Human Health Exposure Analysis Resource (HHEAR): A model for incorporating the exposome into health studies.

BACKGROUND: Characterizing the complexity of environmental exposures in relation to human health is critical to advancing our understanding of health and disease throughout the life span. Extant cohort studies open the door for such investigations more rapidly and inexpensively than launching new cohort studies and the Human Health Exposure Analysis Resource (HHEAR) provides a resource for implementing life-stage exposure studies within existing study populations. Primary challenges to incorporation of environmental exposure assessment in health studies include: (1) lack of widespread knowledge of biospecimen and environmental sampling and storage requirements for environmental exposure assessment among investigators; (2) lack of availability of and access to laboratories capable of analyzing multiple environmental exposures throughout the life-course; and (3) studies lacking sufficient power to assess associations across life-stages. HHEAR includes a consortium of researchers with expertise in laboratory analyses, statistics and logistics to overcome these limitations and enable inclusion of exposomics in human health studies. OBJECTIVE: This manuscript describes the structure and strengths of implementing the harmonized HHEAR resource model, and our approaches to addressing challenges. We describe how HHEAR incorporates analyses of biospecimens and environmental samples and human health studies across the life span - serving as a model for incorporating environmental exposures into national and international research. We also present program successes to date. DISCUSSION: HHEAR provides a full-service laboratory and data analysis exposure assessment resource, linking scientific, life span, and toxicological consultation with both laboratory and data analysis expertise. HHEAR services are provided without cost but require NIH, NCI, NHLBI, or ECHO funding of the original cohort; internal HHEAR scientific review and approval of a brief application; and adherence to data sharing and publication policies. We describe the benefits of HHEAR's structure, collaborative framework and coordination across project investigators, analytical laboratories, biostatisticians and bioinformatics specialists; quality assurance/quality control (QA/QC) including integrated sample management; and tools that have been developed to support the research (exposure information pages, ontology, new analytical methods, common QA/QC approach across laboratories, etc.). This foundation supports HHEAR's inclusion of new laboratory and statistical analysis methods and studies that are enhanced by including targeted analysis of specific exposures and untargeted analysis of chemicals associated with phenotypic endpoints in biological and environmental samples. CONCLUSION: HHEAR is an interdisciplinary team of toxicologists, epidemiologists, laboratory scientists, and data scientists across multiple institutions to address broad and complex questions that benefit from integrated laboratory and data analyses. HHEAR's processes, features, and tools include all life stages and analysis of biospecimens and environmental samples. They are available to the wider scientific community to augment studies by adding state of the art environmental analyses to be linked to human health outcomes.

Associations of the Oral Microbiota with Obesity and Menarche in Inner City Girls.

OBJECTIVE: Alterations of the oral microbiome have been associated with obesity, possibly based on inflammatory processes mediated by bacteria. Specific bacterial strains have been associated with obesity and periodontal disease. Little is known about the oral microbiome in children. Understanding the relationship between oral health and childhood growth could help identify preventable factors contributing to obesity and related conditions, including onset of menarche which is associated with obesity. METHODS: In this pilot study, we investigated the saliva microbiome among 25 girls 7-15 years old (mean 11.1) and their mothers in an inner city dental clinic in New York City. The main outcome measures were body size, presence or absence of menarche and dental practices. We examined associations of microbiome richness, diversity, and relative abundance with pubertal and demographic factors and oral health. RESULTS: Girls had good dental health and a typical rich oral microbiome, based on the Shannon Index of all species detected. Older girls flossed more often and younger girls had more frequent dental check-ups. Microbiome richness among girls was similar to their mothers', but diversity was greater among mothers than girls. Richness was reduced among mothers with gum bleeding, flossing and increased teeth brushing. Overweight girls had greater diversity and less richness than normal weight girls. Certain bacterial species differed in abundance with respect to whether girls had reached menarche (Flavobacteria, Actinobacteria), overweight (Megasphaera, Lactorbacillales, Lactobacillus) and gingivitis in the girls (Scardovia, Bifidobacteriales, Gemellaceae). CONCLUSIONS: Differences found in specific bacteria in the oral microbiome were related to body size and menarche. With increasing interest on studying microbiome variability related to the multifactorial etiology of obesity in children, saliva is capable of providing clinically informative markers of this and related conditions.

Peripubertal dietary flavonol and lignan intake and age at menarche in a longitudinal cohort of girls.

BackgroundDietary phytoestrogens may alter hormonal activity in childhood. Flavonols and lignans are the most prevalent phytoestrogens in the Western diet. We examined whether higher intake of flavonols and lignans was associated with later age at menarche in a prospective study of young girls.MethodsIn all, 1,044 girls aged 6-8 years (mean 7.3 years) with two to four 24-h dietary recalls during their baseline year were followed up for 11 years until the attainment of menarche in the Breast Cancer and Environment Research Project (BCERP). Associations of age at menarche with quintiles of phytoestrogens were assessed using hazard ratios (HR) and 95% confidence intervals (CIs) from Cox proportional hazards models, controlling for body mass index and other covariates.ResultsThe highest quintile of flavonol intake was associated with a later age at menarche, compared with the lowest quintile (adjusted HR: 0.80, 95% CI: (0.66-1.00). For lignans, there was a later age in overweight girls (HR: 0.56, 95% CI=0.40-0.80).ConclusionThese dietary bioactives may reflect a healthy diet, and foods high in phytoestrogens may influence the timing of menarche.

Big and disparate data: considerations for pediatric consortia.

PURPOSE OF REVIEW: Increasingly, there is a need for examining exposure disease associations in large, diverse datasets to understand the complex determinants of pediatric disease and disability. Recognizing that children's health research consortia will be important sources of big data, it is crucial for the pediatric research community to be knowledgeable about the challenges and opportunities that they will face. The present review will provide examples of existing children's health consortia, highlight recent pooled analyses conducted by children's health research consortia, address common challenges of pooled analyses, and provide recommendations to advance collective research efforts in pediatric research. RECENT FINDINGS: Formal consortia and other collective-science initiatives are increasingly being created to share individual data from a set of relevant epidemiological studies to address a common research topic under the concept that the joint effort of many individual groups can accomplish far more than working alone. There are practical challenges to the participation of investigators within consortia that need to be addressed in order for them to work. SUMMARY: Researchers who access consortia with data centers will be able to go far beyond their initial hypotheses and potentially accomplish research that was previously thought infeasible or too costly.

Thyroid Antagonists (Perchlorate, Thiocyanate, and Nitrate) and Childhood Growth in a Longitudinal Study of U.S. Girls.

BACKGROUND: Perchlorate, thiocyanate, and nitrate are sodium/iodide symporter (NIS) inhibitors that block iodide uptake into the thyroid, thus affecting thyroid function. Thyroid dysfunction can adversely affect somatic growth and development in children. To our knowledge, no studies have examined effects of NIS inhibitors on body size measures. OBJECTIVE: We investigated associations between NIS inhibitors and childhood growth in 940 girls from the Puberty Study of the Breast Cancer and Environment Research Program. METHODS: Urine samples collected from girls 6-8 years of age at enrollment (2004-2007) from New York City, greater Cincinnati, Ohio, and the Bay Area in California were analyzed for NIS inhibitors and creatinine (C). The longitudinal association between NIS inhibitors and anthropometric measures [height, waist circumference, and body mass index (BMI)] during at least three visits was examined using mixed effects linear models, adjusted for race and site. RESULTS: Compared with girls in the low-exposure group (3.6, 626, and 500 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) girls with the highest NIS inhibitor exposure (9.6, 2,343, and 955 mg/gC, median perchlorate, thiocyanate, and nitrate, respectively) had slower growth in waist circumference and BMI but not height. Significant differences in the predicted mean waist circumference and BMI between the low- and high-exposure groups were observed beginning at 11 years of age. CONCLUSIONS: Higher NIS inhibitor exposure biomarkers were associated with reductions in waist circumference and BMI. These findings underscore the need to assess exposure to NIS inhibitors with respect to their influence on childhood growth. CITATION: Mervish NA, Pajak A, Teitelbaum SL, Pinney SM, Windham GC, Kushi LH, Biro FM, Valentin-Blasini L, Blount BC, Wolff MS, for the Breast Cancer and Environment Research Project (BCERP). 2016. Thyroid antagonists (perchlorate, thiocyanate, and nitrate) and childhood growth in a longitudinal study of U.S. girls. Environ Health Perspect 124:542-549; http://dx.doi.org/10.1289/ehp.1409309.

Dietary predictors of urinary environmental biomarkers in young girls, BCERP, 2004-7.

BACKGROUND: Exposures of children to phthalates, parabens, and bisphenol-A (BPA) are of concern because of their hormonal potential. These agents are found in a wide range of foods and packaging. We investigated whether intake of certain foods predict exposures to these chemicals in young girls. METHODS: Among 1101 girls (6-8 years at enrollment) from the Breast Cancer and Environment Research Program (BCERP) study, we measured urinary exposure biomarkers for phthalates, parabens, and BPA and assessed dietary intake using 24-h recall 2-4 times. We examined the average daily servings of major and minor food groups categorized as 0 to <0.5, 0.5 to <1 and ≥ 1 servings per day. Items included dairy, eggs, fats, fish, fruit, single grains, meat, non-poultry meats, pasta, poultry and vegetables. Covariate-adjusted least squares geometric means and 95% confidence intervals of creatinine-corrected phthalate and phenol metabolite concentrations in urine were calculated in relation to food intake. RESULTS: Grains, flour and dry mixes and total fish consumption were positively associated with BPA and the sum of four di-2-ethylhexylphthalate (DEHP) urinary metabolite concentrations. Non-fresh vegetables and poultry were both positively associated with BPA and paraben urinary concentrations. Fats, oils and poultry consumption were positively associated with BPA. Whole-fat dairy consumption was associated with ΣDEHP. CONCLUSIONS: Some foods may contribute to child exposures to certain chemicals, and this may constitute modifiable means to reduce these environmental exposures.

Dietary flavonol intake is associated with age of puberty in a longitudinal cohort of girls.

Lignans and flavonols are dietary phytoestrogens found at high concentrations in the Western Diet. They have potential to influence the timing of puberty. We hypothesized that greater consumption of these 2 phytoestrogens would be related to later age at pubertal onset among girls. Pubertal assessment and 24-hour diet recall data were available for 1178 girls, ages 6 to 8 years (mean 7.3 years) in the Breast Cancer and Environment Research Project Puberty Study. Lignan and flavonol intakes were mainly derived from fruit and vegetable consumption. Average consumption was 6.5 mg/d for flavonols and 0.6 mg/d for lignans. Highest flavonol consumption (>5 mg/d) was associated with later breast development (adjusted hazards ratio [HR]: 0.74, 95% CI: [0.61-0.91]) compared to 2 to 5 mg/d (adjusted HR: 0.84, 95% CI: [0.70-1.0]) and <2 mg/d (referent group; P-trend = .006). Flavonol intake was not associated with pubic hair development. Lignan intake was not associated with either breast or pubic hair development. Dietary intake was only weakly correlated with urinary enterolactone, a biomarker for lignans (RS = 0.13). Consistent with biologic properties of phytoestrogens that indicate hormonal activity, their consumption may be associated with reproductive end points, even in childhood.

Dietary and physical activity behaviors of New York City children from different ethnic minority subgroups.

OBJECTIVE: To examine racial/ethnic differences in diet and physical activity behaviors in ethnic minority New York City children. METHODS: Cross-sectional data from a community-based study of 486 6- to 8-year-old children were used. Race/ethnicity was derived using a caregiver's report of child's race and Hispanic ancestry. Dietary intake was obtained by 24-hour diet recalls using the Nutrition Data System for Research. Physical activity was assessed with pedometers and caregiver interviews. We compared diet and activity measures across racial/ethnic subgroups using chi-square and analysis of variance tests. Multivariate analyses adjusted for age, gender, body mass index, and caregiver education (with breastfeeding history and total energy intake included in diet models). RESULTS: Participants (N = 486) were categorized as Mexican (29.4%), Dominican (8.4%), Puerto Rican (20.6%), other/mixed Hispanic (14.0%), or non-Hispanic black (27.6%). Obesity rates were lower in non-Hispanic blacks (18%) than in Hispanics (31%). Mexicans had the lowest obesity rates among Hispanic subgroups (25%), and Dominicans had the highest (39%). There were differences in mean daily servings of food groups, with Mexicans having healthier diets and Puerto Ricans and non-Hispanic Blacks having less healthy diets. Sedentary time was lower in Mexicans than in other groups in adjusted models. Examination of additional models, including home language, did not show significant differences in the estimates. CONCLUSION: Diet and activity behaviors varied across racial/ethnic subgroups. Specifically, Mexican children had healthier diets, the least amount of sedentary time, and the lowest rates of obesity among the Hispanic subgroups examined. Targeted interventions in ethnic subgroups may be warranted to address specific behaviors.

Associations between phthalate metabolite urinary concentrations and body size measures in New York City children.

OBJECTIVE: To examine prospectively associations between urinary phthalate metabolite concentrations and body size measures in children. METHODS: Urinary concentrations of nine phthalate metabolites: monoethyl (MEP); mono-n-butyl (MBP); mono-(3-carboxypropyl) (MCPP); monobenzyl (MBzP); mono-isobutyl (MiBP); mono-(2-ethylhexyl) (MEHP); mono-(2-ethyl-5-oxohexyl) (MEOHP); mono-(2-ethyl-5-carboxypentyl) (MECPP); and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the molar sum of the low molecular-weight phthalate metabolites (low MWP: MEP, MBP and MiBP) and high molecular-weight phthalate metabolites (high MWP: MECPP, MEHHP, MEOHP, MEHP and MBzP) and of four di-(2-ethylhexyl) phthalate (DEHP) metabolites (ΣDEHP: MEHP, MEHHP, MEOHP, MECPP) and anthropometry, including body mass index and waist circumference were measured among 387 Hispanic and Black, New York City children who were between six and eight years at cohort enrollment (2004-2007). Relationships between baseline metabolite concentrations and body size characteristics obtained one year later were examined using multivariate-adjusted geometric means for each body size characteristic by continuous and categories of phthalate metabolite concentrations. Stratified analyses by body size (age/sex specific) were conducted. RESULTS: No significant associations are reported among all girls or boys. Dose response relationships were seen with monoethyl phthalate and the sum of low molecular-weight phthalates and body mass index and waist circumference among overweight children; for increasing monoethyl phthalate concentration quartiles among girls, adjusted mean body mass indexes were as follows: 21.3, 21.7, 23.8, 23.5 and adjusted mean waist circumference (cm) were as follows: 73.4, 73.5, 79.2, 78.8 (p-trend<0.001 for both). CONCLUSION: In this prospective analysis we identified positive relationships between urinary concentrations of monoethyl phthalate and the sum of low molecular-weight phthalates and body size measures in overweight children. These are metabolites with concentrations above 1 µM.

Temporal variability in urinary concentrations of perchlorate, nitrate, thiocyanate and iodide among children.

Perchlorate, nitrate and thiocyanate are ubiquitous in the environment, and human exposure to these chemicals is accurately measured in urine. Biomarkers of these chemicals represent a person's recent exposure, however, little is known on the temporal variability of the use of a single measurement of these biomarkers. Healthy Hispanic and Black children (6-10-year-old) donated urine samples over 6 months. To assess temporal variability, we used three statistical methods (n=29; 153 urine samples): intraclass correlation coefficient (ICC), Spearman's correlation coefficient between concentrations measured at different timepoints and surrogate category analysis to assess how well tertile ranking by a single biomarker measurement represented the average concentration over 6 months. The ICC measure of reproducibility was poor (0.10-0.12) for perchlorate, nitrate and iodide; and fair for thiocyanate (0.36). The correlations for each biomarker across multiple sampling times ranged from 0.01-0.57. Surrogate analysis showed consistent results for almost every surrogate tertile. Results demonstrate fair temporal reliability in the spot urine concentrations of the three NIS inhibitors and iodide. Surrogate analysis show that single-spot urine samples reliably categorize participant's exposure providing support for the use of a single sample as an exposure measure in epidemiological studies that use relative ranking of exposure.

Mercury derived from dental amalgams and neuropsychologic function.

There is widespread concern regarding the safety of silver-mercury amalgam dental restorations, yet little evidence to support their harm or safety. We examined whether mercury dental amalgams are adversely associated with cognitive functioning in a cross-sectional sample of healthy working adults. We studied 550 adults, 30-49 years of age, who were not occupationally exposed to mercury. Participants were representative of employees at a major urban medical center. Each participant underwent a neuropsychologic test battery, a structured questionnaire, a modified dental examination, and collection of blood and urine samples. Mercury exposure was assessed using a) urinary mercury concentration (UHg); b) the total number of amalgam surfaces; and c) the number of occlusal amalgam surfaces. Linear regression analysis was used to estimate associations between each marker of mercury exposure and each neuropsychologic test, adjusting for potential confounding variables. Exposure levels were relatively low. The mean UHg was 1.7 micro g/g creatinine (range, 0.09-17.8); the mean total number of amalgam surfaces was 10.6 (range, 0-46) and the mean number of occlusal amalgam surfaces was 6.1 (range, 0-19). No measure of exposure was significantly associated with the scores on any neuropsychologic test in analyses that adjusted for the sampling design and other covariates. In a sample of healthy working adults, mercury exposure derived from dental amalgam restorations was not associated with any detectable deficits in cognitive or fine motor functioning.