Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study.

BACKGROUND: Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. METHODS AND FINDINGS: Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (ß = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (ß = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (ß = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (ß = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. CONCLUSIONS: Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

Serum perfluoroalkyl substances and lung function in adolescents exposed to the World Trade Center disaster.

The effects of childhood exposure to perfluoroalkyl substances (PFASs) on lung function remain mostly unknown. Previous research indicates that children living or going to school near the World Trade Center (WTC) disaster were exposed to high levels of PFASs, among other toxic chemicals. To explore the effects of PFAS exposure on lung function, we measured serum PFASs in a cohort of children from the WTC Health Registry and a matched control group. Perfluorooctanesulfonate had the highest median concentrations in both groups (WTCHR = 3.72 ng/mL, Comparison = 2.75 ng/mL), while the lowest median concentrations were seen for perfluoroundecanoic acid (WTCHR = 0.12 ng/mL, Comparison = 0.01 ng/mL). Lung function outcomes were measured by spirometry, plethysmography, and oscillometry. Asthma diagnosis and serum eosinophil count were also recorded. We examined the relationships of each PFAS with lung function parameters and eosinophil count using linear regressions. Odds ratios for asthma were obtained for each PFAS using logistic regression. The effect of total PFASs on these outcomes was also assessed. All regression models were adjusted for sex, race/ethnicity, age, body mass index (BMI) and tobacco smoke exposure. We found that serum PFASs were not statistically associated with the measured lung function parameters, asthma diagnosis, or eosinophil count in this cohort (p < 0.05). These findings highlight the need for more longitudinal studies to explore the long-term effects of childhood PFAS exposure on lung function past adolescence and early adulthood.

Racial/ethnic disparities in disease burden and costs related to exposure to endocrine-disrupting chemicals in the United States: an exploratory analysis.

OBJECTIVE: Studies have documented disparities in exposure to endocrine-disrupting chemicals (EDC), but no studies have investigated potential implications for racial/ethnic disparities in chronic disease and associated costs. Our objective was to examine EDC levels in the US population according to race/ethnicity and to quantify disease burden and associated costs. STUDY DESIGN AND SETTING: EDC exposure levels in 2007-2010 were obtained from the National Health and Nutrition Examination Surveys. The associated disease burden and costs for 12 exposure-response relationships were determined for non-Hispanic Whites, non-Hispanic Blacks, Mexican Americans, Other Hispanics, and Other/Multicultural. RESULTS: EDC exposure levels and associated burden of disease and costs were higher in non-Hispanic Blacks ($56.8 billion; 16.5% of total costs) and Mexican Americans ($50.1 billion; 14.6%) compared with their proportion of the total population (12.6% and 13.5%, respectively). Associated costs among non-Hispanic whites comprised 52.3% of total costs ($179.8 billion) although they comprise 66.1% of the US population. These disparities are driven by generally higher exposure to persistent pesticides and flame retardants among non-Hispanic blacks and Mexican Americans. CONCLUSION: Our estimates suggest that racial/ethnic disparities in chronic diseases in the US may be because of chemical exposures and are an important tool to inform policies that address such disparities.

Renal Function and exposure to Bisphenol A and phthalates in children with Chronic Kidney Disease.

RATIONALE AND OBJECTIVE: Exposure to Bisphenol A (BPA) and phthalates is ubiquitous among adults and children in the United States. Among children and adolescents, those with chronic kidney disease (CKD) are potentially at greater risk of adverse effects from BPA and phthalate exposure. The objective of this study was to evaluate BPA and phthalate exposure among children with CKD and evaluate associations with three measures of kidney function. STUDY DESIGN: Cross sectional study. SETTING, PARTICIPANTS, AND MEASUREMENTS: The CKD population was represented by the Chronic Kidney Disease in Children (CKiD) Study, a multicenter, prospective cohort study of children with impaired kidney function in the US. The main outcome was assessment of the relationship between chemical exposures and clinical laboratory findings at enrollment into CKiD. Data collected at baseline from participants 1 to 17 years old (N = 538) were analyzed. Urinary BPA and phthalate levels were evaluated at this time point. Data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative pediatric population, were used for comparison to the CKiD cohort. RESULTS: Urinary BPA and phthalate levels in the CKiD population were consistently lower than levels detected in healthy children. Additionally, BPA was not significantly associated with blood pressure, proteinuria, or estimated glomerular filtration rate (eGFR). Within the CKiD population, for select individual and combined phthalates, there was an inverse relationship with the urinary protein:creatinine ratio (LMW phthalates, - 9.53% change; 95% CI: - 14.21, - 4.21; p = 0.001), and in most cases, a positive relationship with eGFR (LMW phthalates, a 3.46 unit increase in eGFR, 95% CI: 1.85, 5.07; p < 0.001). LIMITATIONS: Lack of longitudinal data, limited assessment of diet and nutritional status. CONCLUSION: In the study cohort, children with CKD did not have increased exposure to BPA and phthalates. Longitudinal studies with repeated measures are likely to be more informative about the possible health effects of prolonged exposure to BPA and phthalates in pediatric patients with CKD.

Respiratory Health and Lung Function in Children Exposed to the World Trade Center Disaster.

OBJECTIVES: To compare lung function in a representative sample of World Trade Center (WTC)-exposed children with matched comparisons, and examine relationships with reported exposures. STUDY DESIGN: Study population consisted of 402 participants. Oscillometry, spirometry, and plethysmography were performed on WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 (n = 180) and a sociodemographically matched group of New York City residents (n = 222). We compared lung function by study arm (WTCHR and comparison group) as well as dust cloud (acute); home dust (subchronic); and other traumatic, nondust exposures. RESULTS: In multivariable models, post-9/11 risk of incident asthma was higher in the WTCHR participants than in the comparison group (OR 1.109, 95% CI 1.021, 1.206; P = .015). Comparing by exposure rather than by group, dust cloud (OR 1.223, 95% CI 1.095, 1.365; P < .001) and home dust (OR 1.123, 95% CI 1.029, 1.226; P = .009) exposures were also associated with a greater risk of incidence of post-9/11 asthma. No differences were identified for lung function measures. CONCLUSIONS: Although we cannot exclude an alternative explanation to the null findings, these results may provide some measure of reassurance to exposed children and their families regarding long-term consequences. Further study with bronchodilation and/or methacholine challenge may be needed to identify and further evaluate effects of WTC exposure. Biomarker studies may also be more informative in delineating exposure-outcome relationships. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02068183.

Perfluorooctanoic acid and low birth weight: Estimates of US attributable burden and economic costs from 2003 through 2014.

BACKGROUND AND OBJECTIVE: In utero exposure to perfluorooctanoic acid (PFOA) has been associated with decreases in birth weight. We aimed to estimate the proportion of PFOA-attributable low birth weight (LBW) births and associated costs in the US from 2003 to 2014, a period during which there were industry-initiated and regulatory activities aimed at reducing exposure. METHODS: Serum PFOA levels among women 18-49 years were obtained from the National Health and Nutrition Examination Survey (NHANES) for 2003-2014; birth weight distributions were obtained from the Vital Statistics Natality Birth Data. The exposure-response relationship identified in a previous meta-analysis (18.9g decrease in birth weight per 1ng/mL of PFOA) was applied to quantify PFOA-attributable LBW (reference level of 3.1ng/mL for our base case, 1 and 3.9ng/mL for sensitivity analyses). Hospitalization costs and lost economic productivity were also estimated. RESULTS: Serum PFOA levels remained approximately constant from 2003-2004 (median: 3.3ng/mL) to 2007-2008 (3.5ng/mL), and declined from 2009-2010 (2.8ng/mL) to 2013-2014 (1.6ng/mL). In 2003-2004, an estimated 12,764 LBW cases (4% of total for those years) were potentially preventable if PFOA exposure were reduced to the base case reference level (10,203 cases in 2009-2010 and 1,491 in 2013-2014). The total cost of PFOA-attributable LBW for 2003 through 2014 was estimated at $13.7 billion, with $2.97 billion in 2003-2004, $2.4 billion in 2009-2010 and $347 million in 2013-2014. CONCLUSIONS: Serum PFOA levels began to decline in women of childbearing age in 2009-2010. Declines were of a magnitude expected to meaningfully reduce the estimated incidence of PFOA-attributable LBW and associated costs.

Cardiometabolic profiles of adolescents and young adults exposed to the World Trade Center Disaster.

BACKGROUND AND OBJECTIVE: Few studies have examined the possible cardiometabolic consequences of World Trade Center-related exposures on children who lived and/or attended school near the disaster site. Our objective was to compare cardiometabolic profiles of participants in the World Trade Center Health Registry (WTCHR) with a matched comparison group. METHODS: We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group. We assessed exposure to dust cloud, home dust, as well as traumatic exposure, and associations with blood pressure, arterial wall stiffness, body mass index (BMI), total cholesterol, triglycerides, HDL, and LDL. RESULTS: A total of 402 participants completed the study, 222 in the comparison group and 180 in the WTCHR group. In multivariable regression analysis, after adjusting for relevant confounders we detected a weak association between participation in the WTCHR group and lower BMI (-1.12kg/m2, 95% CI -2.11, -0.12; p = 0.03), which became non-significant after adjusting for multiple comparisons. With respect to traumatic and psychosocial exposures, the only association that persisted in our multivariable model, below our predefined level of significance, was between post-traumatic stress disorder and higher BMI (2.06kg/m2, 95% CI 0.37, 3.74; p = 0.02). CONCLUSIONS: Our findings do not support an association between self-reported exposures to the WTC disaster and adverse cardiometabolic profile. However, further longitudinal studies may better inform the full extent of WTC-related conditions associated with exposure to the disaster.

Serum perfluoroalkyl substances and cardiometabolic consequences in adolescents exposed to the World Trade Center disaster and a matched comparison group.

BACKGROUND: Large amounts of various chemical contaminants, including perfluoroalkyl substances (PFASs), were released at the time of the World Trade Center (WTC) disaster. Thousands of children who lived and/or attended school near the disaster site were exposed to these substances but few studies have examined the possible consequences related to these exposures. OBJECTIVES: To examine the relationship of PFASs serum levels with cardiometabolic profile in children and adolescents enrolled in the World Trade Center Health Registry (WTCHR) and a matched comparison group. METHODS: We evaluated WTCHR enrollees who resided in New York City and were born between September 11, 1993 and September 10, 2001, and a matched comparison group consisting of individuals who were ineligible for WTCHR participation upon distance of their home, school or work from the WTC and lack of participation in rescue and recovery activities. Matching was based on date of birth, sex, race, ethnicity, and income. We assessed exposure to PFASs, as measured by serum levels and association with cardiometabolic profile as measured by arterial wall stiffness, body mass index, insulin resistance, fasting total cholesterol, HDL, LDL and triglycerides. RESULTS: A total of 402 participants completed the study and serum samples were analyzed from 308 participants, 123 in the WTCHR group and 185 in the comparison group. In multivariable regression analysis, after adjusting for relevant confounders, we observed a significant, positive association of perfluorooctanoic acid (PFOA) with triglycerides (beta coefficient=0.14, 95% CI: 0.02, 0.27, 15.1% change), total cholesterol (beta coefficient=0.09, 95% CI: 0.04, 0.14, 9.2% change), and LDL cholesterol (beta coefficient=0.11, 95% CI: 0.03, 0.19, 11.5% change). Perfluorohexanesulfonic acid levels were associated with decreased insulin resistance (beta coefficient=-0.09, 95% CI: -0.18, -0.003, -8.6% change); PFOA and perfluorononanoic acid were associated with increased brachial artery distensibility. CONCLUSIONS: This research adds to our knowledge of the physical health impacts in a large group of children exposed to the WTC disaster. Abnormal lipid levels in young adults might be an early marker of atherosclerosis and cardiovascular diseases and our findings highlight the importance of conducting longitudinal studies in this population.

Serum perfluoroalkyl substances in children exposed to the world trade center disaster.

The World Trade Center (WTC) disaster released large amounts of various chemical substances into the environment, including perfluoroalkyl substances (PFASs). Yet, no studies have examined exposures in children living or attending schools near the disaster site. We measured serum PFASs in WTC Health Registry (WTCHR) respondents who were ≤8 years of age on September 11, 2001 and a sociodemographically-matched comparison group. We also examined the relationship of PFASs levels with dust cloud exposure; home dust exposure, and with traumatic exposure, the latter to take into account differences related to possible mental health consequences and associated behavioral problems. Serum samples, collected between 2014 and 2016, were analyzed from 123 WTCHR participants and from 185 participants in the comparison group. In the WTCHR group, median perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) levels were 1.81ng/mL and 3.72ng/mL, respectively. Controlling for sex, caloric intake, race/ethnicity, and date of birth, significant increases among WTCHR participants compared with the matched comparison group were detected for perfluorohexanesulfonate (0.23ng/mL increase or 0.24log unit increase, p=0.006); PFOS (0.86ng/mL increase or 0.16log unit increase, p=0.011); PFOA (0.35ng/mL increase or 0.18log unit increase, p<0.001); perfluorononanoic acid (0.12ng/mL increase or 0.17log unit increase, p=0.003); perfluorodecanoic acid (0.06ng/mL increase or 0.42log unit increase, p<0.001); and perfluoroundecanoic acid (0.03ng/mL increase or 0.32log unit increase, p=0.019). Stronger associations were identified for home dust exposures and traumatic exposures than dust cloud. These findings highlight the importance of conducting longitudinal studies in this population to assess possible cardiometabolic and renal consequences related to these exposures.

Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison. METHODS: We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33). FINDINGS: The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion). INTERPRETATION: EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention. FUNDING: Endocrine Society, Ralph S French Charitable Foundation, and Broad Reach Foundation.

Particulate Matter Exposure and Preterm Birth: Estimates of U.S. Attributable Burden and Economic Costs.

BACKGROUND: Preterm birth (PTB) rates (11.4% in 2013) in the United States remain high and are a substantial cause of morbidity. Studies of prenatal exposure have associated particulate matter ≤ 2.5 µm in diameter (PM2.5) and other ambient air pollutants with adverse birth outcomes; yet, to our knowledge, burden and costs of PM2.5-attributable PTB have not been estimated in the United States. OBJECTIVES: We aimed to estimate burden of PTB in the United States and economic costs attributable to PM2.5 exposure in 2010. METHODS: Annual deciles of PM2.5 were obtained from the U.S. Environmental Protection Agency. We converted PTB odds ratio (OR), identified in a previous meta-analysis (1.15 per 10 µg/m3 for our base case, 1.07-1.16 for low- and high-end scenarios) to relative risk (RRs), to obtain an estimate that better represents the true relative risk. A reference level (RL) of 8.8 µg/m3 was applied. We then used the RR estimates and county-level PTB prevalence to quantify PM2.5-attributable PTB. Direct medical costs were obtained from the 2007 Institute of Medicine report, and lost economic productivity (LEP) was estimated using a meta-analysis of PTB-associated IQ loss, and well-established relationships of IQ loss with LEP. All costs were calculated using 2010 dollars. RESULTS: An estimated 3.32% of PTBs nationally (corresponding to 15,808 PTBs) in 2010 could be attributed to PM2.5 (PM2.5 > 8.8 µg/m3). Attributable PTBs cost were estimated at $5.09 billion [sensitivity analysis (SA): $2.43-9.66 B], of which $760 million were spent for medical care (SA: $362 M-1.44 B). The estimated PM2.5 attributable fraction (AF) of PTB was highest in urban counties, with highest AFs in the Ohio Valley and the southern United States. CONCLUSIONS: PM2.5 may contribute substantially to burden and costs of PTB in the United States, and considerable health and economic benefits could be achieved through environmental regulatory interventions that reduce PM2.5 exposure in pregnancy. Citation: Trasande L, Malecha P, Attina TM. 2016. Particulate matter exposure and preterm birth: estimates of U.S. attributable burden and economic costs. Environ Health Perspect 124:1913-1918; http://dx.doi.org/10.1289/ehp.1510810.

Association of exposure to di-2-ethylhexylphthalate replacements with increased blood pressure in children and adolescents.

Phthalates are environmental chemicals widely used in consumer and personal care products. In this study, we examined associations of urinary phthalates with blood pressure, triglycerides, and lipoproteins in children and adolescents, performing a cross-sectional analysis of a subsample of US children 6 to 19 years of age who participated in the National Health and Nutrition Examination Survey between the years 2009 and 2012. We quantified exposure to common environmental phthalates, with a focus on the dietary contaminant di-2-ethylhexylphthalate and 2 increasingly used replacements, di-isononyl phthalate and di-isodecyl phthalate, based on micromolar concentration of urinary metabolites. We assessed descriptive, univariate, and multivariable associations with blood pressure and lipids. Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass, metabolites of di-2-ethylhexylphthalate, di-isononyl phthalate, and di-isodecyl phthalate were associated with higher age-, sex- and height-standardized blood pressure. For each log unit increase in di-isodecyl phthalate metabolites, a 0.105 standard deviation unit increase in systolic blood pressure z score was identified (P=0.004); for di-isononyl phthalate metabolites, a 0.113 standard deviation unit increment was identified (P=0.008). For di-2-ethylhexylphthalate metabolites, a 0.103 standard deviation unit increment (P=0.013) was detected. Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products showed an association with blood pressure (≥90th percentile) in univariate analysis, but this was no longer significant in our full multivariable model, suggesting specificity. Phthalate metabolites were not associated with triglycerides or high-density lipoproteins. Further, longitudinal studies are needed to confirm these associations and to assess opportunities for intervention.

Association of Exposure to Di-2-Ethylhexylphthalate Replacements With Increased Insulin Resistance in Adolescents From NHANES 2009-2012.

CONTEXT: Di-isononyl phthalate (DINP) and di-isodecyl phthalate (DIDP) are environmental chemicals increasingly used to replace di-2-ethylhexylphthalate (DEHP) and commonly found in processed foods. Phthalate exposures, in particular DEHP, have been associated with insulin resistance in adolescents, but there are no data regarding the two substitutes, DINP and DIDP. OBJECTIVE: This study aimed to examine associations of DINP, DIDP, and DEHP with insulin resistance outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional analysis of 2009-2012 National Health and Nutrition Examination Surveys (NHANES) composed of 356 fasting 12-19-year-olds. MAIN OUTCOME MEASURES: Insulin resistance as a categorical outcome expressed as homeostatic model assessment of insulin resistance (HOMA-IR), using a cut point of 4.39 to define insulin resistance. We also examined continuous HOMA-IR as an outcome in secondary analyses. RESULTS: Controlling for demographic and behavioral factors, diet, age, body mass index, and urinary creatinine, for each log increase in DINP metabolite, a 0.08 (P = .001) increase in HOMA-IR was identified. Compared with the first tertile of DINP (23.4% adjusted prevalence), the third tertile was associated with a 34.4% prevalence (95% confidence interval [CI], 27.3-41.6%; P = .033) of insulin resistance. Similarly, compared with the first tertile of DEHP (20.5% adjusted prevalence), the third tertile had 37.7% prevalence (95% CI 29.8-45.6%; P = .003). CONCLUSIONS: Urinary DINP concentrations were associated with increased insulin resistance in this cross-sectional study of adolescents. The previously identified association of DEHP with insulin resistance was also confirmed. Further, longitudinal studies are needed to confirm these associations, with the possibility to assess opportunities for intervention.

Phthalates and the diets of U.S. children and adolescents.

BACKGROUND: Di-2-ethylhexylphthalate (DEHP) is an ester of phthalic acid commonly found in processed foods. DEHP may contribute to obesity and insulin resistance in children and adolescents, yet dietary exposures have been not been studied in this vulnerable subpopulation. OBJECTIVE: To assess diet and its relation to urinary phthalates in a nationally representative sample of US children and adolescents. DESIGN: Cross-sectional analysis of 24-h dietary recall and urinary phthalate metabolites from 2743 6-19 year olds participating in the 2003-8 National Health and Nutrition Examination Surveys. Regression analyses examined relationships of food consumption with log-transformed metabolite concentrations, examined as low-molecular weight, high molecular weight and di-2-ethylhexylphthalate categories, controlling for urinary creatinine, age group, body mass index category, race/ethnicity, caloric intake and gender. RESULTS: We identified a -0.04% (95% CI: -0.08, -0.01) increment in di-2-ethylhexylphthalate metabolite concentration/additional gram fruit consumption, a +0.01% increment/additional calorie dietary intake (95% CI: +0.003, +0.02), and a +0.09% (95% CI: +0.02, +0.17) increment/additional gram meat/poultry/fish consumption. Soy consumption (-0.40% increment/additional gram consumed, 95% CI: -0.66, -0.14) was inversely associated with di-2-ethylhexylphthalate, while poultry (+0.23% increment/additional gram consumed, 95% CI: +0.12, +0.35) was positively associated. Findings were robust to examination of metabolite concentrations per unit body mass index and weight, and inclusion of fasting time. CONCLUSIONS: Diet contributes to urinary phthalate concentrations in children and adolescents. Further study is needed to examine the implications of di-2-ethylhexylphthalate exposure, especially earlier in life, when more permanent metabolic changes may occur.

Urinary phthalates and increased insulin resistance in adolescents.

BACKGROUND: Di-2-ethylhexylphthalate (DEHP) is an environmental chemical commonly found in processed foods. Phthalate exposures, in particular to DEHP, have been associated with insulin resistance in adults, but have not been studied in adolescents. METHODS: Using cross-sectional data from 766 fasting 12- to 19-year-olds in the 2003-2008 NHANES, we examined associations of phthalate metabolites with continuous and categorical measures of homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: Controlling for demographic and behavioral factors, diet, continuous age, BMI category, and urinary creatinine, for each log (roughly threefold) increase in DEHP metabolites, a 0.27 increase (95% confidence interval 0.14-0.40; P < .001) in HOMA-IR was identified. Compared with the first tertile of DEHP metabolite in the study population (14.5% insulin resistant), the third tertile had 21.6% prevalence (95% confidence interval 17.2%-26.0%; P = .02). Associations persisted despite controlling for bisphenol A, another endocrine-disrupting chemical commonly found in foods, and HOMA-IR and insulin resistance were not significantly associated with metabolites of lower molecular weight phthalates commonly found in cosmetics and other personal care products. CONCLUSIONS: Urinary DEHP concentrations were associated with increased insulin resistance in this cross-sectional study of adolescents. This study cannot rule out the possibility that insulin-resistant children ingest food with higher phthalate content, or that insulin-resistant children excrete more DEHP.

Economic costs of childhood lead exposure in low- and middle-income countries.

BACKGROUND: Children's blood lead levels have declined worldwide, especially after the removal of lead in gasoline. However, significant exposure remains, particularly in low- and middle-income countries. To date, there have been no global estimates of the costs related to lead exposure in children in developing countries. OBJECTIVE: Our main aim was to estimate the economic costs attributable to childhood lead exposure in low- and middle-income countries. METHODS: We developed a regression model to estimate mean blood lead levels in our population of interest, represented by each 1-year cohort of children < 5 years of age. We used an environmentally attributable fraction model to estimate lead-attributable economic costs and limited our analysis to the neurodevelopmental impacts of lead, assessed as decrements in IQ points. Our main outcome was lost lifetime economic productivity due to early childhood exposure. RESULTS: We estimated a total cost of $977 billions of international dollars in low- and middle-income countries, with economic losses equal to $134.7 billion in Africa [4.03% of gross domestic product (GDP)], $142.3 billion in Latin America and the Caribbean (2.04% of GDP), and $699.9 billion in Asia (1.88% of GDP). Our sensitivity analysis indicates a total economic loss in the range of $728.6-1162.5 billion. CONCLUSIONS: We estimated that, in low- and middle-income countries, the burden associated with childhood lead exposure amounts to 1.20% of world GDP in 2011. For comparison, in the United States and Europe lead-attributable economic costs have been estimated at $50.9 and $55 billion, respectively, suggesting that the largest burden of lead exposure is now borne by low- and middle-income countries.

Urinary phthalates are associated with higher blood pressure in childhood.

OBJECTIVE: To examine associations of urinary phthalate levels with blood pressure (BP) and serum triglyceride and lipoprotein levels in children. STUDY DESIGN: We performed a cross-sectional analysis of a subsample of US children aged 6-19 years who participated in the National Health and Nutrition Examination Survey between 2003 and 2008. We quantified exposure to 3 families of phthalates--low molecular weight, high molecular weight and di-2-ethylhexylphthalate (DEHP)--based on molar concentration of urinary metabolites. We assessed descriptive, bivariate, and multivariate associations with BP and lipid levels. RESULTS: Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass index, levels of metabolites of DEHP, a phthalate commonly found in processed foods, were associated with higher age-, sex-, and height-standardized BP. For each log unit (roughly 3-fold) increase in DEHP metabolites, a 0.041 SD unit increase in systolic BP z-score was identified (P = .047). Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products were not associated with BP. Phthalate metabolites were not associated with triglyceride levels, high-density lipoprotein level, or prehypertension. CONCLUSIONS: Dietary phthalate exposure is associated with higher systolic BP in children and adolescents. Further work is needed to confirm these associations, as well as to evaluate opportunities for intervention.

Phosphodiesterase type 5 inhibition improves arterial stiffness after exercise but not exercise capacity in hypertensive men.

BACKGROUND: Established hypertension is associated with abnormal exercise hemodynamics and reduced exercise capacity through mechanisms that may include contributions from arterial stiffness and endothelial vasomotor dysfunction. Phosphodiesterase type 5 (PDE5) inhibitors prolong nitric oxide-mediated cyclic guanosine monophosphate (cGMP) signaling in vascular smooth muscle, and have beneficial effects on exercise tolerance in pulmonary hypertension and heart failure. Recent studies suggest they may also be useful antihypertensive agents. We hypothesized they would reduce arterial stiffness and increase exercise capacity in hypertensive men. METHODS: In a 3-way, randomized, placebo-controlled study, 15 untreated hypertensive and 15 matched normotensive male subjects received 50mg sildenafil (PDE5 inhibitor), 25mg hydralazine (control, cGMP-independent vasodilator) or placebo, 3 times daily for 1 week, and the effects on exercise blood pressure (during modest and maximal exercise), peak oxygen uptake, and arterial stiffness were investigated. RESULTS: Peak oxygen uptake was significantly lower in hypertensive than normotensive subjects (analysis of variance [ANOVA] P < 0.0001), but not affected by sildenafil in either group. However, while pulse wave velocity, as a measure of arterial stiffness, increased after exercise in hypertensive men following placebo, sildenafil reversed these changes, significantly reducing pulse wave velocity compared with both placebo and hydralazine (ANOVA P = 0.0001). CONCLUSIONS: PDE5 inhibition with sildenafil did not improve exercise capacity in hypertensive men. Nevertheless, our findings suggest that sildenafil may reduce arterial stiffness in the recovery period after exercise.

Race/ethnicity-specific associations of urinary phthalates with childhood body mass in a nationally representative sample.

BACKGROUND: Phthalates have antiandrogenic effects and may disrupt lipid and carbohydrate metabolism. Racial/ethnic subpopulations have been documented to have varying urinary phthalate concentrations and prevalences of childhood obesity. OBJECTIVE: We examined associations between urinary phthalate metabolites and body mass outcomes in a nationally representative sample of U.S. children and adolescents. METHODS: We performed stratified and whole-sample cross-sectional analyses of 2,884 children 6-19 years of age who participated in the 2003-2008 National Health and Nutrition Examination Survey. Multivariable linear and logistic analyses of body mass index z-score, overweight, and obesity were performed against molar concentrations of low-molecular-weight (LMW), high-molecular-weight (HMW), and di-2-ethylhexylphthalate (DEHP) metabolites, controlling for sex, television watching, caregiver education, caloric intake, poverty-income ratio, race/ethnicity, serum cotinine, and age group. We used sensitivity analysis to examine robustness of results to removing sample weighting, normalizing phthalate concentrations for molecular weight, and examining different dietary intake covariates. RESULTS: In stratified, multivariable models, each log unit (roughly 3-fold) increase in LMW metabolites was associated with 21% and 22% increases in odds (95% CI: 1.05-1.39 and 1.07-1.39, respectively) of overweight and obesity, and a 0.090-SD unit increase in BMI z-score (95% CI: 0.003-0.18), among non-Hispanic blacks. Significant associations were not identified in any other racial/ethnic subgroup or in the study sample as a whole after controlling for potential confounders, associations were not significant for HMW or DEHP metabolites, and results did not change substantially with sensitivity analysis. CONCLUSIONS: We identified a race/ethnicity-specific association of phthalates with childhood obesity in a nationally representative sample. Further study is needed to corroborate the association and evaluate genetic/epigenomic predisposition and/or increased phthalate exposure as possible explanations for differences among racial/ethnic subgroups.