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Abstract

Background: Findings from previous studies on the effect of air pollution exposure on lung function during childhood have been inconsistent. A common limitation has been the quality of exposure data used and few studies have modelled exposure longitudinally throughout early life.

Objectives: To study the long term effects of particulate matter with an aerodynamic diameter <10µm (PM₁₀) and nitrogen dioxide (NO₂) exposure on specific airway resistance (sR_aw) and forced expiratory volume (FEV₁) before and after bronchodilator treatment within the Manchester Asthma and Allergy Study (MAAS) birth cohort (N=1185).

Methods: Spirometry was performed during clinic visits at ages 3, 5, 8 and 11 years. Individual level PM₁₀ and NO₂ exposures were estimated from birth to age 11 through a microenvironmental exposure model. Longitudinal and cross-sectional associations were estimated using generalized estimating equations and multivariable linear regression models.

Results: Lifetime exposure to PM₁₀ and NO₂ was associated with significantly less growth in FEV₁ (% predicted) over time, both before [-1.37% (95% CI: -2.52, -0.23) for a 1-unit increase in PM₁₀ and -0.83% (95% CI: -1.39, -0.28) for a 1-unit increase in NO₂] and after bronchodilator treatment [-3.59% (95% CI: -5.36, -1.83) and -1.20% (95% CI: -1.97, -0.43), respectively]. No association was found between lifetime exposure and sR_aw over time. Cross-sectional analyses of detailed exposure estimates for the summer and winter prior to age 11 and lung function at age 11 indicated no significant associations.

Conclusions: Long term PM₁₀ and NO₂ exposures were associated with small, but statistically significant, reductions in lung volume growth in children of elementary school age.

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Abstract

Background: The microcirculation plays an important role in the physiology of cardiovascular health. Air pollution is an independent risk factor for the development and progression of cardiovascular diseases, but the number of studies on the relation between air pollution and the microcirculation is limited.

Objectives: To examine the relationship between short-term changes in air pollution and microvascular changes.

Methods: We measured retinal microvasculature using fundus image analysis in a panel of 84 healthy adults (52% women) aged 22 to 63y between January and May 2012. Blood vessels were measured as Central Retinal Arteriolar/Venular Equivalent (CRAE/CRVE). The median number of measurements was 2 (range: 1-3). We used monitoring data on particulate air pollution (PM₁₀) and black carbon (BC). Mixed-effect models were used to estimate associations between CRAE/CRVE and exposure to PM₁₀ and BC using various exposure windows.

Results: CRAE and CRVE were associated with PM₁₀ and BC concentrations, averaged over 24 hours before the retinal examinations. Each 10-µg/m³ increase in PM₁₀ was associated with a 0.93 µm decrease (95% CI: -1.42, -0.45; p=0.0003) in CRAE, and a 0.86-µm decrease (95% CI: -1.42, -0.30; p=0.004) in CRVE after adjustment for individual characteristics and time varying conditions such as ambient temperature. Each 1-µg/m³ increase in BC was associated with a 1.84 µm decrease (95% CI: -3.18, -0.51; p<0.001) in CRAE.

Conclusions: These findings suggest that the retinal microvasculature responds to short-term changes in air pollution levels. These results support a mechanistic pathway through which air pollution can act as a trigger of cardiovascular events at least in part through effects on the microvasculature.

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Abstract

Background: Evidence on the short-term effects of fine and coarse particles on morbidity in Europe is scarce and inconsistent.

Objectives: To estimate the association between daily concentrations of fine and coarse particles with hospitalizations for cardiovascular and respiratory conditions in 8 Southern European cities, within the MED-PARTICLES project.

Methods: City-specific Poisson models were fitted to estimate associations of daily concentrations of particulate matter with aerodynamic diameter < 2.5 μm (PM_2.5), 10 (PM₁₀) and their difference (PM_2.5-10), with daily counts of emergency hospitalizations for cardiovascular and respiratory diseases. Pooled estimates were derived from random-effects meta-analysis and the robustness of results to co-pollutant exposure adjustment and model specification was evaluated. Pooled concentration-response curves were estimated using a meta-smoothing approach.

Results: We found significant associations between all PM fractions and cardiovascular admissions. Increases of 10-μg/m³ in PM_2.5, 6.3-μg/m³ in PM_2.5-10 and 14.4-μg/m³ in PM₁₀ (lag 0-1 days) were associated with increases in cardiovascular admissions of 0.51% (95% CI: 0.12, 0.90%), 0.46% (95% CI: 0.10, 0.82%) and 0.53% (95% CI: 0.06, 1.00%), respectively. Stronger associations were estimated for respiratory hospitalizations, ranging from 1.15% (95% CI: 0.21, 2.11%) for PM₁₀ to 1.36% (95% CI: 0.23, 2.49) for PM_2.5 (lag 0-5 days).

Conclusions: PM_2.5 and PM_2.5-10 were positively associated with cardiovascular and respiratory admissions in 8 Mediterranean cities. Information on the short-term effects of different PM fractions on morbidity in Southern Europe will be useful to inform European policies on air quality standards.

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Abstract

Objective: Air pollution contains many toxicants known to affect neurological function and to have effects on the fetus in utero. Recent studies have reported associations between perinatal exposure to air pollutants and autism spectrum disorder (ASD) in children. We tested the hypothesis that perinatal exposure to air pollutants is associated with ASD, focusing on pollutants associated with ASD in prior studies.

Methods: We estimated associations between U.S. Environmental Protection Agency modeled levels of hazardous air pollutants at the time and place of birth and ASD in the children of participants in the Nurses’ Health Study II (325 cases, 22,101 controls). Our analyses focused on pollutants associated with ASD in prior research. We accounted for possible confounding and ascertainment bias by adjusting for family-level socioeconomic status (maternal grandparents’ education) and census-tract-level socioeconomic measures (e.g., tract median income and percent college educated), as well as maternal age at birth and year of birth. We also examined possible differences in the relationship between ASD and pollutant exposures by child’s sex.

Results: Perinatal exposures to the highest versus lowest quintile of diesel, lead, manganese, mercury, methylene chloride, and an overall measure of metals were significantly associated with ASD, with odds ratios ranging from 1.5 (for overall metals measure) to 2.0 (for diesel and mercury). In addition, linear trends were positive and statistically significant for these exposures (P < .05 for each). For most pollutants, associations were stronger for boys (279 cases) than girls (46 cases) and significantly different according to sex.

Conclusions: Perinatal exposure to air pollutants may increase risk for ASD. Additionally, future studies should consider sex-specific biological pathways connecting perinatal exposure to pollutants with ASD.

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Abstract

Background: Previous studies of prenatal exposure to drinking water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs.

Objectives: We examined the relation between prenatal exposure to drinking water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure.

Methods: With data from the National Birth Defects Prevention Study, we linked addresses of 3300 case-mothers and 1121 control-mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work.

Results: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. <0.91 mg) than control-mothers. During one month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control-mothers to ingest ≥ 5.42 mg of nitrate daily (vs. <1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects.

Conclusions: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects.

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Abstract

Background: Traditional animal toxicity tests can be time and resource intensive thereby limiting the number of chemicals that can be comprehensively tested for potential hazards to humans and/or to the environment.

Objectives: We compared several types of data to demonstrate how alternative models can be used to inform both human and ecological risk assessment.

Methods: We compared data derived from high-throughput in vitro assays to fish reproductive tests for seven chemicals, and show that human-focused assays can be predictive of chemical hazards in the environment. We also discuss how conserved pathways enable the use of non-mammalian models, such as fathead minnow, zebrafish and Xenopus laevis, to understand modes of action and screen for chemical risks to humans. As an extension of this we illustrate how dose-dependent responses of zebrafish embryos exposed to flusilazole can be extrapolated, using pathway point of departure data and reverse toxicokinetics, to obtain human oral dose hazard values that are similar to published mammalian chronic toxicity values for the chemical. In another example, we address how development/safety data for human health can be used to help assess potential risks of pharmaceuticals to non-target species in the environment.

Discussion: Using several examples, we demonstrate that pathway-based analysis of chemical effects provides new opportunities to use alternative models (non-mammalian species, in vitro tests) to support decision making, while reducing animal use and associated costs.

Conclusions: These analyses and examples demonstrate how alternative models can be used to reduce cost and animal use while being protective of both human and ecological health.

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Abstract

Background: Results from animal toxicology studies are critical to evaluating potential harm from exposure to environmental chemicals or safety of drugs prior to human testing. However, there is significant debate about how to evaluate the methodology and potential biases of the animal studies. There is no agreed upon approach, and a systematic evaluation of current best practices is lacking.

Objective: We performed a systematic review to identify and evaluate instruments for assessing risk of bias and/or other methodological criteria of animal studies.

Method: We searched Medline (January 1966 – November 2011) to identify all relevant articles. We extracted data on risk of bias criteria (e.g. randomization, blinding, allocation concealment) and other study design features included in each assessment instrument.

Discussion: Thirty distinct instruments were identified with the total number of assessed risk of bias, methodological, and/or reporting criteria ranging from 2 to 25. The most common criteria assessed were randomization (25/30, 83%), investigator blinding (23/30, 77%) and sample size calculation (18/30, 60%). In general, authors failed to empirically justify why these or other criteria were included. Nearly all (28/30, 93%) instruments have not been rigorously tested for validity or reliability.

Conclusion: Our review highlights a number of risk of bias assessment criteria that have been empirically tested for animal research including randomization, concealment of allocation, blinding and accounting for all animals. Additionally, there is a need for empirically testing additional methodological criteria, and assessing the validity and reliability of a standard risk of bias assessment instrument.

¹INRA (Institut National de la Recherche Agronomique), UMR1331 (Unité Mixe de Recherche 1331), Toxalim, Research Center in Food Toxicology, F-31027 Toulouse, France; ²Université de Toulouse, INPT (Institut National Polytechnique de Toulouse), ENVT (Ecole Nationale Vétérinaire de Toulouse), EIP (Ecole d’Ingénieurs de Purpan), UPS (Université Paul Sabatier), F-31076 Toulouse, France

Advance Publication

Abstract

Background: Bisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher than expected BPA plasma concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG).

Objectives: Using dogs as a valid model, plasma concentrations of BPA were compared over a 24-h period after intravenous, orogastric and sublingual administrations, in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability.

Methods: Six dogs were sublingually administered with BPA at 0.05 mg/kg and 5mg/kg. The time course of plasma BPA concentrations was compared with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20mg/kg BPA dose administrated by orogastric gavage.

Results: The data indicated that the systemic bioavailability of BPA deposited sublingually was high (70-90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastro-intestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after oral dosing enabling the two pathways of absorption to be easily distinguished.

Conclusions: These findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa by the sublingual route. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastro-intestinal tract.

Citation: Gayrard V, Lacroix MZ, Collet SH, Viguié C, Bousquet-Melou A, Toutain PL, Picard-Hagen N. Environ Health Perspect (): .doi:10.1289/ehp.1206339

Received: December 01, 2012; Accepted: May 17, 2013; Published: June 12, 2013

Advance Publication

This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. The EHP Advance Publication articles are completely citable using the assigned DOI code for the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

¹Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Lebanon, New Hampshire, USA; ²Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA; ³Department of Public Health, Oregon State University, Corvallis, Oregon, USA; ⁴Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire, USA

Advance Publication

Abstract

Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation

Objectives: This study aims to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure.

Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24-28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord-blood and in utero arsenic exposure and also examined the association between methylation at individual CpG loci and arsenic exposure levels.

Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8+ T-lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG Islands (p = 0.009). Of those in CpG Islands (n = 44), the majority (75%) exhibited higher methylation levels in the highest exposed group compared to the lowest exposed group. There were also several CpG loci that exhibited linear dose-dependent relationship between methylation and arsenic exposure.

Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.

Citation: Koestler DC, Avissar-Whiting M, Houseman EA, Karagas MR, Marsit CJ. Environ Health Perspect (): .doi:10.1289/ehp.1205925

Received: August 23, 2012; Accepted: June 07, 2013; Published: June 11, 2013

Advance Publication

This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. The EHP Advance Publication articles are completely citable using the assigned DOI code for the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

¹Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California-Davis, Davis, California; ²Center for Health and the Environment, University of California-Davis, Davis, California; ³Department of Obstetrics and Gynecology, School of Medicine, and California National Primate Research Center, University of California-Davis, Davis California 

Advance Publication

Abstract

Background: Bisphenol A (BPA) exposure early in life results in organizational changes in reproductive organs, but the effect of BPA on conducting airway cellular maturation has not been studied. Late gestation is characterized by active differentiation of secretory cells in the lung epithelium.

Objectives: We hypothesized that BPA exposure disrupts epithelial secretory cell development in the fetal conducting airway of the Rhesus macaque.

Methods: We exposed animals to BPA during either the second (early term) or the third trimester (late term). There were 4 treatment groups 1) Sham control early term, 2) Sham control late term, 3) BPA early term (BPA-early) and 4) BPA late term (BPA-late). Because cellular maturation occurs non-uniformly in the lung, mRNA and protein expression was defined by airway level using microdissection.

Results: BPA exposure of the dam during late term significantly accelerated secretory cell maturation in the proximal airways of the fetus; both Clara cell secretory protein (CCSP) and MUC5AC/5B mRNA and protein expression increased.

Conclusions: BPA exposure during late gestation accelerates secretory cell maturation in the proximal conducting airways. We have identified a critical window of fetal susceptibility for BPA effects on lung epithelial cell maturation in the third trimester. This is of environmental health importance because increases in airway mucins are hallmarks of a number of childhood lung diseases that may be impacted by BPA exposure.

Citation: Van Winkle LS, Murphy SR, Boetticher MV, VandeVoort CA. Environ Health Perspect (): .doi:10.1289/ehp.1206064

Received: September 25, 2012; Accepted: June 07, 2013; Published: June 11, 2013

Advance Publication

This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. The EHP Advance Publication articles are completely citable using the assigned DOI code for the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.