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BACKGROUND: Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied. OBJECTIVES: We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence. METHODS: Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼21 samples/trimester) and at 2 months and 1-year of age (∼7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals. RESULTS: Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (RDEHP), mono-ethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β=0.78; 95% CI: 0.00, 1.55) and MEP (β=0.92; 95% CI: -0.11, 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and RDEHP were associated with worse Social Awareness (β=0.25; 95% CI: 0.01, 0.50) and Social Communication (β=0.43; 95% CI: -0.02, 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1=1.38; 95% credible interval (CrI): -0.18, 2.97], Social Awareness (Beta 1=0.37; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1=0.91; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected 푝=0.07). DISCUSSION: The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. [ABSTRACT FROM AUTHOR]

BACKGROUND: Consumption of an organic diet reduces exposure to a range of agricultural pesticides. Only three studies have examined the effect of an organic diet intervention on exposure to the herbicide glyphosate, the most heavily used agricultural chemical in the world. Despite its widespread use, the primary sources of glyphosate exposure in humans are poorly understood. OBJECTIVE: Our objective was to examine the effect of an organic diet intervention on urinary glyphosate concentrations among pregnant individuals. METHODS: We conducted a 2-wk randomized crossover trial in which 39 pregnant participants living near (≤0.5 km) and far (>0.5 km) from agricultural fields received a 1-wk supply of conventional groceries and 1 wk of organic groceries, randomized to order. We collected daily first morning void urine samples and analyzed composite samples from each week for glyphosate. We examined differences in urinary glyphosate concentrations between the conventional week and the organic week among all participants and stratified by residential proximity to an agricultural field. RESULTS: Median specific gravity-adjusted glyphosate concentrations were 0.19 μg/L and 0.16 μg/L during the conventional and organic weeks, respectively. We observed modest decreases in urinary glyphosate concentrations from the conventional to organic week among far-field participants, but no difference among near-field participants. In secondary analyses excluding participants who did not meet a priori criteria of compliance with the intervention, we observed significant decreases in urinary glyphosate concentrations, particularly among far-field participants (푝< 0.01-0.02, depending on exclusion criteria). DISCUSSION: This trial is the first to examine the effect of an organic diet intervention on glyphosate among people living near and far from agricultural fields. Our results suggest that diet is an important contributor to glyphosate exposure in people living >0.5 km from agricultural fields; for people living near crops, agriculture may be a dominant exposure source during the pesticide spray season. [ABSTRACT FROM AUTHOR]

BACKGROUND: Findings from national surveys suggest that everyone in the United States is exposed to perchlorate. At high doses, perchlorate, thiocyanate, and nitrate inhibit iodide uptake into the thyroid and decrease thyroid hormone production. Small changes in thyroid hormones during pregnancy, including changes within normal reference ranges, have been linked to cognitive function declines in the offspring. [ABSTRACT FROM AUTHOR]

Background: Benchmark dose (BMD) modeling computes the dose associated with a prespecified response level. While offering advantages over traditional points of departure (PODs), such as no-observed-adverse-effect-levels (NOAELs), BMD methods have lacked consistency and transparency in application, interpretation, and reporting in human health assessments of chemicals. Objectives: We aimed to apply a standardized process for conducting BMD modeling to reduce inconsistencies in model fitting and selection. Methods: We evaluated 880 dose-response data sets for 352 environmental chemicals with existing human health assessments. We calculated benchmark doses and their lower limits [10% extra risk, or change in the mean equal to 1 SD (BMD/L10/1SD)] for each chemical in a standardized way with prespecified criteria for model fit acceptance. We identified study design features associated with acceptable model fits. Results: We derived values for 255 (72%) of the chemicals. Batch-calculated BMD/L10/1SD values were significantly and highly correlated (R2 of 0.95 and 0.83, respectively, n = 42) with PODs previously used in human health assessments, with values similar to reported NOAELs. Specifically, the median ratio of BMDs10/1SD:NOAELs was 1.96, and the median ratio of BMDLs10/1SD:NOAELs was 0.89. We also observed a significant trend of increasing model viability with increasing number of dose groups. Conclusions: BMD/L10/1SD values can be calculated in a standardized way for use in health assessments on a large number of chemicals and critical effects. This facilitates the exploration of health effects across multiple studies of a given chemical or, when chemicals need to be compared, providing greater transparency and efficiency than current approaches. [ABSTRACT FROM AUTHOR]

Background: Animal studies indicate that some phthalate metabolites may harm female reproductive function.Objectives: We assessed the associations between exposure to phthalate metabolites and pregnancy loss.Methods: Using a previously established cohort of couples planning their first pregnancy, we analyzed four primary and two oxidized secondary phthalate metabolites in urine samples collected on day 10 after the first day of the last menstrual period before conception occurred (n = 128) and during the previous cycle (if any, n = 111). Subclinical embryonal loss was identified by repeated measurement of urinary human chorionic gonadotropin, and information on clinical spontaneous abortions was obtained by telephone interview with the mother.Results: Pregnancy loss (n = 48) was increased among women with urinary concentration of monoethylhexyl phthalate (MEHP) in the upper tertile in the conception sample compared with women in the lowest tertile [adjusted odds ratio (OR) = 2.9; 95% confidence interval (CI): 1.1, 7.6]. The corresponding OR for subclinical embryonal loss (n = 32) was 40.7 (95% CI: 4.5, 369.5).Conclusions: The phthalate metabolite MEHP was associated with higher occurrence of preg­nancy loss. Because this is the first human study to show this association and the sample size is small, the findings need to be corroborated in independent studies. [ABSTRACT FROM AUTHOR]

Background: Identifying risk factors for adverse health outcomes in children is important. The intrauterine environment plays a pivotal role for health and disease across life. Objectives: We conducted a comprehensive study to determine whether common psychosocial stress during pregnancy is a risk factor for a wide spectrum of pediatric diseases in the offspring. Methods: The study was conducted using prospective data in a population-based sample of mothers with live singleton births (n = 66,203; 71.4% of those eligible) from the Danish National Birth Cohort. We estimated the association between maternal stress during pregnancy (classified based on two a priori-defined indicators of common stress forms, life stress and emotional stress) and offspring diseases during childhood (grouped into 16 categories of diagnoses from the International Classification of Diseases, 10th Revision, based on data from national registries), controlling for maternal stress after pregnancy. Results: Median age at end of follow-up was 6.2 (range, 3.6-8.9) years. Life stress (highest compared with lowest quartile) was associated with an increased risk of conditions originating in the perinatal period [odds ratio (OR) = 1.13; 95% confidence interval (CI): 1.06, 1.21] and congenital malformations (OR=1.17; CI: 1.06, 1.28) and of the first diagnosis of infection [hazard ratio (HR) = 1.28; CI: 1.17, 1.39], mental disorders (age 0-2.5 years: HR = 2.03; CI: 1.32, 3.14), and eye (age 0-4.5 years: HR = 1.27; CI: 1.06, 1.53), ear (HR = 1.36; CI: 1.23, 1.51), respiratory (HR = 1.27; CI; 1.19, 1.35), digestive (HR = 1.23; CI: 1.11, 1.37), skin (HR = 1.24; CI: 1.09, 1.43), musculoskeletal (HR = 1.15; CI: 1.01-1.30), and genitourinary diseases (HR = 1.25; CI; 1.08, 1.45). Emotional stress was associated with an increased risk for the first diagnosis of infection (HR = 1.09; CI: 1.01, 1.18) and a decreased risk for the first diagnosis of endocrine (HR = 0.81; CI; 0.67, 0.99), eye (HR = 0.84; CI; 0.71, 0.99), and circulatory diseases (age 0-3 years: HR = 0.63; CI: 0.42, 0.95). Conclusions: Maternal life stress during pregnancy may be a common risk factor for impaired child health. The results suggest new approaches to reduce childhood diseases. [ABSTRACT FROM AUTHOR]

Background: A large body of evidence suggests that fine particulate matter (PM) air pollution is a cause of cardiovascular disease, but little is known in particular about the cardiovascular effects of indoor air pollution from household use of solid fuels in developing countries. RESPIRE (Randomized Exposure Study of Pollution Indoors and Respiratory Effects) was a randomized trial of a chimney woodstove that reduces wood smoke exposure. Objectives: We tested the hypotheses that the stove intervention, compared with open fire use, would reduce ST-segment depression and increase heart rate variability (HRV). Methods: We used two complementary study designs: a) between-groups comparisons based on randomized stove assignment, and b) before-and-after comparisons within control subjects who used open fires during the trial and received chimney stoves after the trial. Electrocardiogram sessions that lasted 20 hr were repeated up to three times among 49 intervention and 70 control women 38-84 years of age, and 55 control subjects were also assessed after receiving stoves. HRV and ST-segment values were assessed for each 30-min period. ST-segment depression was defined as an average value below -1.00 mm. Personal fine PM [aerodynamic diameter ≤ 2.5 μm (PM2.5)] exposures were measured for 24 hr before each electrocardiogram. Results: PM2.5 exposure means were 266 and 102 μg/m3 during the trial period in the control and intervention groups, respectively. During the trial, the stove intervention was associated with an odds ratio of 0.26 (95% confidence interval, 0.08-0.90) for ST-segment depression. We found similar associations with the before-and-after comparison. The intervention was not significantly associated with HRV. Conclusions: The stove intervention was associated with reduced occurrence of nonspecific ST-segment depression, suggesting that household wood smoke exposures affect ventricular repolarization and potentially cardiovascular health. [ABSTRACT FROM AUTHOR]

Background: Exposure to ambient air particulate matter (PM) has been shown to increase rates of cardiopulmonary morbidity and mortality, but the underlying mechanisms are still not well understood. Objective: We examined signaling events involved in the expression of the inflammatory gene interleukin-8 (IL8) in human airway epithelial cells (HAECs) exposed to ambient PM collected in an urban area of Mexicali, Mexico. Methods: We studied IL8 expression and regulatory signaling pathways in cultured HAECs exposed to Mexicali PM suspended in media for 0--4 hr. Results: Exposure resulted in a dose-dependent, 2- to 8-fold increase in IL8 mRNA expression relative to controls. PM exposure induced IL8 transcriptional activity in BEAS-2B cells that was dependent on the nuclear factor-kappa B (NF-κB) response element in the IL8 promoter. Chromatin immunoprecipitation (ChIP) assays showed a 3-fold increase in binding of the p65 (RelA) NF-κB isoform to the IL8 promoter sequence in HAECs exposed to PM. Western blot analyses showed elevated levels of phosphorylation of p65 but no changes in IκBα phosphorylation or degradation. IL8 expression was blunted in a dose-dependent manner in BEAS-2B cells transduced with a lenti-virus encoding a dominant negative p65 mutant in which phosphorylation sites were inactivated. Conclusion: Taken together, these findings show that the increase in IL8 mRNA expression in HAECs exposed to PM10 (PM ≤ 10 µm in aerodynamic diameter) is mediated through an NF-κÈ-dependent signaling mechanism that occurs through a pathway involving direct phosphorylation of the transcription factor p65 in the absence of IκBα degradation. These data show that exposure to PM10 in ambient air can induce inflammatory responses by activating specific signaling mechanisms in HAECs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ocean pollution affects marine organisms and ecosystems as well as humans. The International Oceanographic Commission recommends ocean health monitoring programs to investigate the presence of marine contaminants and the health of threatened species and the use of multiple and early-warning biomarker approaches. OBJECTIVE: We explored the hypothesis that biomarker and contaminant analyses in skin biopsies of the threatened sperm whale (Physeter macrocephalus) could reveal geographical trends in exposure on an oceanwide scale. METHODS: We analyzed cytochrome P450 1A1 (CYP1A1) expression (by immunohistochemistry), stable nitrogen and carbon isotope ratios (as general indicators of trophic position and latitude, respectively), and contaminant burdens in skin biopsies to explore regional trends in the Pacific Ocean. RESULTS: Biomarker analyses revealed significant regional differences within the Pacific Ocean. CYP1A1 expression was highest in whales from the Galapagos, a United Nations Educational, Scientific, and Cultural Organization World Heritage marine reserve, and was lowest in the sampling sites farthest away from continents. We examined the possible influence of the whales' sex, diet, or range and other parameters on regional variation in CYP1A1 expression, but data were inconclusive. In general, CYP1A1 expression was not significantly correlated with contaminant burdens in blubber. However, small sample sizes precluded detailed chemical analyses, and power to detect significant associations was limited. CONCLUSIONS: Our large-scale monitoring study was successful at identifying regional differences in CYP1A1 expression, providing a baseline for this known biomarker of exposure to aryl hydrocarbon receptor agonists. However, we could not identify factors that explained this variation. Future oceanwide CYP1A1 expression profiles in cetacean skin biopsies are warranted and could reveal whether globally distributed chemicals occur at biochemically relevant concentrations on a global basis, which may provide a measure of ocean integrity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Exposure to excessive levels of manganese (Mn) is known to induce psychiatric and motor disorders, including parkinsonian symptoms. Therefore, finding a reliable means for early detection of Mn neurotoxicity is desirable. OBJECTIVES: Our goal was to determine whether in vivo brain levels of γ-aminobutyric acid (GABA), N.-acetylaspartate (NAA), and other brain metabolites in male smelters were altered as a consequence of Mn exposure. METHODS: We used T1-weighted magnetic resonance imaging (MRI) to visualize Mn deposition in the brain. Magnetic resonance spectroscopy (MRS) was used to quantify concentrations of NAA, glutamate, and other brain metabolites in globus pallidus, putamen, thalamus, and frontal cortex from a well-established cohort of 10 male Mn-exposed smelters and 10 male age-matched control subjects. We used the MEGA-PRESS MRS sequence to determine GABA levels in a region encompassing the thalamus and adjacent parts of the basal ganglia [GABA-VOI (volume of interest)]. RESULTS: Seven of 10 exposed subjects showed clear T1-hyperintense signals in the globus pallidus indicating Mn accumulation. We found a significant increase (82%; p = 0.014) in the ratio of GABA to total creatine (GABA/tCr) in the GABA-VOI of Mn-exposed subjects, as well as a distinct decrease (9%; p = 0.04) of NAA/tCr in frontal cortex that strongly correlated with cumulative Mn exposure (R = -0.93; p < 0.001). CONCLUSIONS: We demonstrated elevated GABA levels in the thalamus and adjacent basal ganglia and decreased NAA levels in the frontal cortex, indicating neuronal dysfunction in a brain area not primarily targeted by Mn. Therefore, the noninvasive in vivo MRS measurement of GABA and NAA may prove to be a powerful tool for detecting presymptomatic effects of Mn neurotoxicity. [ABSTRACT FROM AUTHOR]