal serum PFOA and PFOS concentrations were 5.6 ng/mL and 14 ng/mL, respectively. Leptin was positively correlated with infant birthweight (p < 0.001). There were no statistically significant associations between maternal perfluoroalkyl substances and neonatal adipocytokine concentrations; each 2-fold increase in PFOA was associated with a non-significant increase in leptin (5%; 95% CI: -10, 22) and adiponectin (7%; 95% CI: -4, 19). CONCLUSION: Despite known associations with reduced birthweight, gestational serum perfluoroalkyl substances concentrations were not associated with neonatal adipocytokine concentrations. Further exploration of pathways of perfluoroalkyl substances associated changes in birthweight may help identify biomarkers that could be used to identify at-risk populations and develop interventions.

Variability and predictors of serum perfluoroalkyl substance concentrations during pregnancy and early childhood.

Exposure to poly- and perfluoroalkyl substances (PFAS), ubiquitous and persistent environmental contaminants, could be associated with adverse health outcomes, but there are limited longitudinal data assessing patterns and predictors of exposure during childhood. We quantified concentrations of eight different PFAS in sera collected from women during pregnancy and children at delivery and ages 3 and 8 years in 367 mother-child pairs enrolled in a prospective cohort from 2003 to 2006. In general, median childhood PFAS concentrations increased from birth to age 3 and then decreased by age 8. Maternal serum PFAS concentrations during pregnancy were strongly correlated with cord serum concentrations (0.76 < r < 0.94), but were weakly correlated with childhood concentrations (0.12 < r < 0.30). Several sociodemographic factors were associated with maternal PFAS concentrations, including income, race, and parity. In children, serum PFAS concentrations were associated with maternal age at delivery, race, parity, and child age. Breastfeeding duration was positively associated with childhood PFAS concentrations at ages 3 and 8 years. In addition, stain repellant use was associated with higher perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations at age 8 years. Serum PFAS concentrations are higher during early childhood, a potentially sensitive period of development, and were highest among breastfed children.

Residential green space and birth outcomes in a coastal setting.

BACKGROUND: Residential green space may improve birth outcomes, with prior studies reporting higher birthweight among infants of women living in greener areas. However, results from studies evaluating associations between green space and preterm birth have been mixed. Further, the potential influence of residential proximity to water, or 'blue space', on health has not previously been evaluated. OBJECTIVES: To evaluate associations between green and blue space and birth outcomes in a coastal area of the northeastern United States. METHODS: Using residential surrounding greenness (measured by Normalized Difference Vegetation Index [NDVI]) and proximity to recreational facilities, coastline, and freshwater as measures of green and blue space, we examined associations with preterm birth (PTB), term birthweight, and term small for gestational age (SGA) among 61,640 births in Rhode Island. We evaluated incremental adjustment for socioeconomic and environmental metrics. RESULTS: In models adjusted for individual - and neighborhood-level markers of socioeconomic status (SES), an interquartile range (IQR) increase in NDVI was associated with a 12% higher (95% CI: 4, 20%) odds of PTB and, conversely, living within 500 m of a recreational facility was associated with a 7% lower (95% CI: 1, 13%) odds of PTB. These associations were eliminated after further adjustment for town of residence. NDVI was associated with higher birthweight (7.4 g, 95% CI: 0.4-14.4 g) and lower odds of SGA (OR = 0.92, 95% CI: 0.87-0.98) when adjusted for individual-level markers of SES, but not when further adjusted for neighborhood SES or town. Living within 500 m of a freshwater body was associated with a higher birthweight of 10.1 g (95% CI: 2.0, 18.2) in fully adjusted models. CONCLUSIONS: Findings from this study do not support the hypothesis that residential green space is associated with reduced risk of preterm birth or higher birthweight after adjustment for individual and contextual socioeconomic factors, but variation in results with incremental adjustment raises questions about the optimal degree of control for confounding by markers of SES. We found that living near a freshwater body was associated with higher birthweight. This result is novel and bears further investigation in other settings and populations.

Genome-scale identification of microRNA-related SNPs associated with risk of head and neck squamous cell carcinoma.

Polymorphisms in microRNAs and their target sites can disrupt microRNA-dependent gene regulation, and have been associated with cancer susceptibility. However, genome-scale analyses of microRNA-related genetic variation in cancer are lacking. We tested the associations of ~40 000 common [minor allele frequency (MAF) ≥5%], microRNA-related single nucleotide polymorphisms (miR-SNPs), with risk of head and neck squamous cell carcinoma (HNSCC) in a discovery population, and validated selected loci in an independent population among a total of 2198 cases and 2180 controls. Joint analyses across the discovery and validation populations revealed six novel miR-SNP associations with risk of HNSCC. An upstream variant of MIR548H4 (rs7834169), replicated its association with overall HNSCC risk as well as risk of oral cavity cancer. Four other variants were specifically associated with oral cavity cancer risk (rs16914640, rs1134367, rs7306991 and rs1373756). 3'UTR variant of HADH, rs221347 and rs4975616, located within known cancer risk locus 5p15.33, were specific to risk of laryngeal cancer. High confidence predicted microRNA binding sites were identified for CLEC2D, LOC37443, KDM8 and HADH overlapping rs16914640, rs7306991, rs1134367 and rs221347, respectively. Furthermore, we identified several microRNA interactions with KDM8 and HADH predicted to be disrupted by genetic variation at rs1134367 and rs221347. These results suggest microRNA-related genetic variation may contribute to the genetic susceptibility of HNSCC, and that more powerful evaluation of this class of genetic variation and their relationship with cancer risk is warranted.

Parental Concern about Environmental Chemical Exposures and Children's Urinary Concentrations of Phthalates and Phenols.

OBJECTIVES: To examine whether parents' concerns about environmental chemical exposures were associated with urinary phthalate and phenol concentrations in their school-age children. STUDY DESIGN: In a prospective cohort of 218 mother-child pairs from Cincinnati, Ohio (2010-2014), we measured 11 phthalate metabolites and 5 phenols in urine samples when children were age 8 years and used questionnaire data from caregivers. We estimated the covariate-adjusted percent difference in phthalates and phenols among children of parents who expressed concern about environmental chemical exposures compared with children whose parents did not. RESULTS: Concentrations of 4 phthalates, bisphenol S, and bisphenol A were lower among children whose parents expressed concern about environmental chemicals (n = 122) compared with those who did not (n = 96). Di-2-ethylhexyl phthalate metabolites, bisphenol S, and bisphenol A concentrations were 23% (95% CI -38, -5), 37% (95% CI -49, -21), and 13% (95% CI -26, 3) lower, respectively, among children whose parents expressed concern compared with those whose parents did not. Triclosan concentrations were 35% greater (95% CI -2, 87) among children whose parents expressed concern compared with children whose parents did not. CONCLUSIONS: Parental concern about environmental chemicals was associated with lower childhood urine concentrations of several phthalates and phenols; unexpectedly, parental concern was associated with greater triclosan concentrations. These results suggest that parental concern may be an important factor in mitigating children's phthalate and phenol exposures.

Patterns, Variability, and Predictors of Urinary Triclosan Concentrations during Pregnancy and Childhood.

Exposure to triclosan, an antimicrobial used in many consumer products, is ubiquitous in the United States, yet only limited data are available on the predictors and variability of exposure, particularly in children. We examined the patterns, variability, and predictors of urinary triclosan concentrations in 389 mother-child pairs enrolled in the Health Outcomes and Measures of the Environment Study from 2003 to 2006. We quantified triclosan in 3 urine samples collected from women between 16 weeks of pregnancy and birth and 6 urine samples collected from children between the ages of 1-8 years. For maternal and child samples, we calculated intraclass correlation coefficients (ICCs) to assess triclosan reproducibility and identified sociodemographic predictors of triclosan. Among 8 year old children, we examined associations between triclosan and personal-care product use. We detected triclosan in >70% of urine samples. Median maternal triclosan varied across pregnancy from 17 to 11 ng/mL, while in children, median concentrations increased from 3.6 to 17 ng/mL over the first 4 years of life, declining slightly at later ages. Triclosan reproducibility was fair to good during pregnancy and for child samples taken weeks apart (ICCs = 0.4-0.6) but poor for annual child samples (ICCs = 0.2-0.4). Triclosan was 66% (95% CI: 29-113) higher in 8 year olds using hand soap compared to nonusers and increased monotonically with hand-washing frequency. Toothpaste use in children was also positively associated with triclosan. Our results suggest that urinary triclosan concentrations have modest stability over weeks to months; children are exposed to triclosan through the use of some personal-care products.

Heat-related morbidity and mortality in New England: Evidence for local policy.

BACKGROUND: Heat-related morbidity and mortality is a recognized public health concern. However, public health officials need to base policy decisions on local evidence, which is often lacking for smaller communities. OBJECTIVES: To evaluate the association between maximum daily heat index (HI) and morbidity and mortality in 15 New England communities (combined population: 2.7 million) in order to provide actionable evidence for local officials. METHODS: We applied overdispersed Poisson nonlinear distributed lag models to evaluate the association between HI and daily (May-September) emergency department (ED) admissions and deaths in each of 15 study sites in New Hampshire, Maine, and Rhode Island, controlling for time trends, day of week, and federal holidays. Site-specific estimates were meta-analyzed to provide regional estimates. RESULTS: Associations (sometimes non-linear) were observed between HI and each health outcome. For example, a day with a HI of 95°F vs. 75°F was associated with a cumulative 7.5% (95% confidence interval [CI]: 6.5%, 8.5%) and 5.1% (95% CI: 0.2%, 10.3%) higher rate of all-cause ED visits and deaths, respectively, with some evidence of regional heterogeneity. We estimate that in the study area, days with a HI≥95°F were associated with an annual average of 784 (95% CI: 658, 908) excess ED visits and 22 (95% CI: 3, 39) excess deaths. CONCLUSIONS: Our results suggest the presence of adverse health impacts associated with HI below the current local guideline criteria of HI≥100°F used to issue heat advisories. We hypothesize that lowering this threshold may lead to substantially reduced heat-related morbidity and mortality in the study area.

Maternal serum PFOA concentration and DNA methylation in cord blood: A pilot study.

Perfluorooctanoic acid (PFOA), a perfluoroalkyl substance, is commonly detected in the serum of pregnant women and may impact fetal development via epigenetic re-programming. In a pilot study, we explored associations between serum PFOA concentrations during pregnancy and offspring peripheral leukocyte DNA methylation at delivery in women with high (n = 22, range: 12-26ng/mL) and low (n = 22, range: 1.1-3.1ng/mL) PFOA concentrations. After adjusting for cell type, child sex, and income, we did not find differences in CpG methylation in the two exposure groups that reached epigenome-wide significance. Among the 20 CpGs with the lowest p-values we found that seven CpG sites in three genes differed by exposure status. In a confirmatory cluster analysis, these 20 CpGs clustered into two groups that perfectly identified exposure status. Future studies with larger sample sizes should confirm these findings and determine if PFOA-associated changes in DNA methylation underlie potential health effects of PFOA.

Variability and predictors of urinary concentrations of organophosphate flame retardant metabolites among pregnant women in Rhode Island.

BACKGROUND: Organophospate flame retardants (PFRs) are chemicals of emerging concern due to restrictions on polybrominated diphenyl ether flame retardant formulations. We describe the occurrence, variability, and predictors of urinary metabolites of PFRs among pregnant women. METHODS: In 2014-2015, 59 women from Providence, RI provided up to 3 spot urine samples during pregnancy (~12, 28, and 35 weeks' gestation). We created a pooled urine sample per woman and measured nine relevant metabolites in individual and pooled samples. We used linear mixed models to calculate intraclass correlation coefficients (ICCs) across the 3 measurements and to assess sociodemographic and dietary predictors of PFRs. RESULTS: The median (IQR) of bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCPP), and diphenyl phosphate (DPhP), the metabolites most frequently detected, from pooled samples were: 0.31 µg/L (0.17-0.54), 1.18 µg/L (0.64-2.19), 0.93 µg/L (0.72-1.97), respectively. We observed fair to good reproducibility for BCEP (ICC = 0.50), BDCPP (ICC = 0.60), and DPhP (ICC = 0.43), and excellent agreement between the urinary flame retardant metabolite concentrations averaged across pregnancy versus pooled urine sample concentrations for BCEP (ICC = 0.95), BDCPP (ICC = 0.89), and DPhP (ICC = 0.93). Adjusting for pertinent sociodemographic factors and gestational week of urine collection, each 1 kg increase in pre-pregnancy weight was associated with greater BCEP (1.1%; 95% CI: 0.1, 2.1), BDCPP (1.5%; 95% CI: 0.3, 2.7), and DPhP (0.5%; 95% CI: 0.0, 1.1). Dietary factors were generally not associated with urinary flame retardant metabolites. CONCLUSIONS: Urinary concentrations of BCEP, BDCPP, and DPhP were frequently detected among women in this pilot study and had fair reproducibility across pregnancy. Body size may be an important predictor of urinary flame retardant metabolite concentrations.