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USAID Acting Administrator Wade Warren Provides Welcome Remarks at 2017 Mandela Washington Leadership Summit


English
Friday, July 28, 2017

U.S. Agency for International Development (USAID) Acting Administrator Wade Warren will join the Department of State in welcoming the 2017 Mandela Washington Fellowship Summit, the flagship program of the Young African Leaders Initiative (YALI), which represents the United States’ investment in the next generation of African leaders. The Summit brings together 1,000 talented young leaders from Sub-Saharan Africa who play important roles in enhancing peace and security, spurring economic growth, and strengthening democratic institutions in the United States and Africa.

Endogenous System Microbes as Treatment Process Indicators for Decentralized Non-potable Water Reuse

Monitoring the efficacy of treatment strategies to remove pathogens in decentralized systems remains a challenge. Evaluating log reduction targets by measuring pathogen levels is hampered by their sporadic and low occurrence rates. Fecal indicator bacteria are used in centralized systems to indicate the presence of fecal pathogens, but are ineffective decentralized treatment process indicators as they generally occur at levels too low to assess log reduction targets. System challenge testing by spiking with high loads of fecal indicator organisms, like MS2 coliphage, has limitations, especially for large systems. Microbes that are endogenous to the decentralized system, occur in high abundances and mimic removal rates of bacterial, viral and/or parasitic protozoan pathogens during treatment could serve as alternative treatment process indicators to verify log reduction targets. To identify abundant microbes in wastewater, the bacterial and viral communities were examined using deep sequencing. Building infrastructure-associated bacteria, like Zoogloea, were observed as dominant members of the bacterial community in graywater. In blackwater, bacteriophage of the order Caudovirales constituted the majority of contiguous sequences from the viral community. This study identifies candidate treatment process indicators in decentralized systems that could be used to verify log removal during treatment. The association of the presence of treatment process indicators with real-time, continuous measurements made with on-line physical and chemical sensors will be discussed as a framework to monitor treatment integrity in decentralized systems.

Identifying Metabolically Active Chemicals Using a Consensus Quantitative Structure Activity Relationship Model for Estrogen Receptor Binding

Traditional toxicity testing provides insight into the mechanisms underlying toxicological responses but requires a high investment in a large number of resources. The new paradigm of testing approaches involves rapid screening studies able to evaluate thousands of chemicals across hundreds of biological targets through use of in vitro assays. Endocrine disrupting chemicals (EDCs) are of concern due to their ability to alter neurodevelopment, behavior, and reproductive success of humans and other species. A recent integrated computational model examined results across 18 ER-related assays in the ToxCast in vitro screening program to eliminate chemicals that produce a false signal by possibly interfering with the technological attributes of an individual assay. However, in vitro assays can also lead to false negatives when the complex metabolic processes that render a chemical bioactive in a living system might be unable to be replicated in an in vitro environment. In the current study, the influence of metabolism was examined for over 1,400 chemicals considered inactive using the integrated computational model. Over 2,000 first-generation and over 4,000 second-generation metabolites were generated for the inactive chemicals using in silico techniques. Next, a consensus model comprised of individual structure activity relationship (SAR) models was used to predict ER-binding activity for each of the metabolites. Binding activity was predicted for 8-10% of the metabolites within each generation. Additionally, it was found that approximately 20% of the inactive parents have at least one potentially active metabolite. The approaches presented here can be used to identify potential parents that are inactive under in vitro conditions but that might become metabolically active in a living organism.

Scoring and ranking of metabolic trees to computationally prioritize chemicals for testing using fit-for-purpose in vitro estrogen receptor assay

Increasing awareness about endocrine disrupting chemicals (EDCs) in the environment has driven concern about their potential impact on human health and wildlife. Tens of thousands of natural and synthetic xenobiotics are presently in commerce with little to no toxicity data and therefore uncertainty about their impact on estrogen receptor (ER) signaling pathways and other toxicity endpoints. As such, there is a need for strategies that make use of available data to prioritize chemicals for testing. One of the major achievements within the EPA’s Endocrine Disruptor Screening Program (EDSP), was the network model combining 18 ER in vitro assays from ToxCast to predict in vivo estrogenic activity. This model overcomes the limitations of single in vitro assays at different steps of the ER pathway. However, it lacks many relevant features required to estimate safe exposure levels and the composite assays do not consider the complex metabolic processes that might produce bioactive entities in a living system. This problem is typically addressed using in vivo assays. The aim of this work is to design a computational and in vitro approach to prioritize compounds and perform a quantitative safety assessment. To this end, we pursue a tiered approach taking into account bioactivity and bioavailability of chemicals and their metabolites using a human uterine epithelial cell (Ishikawa)-based assay. This biologically relevant fit-for-purpose assay was designed to quantitatively recapitulate in vivo human response and establish a margin of exposure. In order to overcome the overwhelming number of metabolites to test, a prioritization workflow was developed based on ToxCast chemicals (1677) and their predicted metabolites (15,406). A scoring function was used to rank the metabolic trees of the considered chemicals combining in vitro data from ToxCast and the literature in addition to in silico data from the Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) consensus and five of its single QSAR models. The bioavailability of the parent chemicals as well as the metabolites and their structures were predicted using ChemAxon metabolizer software. The designed workflow categorized the metabolic trees into true positives, true negatives, false positives and false negatives. The final output was a top priority list of 345 ranked chemicals and related metabolites from the ToxCast library as well as an additional list of 593 purchasable chemicals with known CASRNs. We are currently moving forward to test the highest-priority metabolic trees in the Ishikawa assay and are using a liver bioreactor to confirm important metabolites.

NSF-funded supercomputer Stampede2 forges new frontier in advanced computing

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The National Science Foundation (NSF) today realized the initial phase of its $30 million investment to upgrade the nation’s computational research infrastructure through the dedication of Stampede2, one of the most powerful supercomputing systems in the world. Based at the Texas Advanced Computing Center (TACC) at The University of Texas at Austin, this strategic national resource will

More at https://www.nsf.gov/news/news_summ.jsp?cntn_id=242528&WT.mc_id=USNSF_51&WT.mc_ev=click


This is an NSF News item.

Temporal and spatial behavior of pharmaceuticals in Narragansett Bay, Rhode Island, United States.

The behavior and fate of pharmaceutical ingredients in coastal marine ecosystems are not well understood. To address this, the spatial and temporal distribution of 15 high-volume pharmaceuticals were measured over a 1-yr period in Narragansett Bay (RI, USA) to elucidate factors and processes regulating their concentration and distribution. Dissolved concentrations ranged from below detection to 313 ng/L, with 4 pharmaceuticals present at all sites and sampling periods. Eight pharmaceuticals were present in suspended particulate material, ranging in concentration from below detection to 44 ng/g. Partitioning coefficients were determined for some pharmaceuticals, with their range and variability remaining relatively constant throughout the study. Normalization to organic carbon content provided no benefit, indicating other factors played a greater role in regulating partitioning behavior. Within the upper bay, the continuous influx of wastewater treatment plant effluents resulted in sustained, elevated levels of pharmaceuticals. A pharmaceutical concentration gradient was apparent from this zone to the mouth of the bay. For most of the pharmaceuticals, there was a strong relationship with salinity, indicating conservative behavior within the estuary. Short flushing times in Narragansett Bay coupled with pharmaceuticals’ presence overwhelmingly in the dissolved phase indicate that most pharmaceuticals will be diluted and transported out of the estuary, with only trace amounts of several compounds sequestered in sediments. The present study identifies factors controlling the temporal and spatial dynamics of dissolved and particulate pharmaceuticals; their partitioning behavior provides an increased understanding of their fate, including bioavailability in an urban estuary. Environ Toxicol Chem 2017;36:1846–1855. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

MITSUBISHI ( 17V461000 )

Dated: JUL 20, 2017 Mitsubishi Motors North America, Inc. (MMNA) is recalling certain 2007-2013 Outlander vehicles. In the affected vehicles, water may drop between the hood and the windshield and leak into the wiper mo…

ENTEGRA ( 17V441000 )

Dated: JUL 13, 2017 Entegra Coach (Entegra) is recalling certain 2018 Cornerstone motorhomes equipped with Cummins ISX 15L engines. These engines have a fuel pump whose drive gear could possibly slip on its drive shaft,…

KEYSTONE ( 17V439000 )

Dated: JUL 13, 2017 Keystone RV Company (Keystone) is recalling certain 2016-2017 Keystone Outback travel trailers, models 220URB, 240URS, 250URS, 255UBH, and 293UBH. The affected vehicles were built with an incorrect d…

KAWASAKI ( 17V465000 )

Dated: JUL 11, 2017 Kawasaki Motors Corp., U.S.A. (Kawasaki) is recalling certain 2017 Versys-X 300 motorcycles. A loose tail/brake light socket may allow the bulb to fall out.

Exposure to Ambient Particulate Matter during Specific Gestational Periods Produces Adverse Obstetric Consequences in Mice

Author Affiliations open

1Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, USA

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  • Background:
    Epidemiological studies associate inhalation of fine-sized particulate matter (PM2.5) during pregnancy with preterm birth (PTB) and low birth weight (LBW) but disagree over which time frames are most sensitive, or if effects are cumulative.
    Objectives:
    Our objective was to provide experimental plausibility for epidemiological observations by testing the hypothesis that exposure to PM2.5 during discrete periods of pregnancy results in PTB and LBW.
    Methods:
    For the first study, timed-pregnant B6C3F1 mice were exposed to concentrated ambient PM2.5 (CAPs) or filtered air (FA) throughout pregnancy [6 h/d from gestational day (GD) 0.5 through GD16.5]. A follow-up study examined the effects of CAPs exposure during discrete gestational periods (1: GD0.5–5.5; 2: GD6.5–14.5; 3: GD14.5–16.5; 4: GD0.5–16.5) aligning to milestones during human development.
    Results:
    In the first experiment, exposure to 160 μg CAPs/m3 throughout pregnancy decreased gestational term by 0.5 d (∼1.1  wk decrease for humans) and birth weight by 11.4% compared with FA. The follow-up experiment investigated timing of CAPs exposure (mean concentrations at 178, 193, 171, and 173 μg/m3 for periods 1–4, respectively). Pregnancy was significantly shortened (vs. FA) by ∼0.4d when exposure occurred during gestational periods 2 and 4, and by ∼0.5d if exposure occurred during period 3. Exposure during periods 1, 2, and 4 reduced birth weight by ∼10% compared with FA, and placental weight was reduced (∼8%) on GD17.5 if exposure occurred only during period 3.
    Conclusions:
    Adverse PM2.5-induced outcomes such as PTB and LBW are dependent upon the periods of maternal exposure. The results of these experimental studies could contribute significantly to air pollution policy decisions in the future. https://doi.org/10.1289/EHP1029
  • Received: 26 August 2016
    Revised: 12 December 2016
    Accepted: 23 January 2017
    Published: 27 July 2017

    Address correspondence to J. Zelikoff, Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987 USA. Telephone: (845) 731-3528. Email: Judith.Zelikoff@nyumc.org

    The authors declare they have no actual or potential competing financial interests.

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Introduction

In the United States, ∼11% of all pregnancies result in preterm birth (PTB; birth prior to 37 wk gestation) (March of Dimes 2014). Although the reasons for this outcome are varied, exposure of pregnant women to elevated levels of fine-sized ambient particulate matter (PM2.5) has been identified in numerous epidemiologic studies as a contributing factor (Bell et al. 2010; Ha et al. 2014; Pereira et al. 2014; Ritz et al. 2007). Exposure to PM2.5 is not only associated with PTB but also with low birth weight (LBW; <2,500 g) as a result of restricted fetal growth in infants born early and in those carried to full term (Ha et al. 2014). The link between PM2.5 and increased risk for PTB was first reported by Xu et al. (1995) in a community-based cohort study. Since that time, epidemiological evidence strengthening the association between PM exposure and PTB and LBW continues to accumulate (Ha et al. 2014; Huynh et al. 2006; Jiang et al. 2007; Malmqvist et al. 2011; Ritz et al. 2000, 2007; Srám et al. 2005; Zhao et al. 2011). Such outcomes are also associated with increased risk for long-term health issues including eye/vision problems (O’Connor and Fielder 2007), learning disabilities (Johnson and Breslau 2000), and later-life chronic diseases including cardiovascular disease (Lewandowski et al. 2013) and type 1 and type 2 diabetes (Li et al. 2014).

A question that remains highly debated among human studies is whether timing of PM2.5 exposure during pregnancy is a relevant risk factor for PTB and/or LBW. Although a number of epidemiological studies have attempted to address this critical question, the data remain inconsistent. A case–control survey performed in 2003 and nested within a birth cohort (2,543 of 6,374 women sampled in California from a cohort of ∼58,000 births in Los Angeles County), Ritz et al. (2007) demonstrated that the occurrence of PTB is proportional to PM2.5 exposure levels during the first trimester only. A more recent epidemiological study by Pereira et al. (2014) reported that exposure of Hispanic women to PM2.5 during either the first trimester or throughout the entirety of pregnancy resulted in a greater risk for PTB than at other times during pregnancy. A study from Florida revealed that maternal exposure to PM2.5 during any point of pregnancy increased the risk for both PTB and LBW but that the second trimester was most sensitive (Ha et al. 2014). Bell et al. (2010) reported an increased risk for LBW following maternal exposure to PM2.5 derived from oil burning, but only during the third trimester. Thus, the period (or periods) of greatest sensitivity during pregnancy for PM-induced effects on gestational duration and birth weight remains unsolved.

Studies performed using animal models to examine the effects of prenatal exposure to ambient PM on fetal or gestational outcomes are limited. A study by Veras et al. (2008) demonstrated that a 24 h/d exposure of pregnant Balb/c mice to 27.5 μg/m3 PM2.5 from the start of pregnancy through gestational day (GD) 17 decreased placental weight. This change in placental weight was associated with decreased blood vessel diameter on the maternal side of the placental vasculature; capillary surface area on the fetal side of the placenta was significantly increased. The study concluded that PM-induced changes in placental perfusion were, at least in part, responsible for the observed reduction in fetal weight.

The present study was designed to establish feasibility for the epidemiologic observations that inhalation exposure during pregnancy to PM2.5 leads to PTB and LBW and to determine which (if any) gestational periods are most sensitive for PM-induced LBW, PTB, or both.

Methods

Animals

Seven- to eight-week-old female and male (for breeding purposes only) B6C3F1 mice (Jackson Laboratory) were housed in single-sex pairs upon arrival and were provided food and water ad libitum at all times except during concentrated ambient PM2.5 (CAPs) exposure. Beginning one day after arrival, estrous cycles were monitored daily for at least two complete normal estrous cycles. On the third proestrus, following two normal cycles, a single female mouse was paired overnight with one male. The next morning, confirmation of successful mating was determined by the presence of a copulatory plug and was considered GD0.5. Mated females were weighed and randomly assigned to one treatment group [i.e., filtered air (FA) control vs. CAPs] and to one of four gestational exposure periods: period 1 (GD0.5–GD5.5); period 2 (GD6.5–GD14.5); period 3 (GD14.5–GD16.5); or period 4 (GD0.5–GD16.5) (Figure 1). A group of pregnant naïve mice (n=4) remained in their home cages during the exposure period and served as chamber controls to assure that any observed effects were due solely to treatment rather than to the exposure system itself. When not being exposed, all experimental animals were housed in rooms equipped with HEPA and charcoal filters to remove any ambient particles and gaseous pollutants.

Timeline indicating four gestational exposure periods.
Figure 1. Timeline for inhalation CAPs exposure. Upon arrival, female mice were staged for phase of the estrous cycle. On the third proestrus following two normal cycles, the female was paired with a single male to breed overnight. Upon confirmation of breeding, the female was weighed and assigned to a treatment and to an exposure period. Exposures were 6 h/d, 7 d/wk. Dams were weighed daily before being placed into the exposure box if being exposed or returned to the home cage if not being exposed. Mice from all periods were either euthanized on GD17.5 or allowed to give birth as described in “Methods.” Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); NYU, New York University.

A total of three CAPs exposure experiments were performed between 2012 and 2013: The first (summer of 2012) and second (winter of 2013) exposure examined the effects of maternal CAPs exposure throughout gestation (i.e., period 4) only. The third exposure occurred during the summer of 2013 for the purpose of assessing specific gestational periods of greatest vulnerability to PM2.5.

Exposure System

A particle concentrator system was used to collect and concentrate PM2.5 for each experiment as described previously (Maciejczyk et al. 2005). Briefly, the system is a modified versatile aerosol concentration enrichment system (VACES) originally developed by Sioutas et al. (1999). The principle of VACES is “condensational growth of ambient particles followed by virtual impaction to concentrate the aerosol” (Maciejczyk et al. 2005; Sioutas et al. 1999). Ambient air was drawn through an Aerotec 2 cyclone inlet that removes the majority of particles >2.5 μm in diameter and was then passed through silica gel and carbon filters to remove excess moisture and organic pollutants. Water-soluble [e.g., sulfur dioxide (SO2)] and reactive [ozone, nitrogen oxides (NOx)] gases were removed by the system itself. The PM aerosol was then quickly chilled to ∼20°C in a condenser tube. The remaining concentrated particles were then passed over a warmed water bath to restore relative humidity similar to that of ambient air. From there, the CAPs aerosol was divided into three streams: 27% of the particle flow was directed toward Teflon™ filters housed in Harvard impactors (Air Diagnostics and Engineering Inc.) and was used for gravimetric and chemical analysis (described below); 10% of the flow was directed toward a DataRAM™ nephelometer (Thermo Electron Corporation) to allow for continuous monitoring of CAPs mass concentration; the remaining particles were streamed toward the animal exposure chamber. The same system was used for the control mice, which were exposed to house air that passed through HEPA filters, which removed ∼98% of ambient particles before entering the VACES inlet.

For each of the exposures, the target CAPs concentration was 150 μg/m3; this level is ∼10–15 times that of the ambient PM2.5 concentration usually found at the New York University (NYU) Sterling Forest (Tuxedo, NY) facility where the ambient PM2.5 was collected. The selected concentration was chosen such that a 6-h exposure period, when averaged over a 24-h period, was relevant to that measured in some U.S. urban centers (Samet et al. 2000). Because no energy generation plants or other types of industrial operations are located within 20 miles of the exposure system, CAPs produced by the system was representative of the regional PM2.5 background for the megalopolis extending from Virginia to Maine on the eastern coast of the United States. Use of the VACES system neither chemically nor physically modifies the ambient particles collected by the CAPs exposure system (Chen et al. 2005).

Mouse Exposure

Individual mice were placed into single compartments of a 32-compartment stainless steel exposure chamber. The exposure box was covered by a Plexiglass lid through which perforated aluminum tubes delivered CAPs evenly throughout the exposure box (Maciejczyk et al. 2005). Mice were weighed each morning before being placed into the exposure box; those that were not being exposed were returned to their cages after weighing. For experiment 3, mice were exposed during one of four exposure periods. To reduce possible effects from differences in PM content between exposures, mice from each period were overlapping (i.e., not in a sequential manner). A subset of pregnant mice (n=6–8) from each gestational exposure period was euthanized on GD17.5 using sodium pentobarbital (150 mg/kg, IP), and the uteri were collected and opened to collect each fetal-placental unit. After all fetal–placental units were excised, the amniotic sacs were carefully opened, the umbilical cords were severed at the fetal-umbilical attachment site, and the umbilical cords and amniotic membranes were dissected away from the placenta. The position of the fetal-placental unit within the uterus was not recorded for these studies. All fetuses and placentas recovered from each dam were weighed, and fetal crown-to-rump length (CRL) was determined using digital calipers. The remaining timed-pregnant dams (n=8–17) in each exposure period were permitted to give birth, and the day of parturition was recorded; each neonate was weighed, and CRL was measured at birth and daily for 21 d, at which point they were weaned.

Starting on GD18.5, cages were checked for the presence of pups starting at 0800 hours. If present, pups were immediately counted and weighed. Alternatively, if no pups were present at that time, mice were checked every 2–3 hours until midafternoon. If pups were not observed on any given day by 1630 hours, dams were checked again the following morning. To avoid data biasing, neonatal weights were collected only after milk was viewed by eye in their stomachs; pups that had not been fed weighed less than those that had been nursed. In circumstances where litters contained more than 10 pups at birth, the number of neonates was culled to 10 on postnatal day (PND) 0. On PND10 and PND21, neonatal anogenital distance (AGD) was measured in both male and female offspring. All procedures using animals were approved by the New York University School of Medicine Institutional Animal Care and Use Committee.

Genetic Sexing of Fetal Mice

Sexing of GD17.5 fetal mice followed the same protocol as previously described (Blum Het al. 2012). Briefly, a 1-mm section of the fetal tail was clipped from each fetus after weighing, placed into a microcentrifuge tube containing 100 μL digestion buffer [25 mM sodium hydroxide (NaOH)/0.2 mM ethylenediaminetetraacetic acid (EDTA), pH 12.0], and incubated at 95°C for 1 h. Once digested, 100 μL of neutralization buffer (40 mM Tris, pH 5.5) was added to each tube and thoroughly mixed by vortexing. Undigested material was separated via centrifugation (1,000×g for 10 min), and the supernatant was collected and diluted 1:100 in ultrapure water. The diluted DNA sample was used as a template for duplex polymerase chain reaction (PCR) using primers for interleukin-3 and the sex-determining region of chromosome Y (SRY) gene. PCR products were separated using 1% agarose gel electrophoresis in tris-acetate-EDTA buffer and were visualized using ethidium bromide staining and ultraviolet light illumination.

Elemental Characterization and Mass Concentration of Collected PM2.5 Particles

Using preweighed Teflon filters (37 mm, 0.2 μm pore size; Pall), the mass concentration of CAPs was determined daily; the particle concentration from filtered air (FA) was determined on a weekly basis. Particle-laden filters were equilibrated overnight in a temperature/humidity-controlled weigh room (21°C±0.5°C and 40±5% relative humidity) and were weighed gravimetrically on an MT5 microbalance (Mettler Toledo). Filters from every third exposure day, as well as lot-matched unexposed blank control filters, were analyzed by X-ray fluorescence spectroscopy (XRF) to determine elemental content using an ARL™ Quant’X EDXRF Analyzer (ThermoScientific).

Statistical Analyses

In all cases, the dam was the experimental unit (Table 1 details sample sizes across experiments and exposure periods). Gestational days of birth, birth weights, fetal body weight, CRL, placental weight, weight-to-length ratio, and anogenital distance were compared using analysis of variance (ANOVA). For the first two experiments, the main effect was treatment. Because no statistical differences were observed across exposure periods for FA-exposed dams in experiment 3, data from all FA-treated dams in this experiment were pooled for statistical analyses and graphical presentations. For data generated from experiment 3, the main effects tested were treatment and exposure period, along with the interaction effect of treatment×exposure period. For measurements of body weight gain (percent change from birth and percent change day-over-day), data from days postpartum were compared between the four CAPs exposure periods and the pooled FA control. When statistically significant differences were observed (ANOVA p-value<0.05), post hoc testing was performed using Fisher’s Least Significant Difference (LSD) to identify differences between treatments in the case of experiment 1, or between individual CAPs exposure periods, or in comparison to the pooled FA control in experiment 3. Comparisons of offspring sex ratios between exposure periods, between treatments, or between exposure periods and treatments were performed using χ2 analysis. All statistical comparisons were performed using SAS (v.9.1.3; SAS Insitute Inc.). Data presented are the means±standard error (SE) unless otherwise stated.

Table 1. Experimental sample sizes for each treatment in each experiment.
Experiment Treatment Total sample size Number of dams used for GD17.5 Number of dams used for PTB/LBW
Experiment 1 Naïve 4 0 4
FA 10 0 10
CAPs 15 0 15
Experiment 2 FA 22 0 22
CAPs 22 0 22
Experiment 3 Period 1 10 4 6
FA Period 2 10 4 6
Period 3 13 4 9
Period 4 10 5 5
CAPs Period 1 13 5 8
Period 2 13 5 8
Period 3 13 5 8
Period 4 16 5 11
Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); FA, fitered air; GD, gestation day; LBW, low birth weight; PTB, preterm birth.

Results

Physicochemical Analyses of CAPs

Concentrations of CAPs varied moderately between each of the three experiments (Table 2). For the first and second exposures, pregnant mice were exposed to CAPs throughout gestation (GD0.5–GD16.5). The mean CAPs concentration for the first experiment was 15.2 times greater than ambient air levels and 44.3 times higher than FA levels. The CAPs mass concentration for the second experiment was 24.6 times higher than ambient air and 29.1 times higher than FA. For the third experiment, pregnant mice were exposed to CAPs only during one of four preselected gestational exposure periods in an overlapping manner. Compared with the ambient PM2.5 concentrations measured during these same periods, the mean CAPs concentrations were 15.3-, 16.6-, 14.8-, and 14.9 times higher for periods 1–4, respectively; compared with FA, CAPs concentrations were 65.7-, 71.3-, 63.4-, and 64.2 times higher for the same gestational periods.

Table 2. Average daily CAPs concentrations.
Experiment 1a Experiment 2b Experiment 3c
Treatment Period 4(GD 0.5 – 16.5) Period 4(GD 0.5 – 16.5) Period 1(GD 0.5 – 5.5) Period 2(GD 6.5 – 14.5) Period 3(GD 14.5 – 16.5) Period 4(GD 0.5 – 16.5)
FA 3.7±1.7d 3.9±2.6 2.7±1.6
CAPs 163.8±100.0 113.4±93.7 177.5±104.7 192.5±96.2 171.3±94.1 173.4±92.2
Ambiente 10.9±6.5 4.7±3.4 11.6±6.1
Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); FA, fitered air; GD, gestation day.

aExperiment 1 occurred during summer 2012.

bExperiment 2 occurred during winter 2013.

cExperiment 3 occurred during summer 2013.

dValues are mean daily concentrations (μg/m3)±standard deviation (SD) for each particular gestational time frame.

eAmbient concentrations provided for comparison only.

Elemental analyses were performed on particle-laden filters collected every third exposure day from all three experiments; the results are shown in Table 3. Elemental levels, with the exceptions of copper (Cu), zinc (Zn), bromine (Br), and lead (Pb), were greater during the summer exposures than during the winter months. For both summer experiments (experiments 1 and 3), the 10 most abundant CAPs-associated elements were sodium (Na), magnesium (Mg), aluminum (Al), silicon (Si), sulfur (S), potassium (K), calcium (Ca), titanium (Ti), iron (Fe), and bromine (Br). For the winter exposure (experiment 2), the most abundant CAPs-associated elements were the same as those measured during the summer except that Al and Si were replaced by Cu and Zn. Elements collected on filters collected from the FA exposure line did not show significant variability across the three experiments.

Table 3. Concentrations of various elements found on collection filters identified by XRF.
Element FA: Summer 2012 FA: Winter 2013 FA: Summer 2013 Ambientb: Summer 2012 Ambient: Winter 2013 Ambient: Summer 2013 CAPs: Summer 2012 CAPs: Winter 2013 CAPs: Summer 2013
Sodium (Na) 16.8±10.0a −12.3±25.2 56.9±32.6 188.3±161.6 110.0±60.6 162.6±88.0 1411.6±1871.8 1154.5±601.1 1593.6±1003.2
Magnesium (Mg) 0.7±5.1 −1.0±5.4 15.8±8.6 45.4±30.3 20.0±11.1 46.7±25.8 349.6±305.1 253.5±253.5 510.8±353.8
Aluminum (Al) −9.4±11.1 40.7±75.9 4.7±11.6 10.3±22.5 −5.2±12.1 46.5±96.9 241.2±205.1 −34.0±70.0 755.5±1589.6
Silicon (Si) 0.0±0.0 0.0±0.0 0.0±0.0 1.1±3.2 0.0±0.0 50.1±186.4 329.2±573.5 0.0±0.0 1376.5±3426.5
Sulfur (S) 10.2±4.9 13.1±0.8 10.9±4.5 686.0±755.6 402.3±109.2 1101.1±803.8 10057.4±12697.3 6750.3±2262.1 18000.9±13109.9
Potassium (K) 4.3±1.5 1.4±0.6 1.5±2.6 31.6±11.4 33.4±8.5 52.0±33.9 398.2±204.1 493.0±74.6 708.7±474.2
Calcium (Ca) 8.7±6.0 5.1±2.6 4.0±1.7 34.7±26.5 22.5±10.1 40.9±32.5 445.7±335.9 294.9±139.6 538.9±516.2
Titanium (Ti) 3.2±1.8 1.6±1.1 2.7±1.2 14.1±5.3 14.6±3.8 17.7±12.5 347.7±132.8 472.5±177.5 1000.5±1110.0
Vanadium (V) 0.1±0.4 0.3±0.0 0.1±0.3 1.3±1.4 0.3±1.0 0.7±1.0 4.1±11.3 3.9±8.7 7.2±7.8
Chromium (Cr) 0.7±0.4 −0.2±0.4 0.0±0.3 −0.3±2.3 −0.4±1.2 −0.2±0.9 2.4±7.3 −1.8±4.2 4.5±8.3
Manganese (Mn) 0.0±0.2 0.2±0.1 −0.1±0.3 1.3±1.2 0.5±1.0 1.3±1.2 14.8±8.8 11.9±8.5 23.2±18.5
Iron (Fe) 5.4±5.3 2.9±1.4 0.3±0.5 35.4±18.6 19.9±4.4 58.3±62.4 473.0±248.2 292.1±62.3 905.5±1067.9
Nickel (Ni) 0.2±0.1 0.2±0.4 0.2±0.3 1.0±0.6 0.3±0.7 1.6±3.4 8.7±5.0 7.7±3.4 7.7±6.1
Copper (Cu) 0.5±0.3 0.7±0.3 0.4±0.5 1.8±0.9 0.8±0.5 1.5±1.5 11.6±7.3 27.1±22.8 21.0±9.6
Zinc (Zn) 1.4±0.4 0.7±0.8 1.7±2.5 4.1±1.4 4.7±3.3 9.4±17.3 48.7±31.1 80.2±31.9 70.9±39.7
Bromine (Br) 0.1±0.6 0.4±1.5 0.4±0.9 6.1±8.2 8.3±8.2 6.3±6.1 108.9±119.6 214.5±109.6 156.1±84.2
Strontium (Sr) 0.1±0.4 0.2±0.4 0.3±0.5 0.3±1.3 0.6±0.8 0.8±1.2 6.8±5.2 7.7±7.8 13.9±11.8
Barium (Ba) −0.3±0.9 2.1±5.0 1.4±2.0 3.0±5.5 −1.0±1.6 1.9±5.1 7.5±28.0 5.1±18.3 25.9±44.2
Erbium (Er) 0.8±0.5 1.0±0.5 0.3±0.6 1.1±1.6 0.4±1.0 0.8±1.7 5.3±6.6 8.3±7.4 13.8±8.2
Lutetium (Lu) 0.6±0.9 0.6±0.9 0.6±0.6 1.4±1.4 2.6±1.2 2.7±3.8 18.6±9.3 24.4±6.9 24.9±11.0
Lead (Pb) −0.2±0.1 0.2±0.5 0.0±0.2 −0.2±0.8 0.4±0.9 1.6±1.3 12.7±14.7 17.1±9.7 15.4±10.8
Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); FA, fitered air; GD, gestation day; XRF, X-ray fluorescence spectroscopy.

aData presented are mean ng/m3±standard deviation (SD) from filters collected during each exposure. Each mean represents 4–18 filters across each respective exposure period that were analyzed via XRF as described in “Methods.”

bData presented for ambient are for informational purposes only. No mice were exposed to these particles.

Exposure of Pregnant Mice to CAPs Results in PTB and LBW

In the first experiment (summer 2012), pregnant mice exposed to CAPs (163.8 μg CAPs/m3) throughout gestation (GD0.5–GD16.5) demonstrated a 0.5-d reduction (p=0.0018) in gestational duration compared with both naïve and FA-exposed mice (Figure 2A). A significant (p=0.0059) decrease (11.4%) in birth weight was also observed for offspring born prematurely (Figure 2B). There were no significant differences in gestational duration or birth weight between naïve and FA-exposed groups, demonstrating that exposure to CAPs, specifically, rather than confinement stress, was responsible for the observed effects. The results from the second experiment (winter 2012), also encompassing CAPs exposure throughout gestation, supported the PTB and LBW findings from the first exposure despite the difference in season. In this case, pregnant mice exposed to CAPs at a lower concentration than in the first experiment (113.4 μg/m3 vs. 163.8 μg/m3, respectively) had a reduction of ∼0.3 d (p=0.0423) in pregnancy duration compared with FA-exposed mice (Figure 2C) that was also associated with an 8.8% decrease (p=0.0005) in average litter birth weight (Figure 2D).

Bar graphs A and C with confidence intervals plotting gestational day (y-axis) across treatment groups, namely, naïve, control, and CAPS, and control and CAPS, respectively, (x-axis). Bar graphs B and D with confidence intervals plotting birth weight in milligrams (y-axis) across treatment groups, namely, naïve, control, and CAPS, and control and CAPS, respectively, (x-axis).
Figure 2. Maternal exposure to inhaled CAPs results in preterm birth and low birth weight. Dams were exposed to CAPs during period 4 (GD0.5–16.5) and were allowed to give birth. Data are from experiment 1 (A, B) and experiment 2 (C, D). In experiment 1, some naïve dams (n=4) were used to control for changes resulting from the exposure system. Data for experiment 1 are the means±standard error (SE) from n=10 (FA) or n=15 (CAPs); for experiment 2, n=22 for each treatment. In all panels, the treatment effect is significant [analysis of variance (ANOVA) p<0.05]. Bars in panels A and B with different letters are significantly different based on Fisher’s Least Significant Difference (LSD) post hoc testing. Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); FA, filtered air. *p<0.05 based on ANOVA.

Assessments of litter sizes and sex ratios were performed for all experiments (Table 4). Across all experiments and treatments, the average litter size was 8.3 pups per litter, with an overall range of 3–12. Within each experiment, there were no significant differences (p>0.05) between treatments for litter size, numbers of a given sex (determined by ANOVA) or sex ratios (determined by χ2 analysis). In experiment 3, no statistically significant differences were observed across exposure periods within treatment groups or between treatment groups for each period.

Table 4. Average litter size and sex breakdown by experiment, treatment, and exposure period.
Experiment/treatment Treatment/gestational period Litter size Mean number of males Mean number of females % Male % Female
Experiment 1 Naïve 8.2±1.5a 4.3±1.7 4.0±0.8 50.0±14.3 50.0±14.3
FA 7.8±1.9 3.4±0.7 4.3±2.0 45.8±14.3 54.2±20.7
CAPs 7.9±2.1 3.9±1.2 3.8±2.0 51.8±16.1 48.2±17.3
Experiment 2 FA 8.7±1.3 4.2±1.3 4.5±1.6 49.0±15.4 51.0±15.4
CAPs 8.3±1.3 3.8±1.7 4.5±1.7 45.9±16.4 54.1±16.4
Experiment 3 Period 1 9.0±0.6 4.2±1.5 4.8±1.3 46.1±15.0 53.9±15.0
FA Period 2 8.5±1.6 5.0±1.6 3.2±1.8 62.7±18.5 37.3±18.5
Period 3 9.0±1.3 5.0±1.4 4.5±1.4 52.5±12.9 47.5±12.9
Period 4 8.4±0.7 4.4±1.7 4.0±2.0 53.0±22.0 47.0±22.0
Across periods 8.7±1.1 4.6±1.5 4.2±1.7 53.2±16.9 46.8±16.9
CAPs Period 1 8.7±1.0 4.0±1.8 5.0±1.9 44.6±21.5 55.4±21.5
Period 2 8.3±1.0 4.9±1.7 3.4±1.8 59.5±20.8 40.5±20.8
Period 3 7.2±2.7 4.6±0.9 2.6±1.5 65.6±16.6 34.4±16.6
Period 4 8.3±1.3 4.0±1.2 4.0±1.7 50.9±17.7 49.7±17.7
Across periods 8.1±1.7 4.4±1.4 3.8±1.8 57.6±19.7 45.4±19.7
Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); FA, fitered air.

aData presented are means±standard deviation (SD) from all litters generated in these experiments. Fetal mice were sexed using polymerase chain reaction (PCR) as described in “Methods,” and neonatal mice were sexed by visual observation on postnatal day 8. Exposure treatment groups were assessed within experiment, and no significant differences were observed.

Effects of Exposure of Pregnant Mice to CAPs on Fetal Weight, Fetal CRL, and Placental Weight (Experiment 3)

Based on the observations from the first two experiments, follow-up studies were performed in the third experiment that focused on fetal, neonatal, and placental parameters. Fetal body weights examined on GD17.5 in experiment 3 revealed that effects were dependent (p=0.0115) upon the period during pregnancy when exposure to CAPs occurred (Figure 3A). Fetuses collected at GD17.5 from dams exposed to CAPs during only the fetal growth period (period 3) and throughout gestation (period 4) at similar CAPs concentrations (171.3 vs. 173.4 μg/m3, respectively) were 8.1% and 7.7% lighter, respectively, than GD-matched counterparts from FA-exposed dams. Moreover, maternal CAPs exposure during periods 1 (177.5 μg/m3), 3, and 4 led to significant (p=0.0468) decreases in CRL of 2.7%, 5.0%, and 1.8%, respectively (Figure 3B). In addition, maternal exposure to CAPs resulted in significant (p=0.0138) changes in placental weight. Maternal exposure to CAPs during the fetal growth period alone (period 3) resulted in an 8.1% decrease in placental weight. When exposure to CAPs occurred throughout pregnancy (period 4), a 3.8% increase in placental weight was observed (Figure 3C). Exposures that occurred only during placentation/organogenesis (period 2) had no effect on fetal weight, CRL, or placental weight.

Bar graphs A, B, and C with confidence intervals plotting fetal body weight in milligrams, crown to rump length in millimeters, and placental weight in milligrams (y-axis), respectively, across exposure to filtered air and four gestational exposure periods (x-axis).
Figure 3. Exposure of pregnant mice to CAPs during different exposure periods (experiment 3) is associated with decreased body weight (A), decreased CRL (B), and altered placental weight (C) on GD17.5. The results from analysis of variance (ANOVA) showed significant differences (p<0.05) among the groups for each endpoint which was followed by Fisher’s Least Significant Difference (LSD) post hoc testing to determine differences compared with FA. Data are the means±standard error (SE) from n=5 dams from each CAPs exposure period or n=16 from the pooled FA control dams. Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); CRL, crown-to-rump length; FA, filtered air; GD, gestational day. *p<0.05 compared with FA dams based on post hoc testing.

Effects of Exposure of Pregnant Mice to CAPs on Newborn Body Weight and CRL

In the third experiment carried out in the summer of 2014, pregnant mice were exposed to CAPs during one of four gestational periods. CAPs exposure caused an exposure period–dependent decrease (p=0.0003) in gestational duration. As shown in Figure 4A, no change in gestational duration was observed for mice born to mothers exposed only before implantation (period 1). In contrast, offspring from dams exposed to CAPs during either organogenesis (period 2) or growth (period 3) or throughout gestation (period 4) demonstrated reduced gestational duration of 0.4, 0.5, or 0.4 d, respectively. Birth weights were significantly (p=0.0003) reduced by 10.3%, 9.8%, and 10.3% (compared with controls) following maternal exposure to CAPs during periods 1, 2, and 4, respectively, whereas exposure to CAPs only during the fetal growth period had no effect on birth weight (Figure 4B).

Bar graphs A, B, C, and D with confidence intervals plotting day of birth in gestational day, mean birth weight in milligrams, mean birth length in millimeters, and mean weight/length ratio in milligrams per millimeter (y-axis), respectively, across exposure to filtered air and four gestational exposure periods (x-axis).
Figure 4. Maternal exposure to inhaled CAPs during different periods of pregnancy in experiment 3 as described in “Methods” are associated with PTB (A), LBW (B), decreased CRL (C) and decreased SGA (D). The results from analysis of variance (ANOVA) showed significant differences (p<0.05) among the groups for each end point; ANOVA was followed by Fisher’s Least Significant Difference (LSD) post hoc testing to determine differences compared with FA. Data are the means±standard error (SE) from n=8–11 dams for CAPs-exposed mice during periods 1 – 4. Because no differences were observed among the four periods for FA control values, the values were pooled (n=26). Note: CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); CRL, crown-to-rump length; FA, filtered air; LBW, low birth weight; PTB, preterm birth; SGA, size for gestational age. *p<0.05 compared with FA dams based on post hoc testing.

At birth, CRL was significantly (p<0.0001) decreased irrespective of the maternal exposure period in experiment 3 (Figure 4C). CRLs were reduced by 4.0%, 3.9%, 3.3%, and 4.6% for CAPs exposure periods 1–4, respectively. Decreased size-for-gestational age (SGA; weight/length) was observed in offspring born to dams exposed only during periods 1, 2, and 4; differences in SGA were reflected by decreases of 7.4%, 6.1%, and 6.0%, respectively, compared with FA-exposed mice (p=0.0054). Exposure of dams to CAPs only during period 3 had no effect on neonatal size for gestational age (Figure 4D).

Maternal CAPs Exposure Did Not Alter Postnatal Weight Gain in Neonatal Offspring (Experiment 3)

The effects of prenatal CAPs exposure on neonatal weight gain were dependent upon the method used to calculate the outcome. When weight gain was calculated as increase in body weight over time relative to birth weight, no differences (p>0.05) in growth rates were observed compared with the FA control (Figure 5A). Furthermore, calculation of day-to-day percentage body weight gain also revealed no clear CAPs exposure–related effects (p>0.05) (Figure 5B).

Line graphs A and B with confidence interval plotting body weight gain and weight gain (y-axis), respectively, across days postpartum (x-axis) exposed to filtered air and four gestational exposure periods.
Figure 5. Exposure of pregnant mice does not affect growth rates of offspring (experiment 3). Neonatal body weight gain was computed as a percentage over birth weight (A) or daily body weight gain (percent day-to-day gain) (B). Analysis of percent weight gain compared to birth weight (A) showed no significant differences by ANOVA (p>0.05) for the interaction of treatment and time. Comparison of weight gain day-to-day (B) also revealed no significant differences among the groups when data were analyzed by day postpartum. Data are means±SE from 8–11 dams for each CAPs exposure Period and 26 dams for the pooled FA controls.

Effects of CAPs Exposure on Body Length and AGD on PND10 and PND21 (Experiment 3)

On PND10, male offspring born to dams that were exposed to CAPs only prior to implantation (period 1) displayed a 2.9% decrease (p=0.0138) in CRL compared with time-matched FA-exposed dams (Figure 6A). In contrast, CRL was significantly (p=0.0263) increased by 1.8% at PND21 in males born to dams exposed to CAPs during mid- to late pregnancy (i.e., period 3) (Figure 6B).

Bar graphs A and B with confidence intervals plotting body length in millimeters ranging from 36 to 44 (in 6A) and from 46 to 58 (in 6B), (y-axis) across exposure to filtered air and four gestational exposure periods (x-axis). Bar graphs C and D with confidence intervals plotting anogenital distance in millimeters ranging from 1 to 4 (in 4C) and 7.5 to 10 (in 4D) (y-axis) across exposure to filtered air and four gestational exposure periods (x-axis).
Figure 6. Exposure of pregnant mice to CAPs during different pregnancy periods results in alterations in CRL and AGD in male offspring on PND10 and PND21. CRLs of male offspring were measured on PND10 and PND21 (A, B), and AGDs were measured at these same time points (C, D). The results from analysis of variance (ANOVA) showed significant differences (p<0.05) among the groups for each end point; ANOVA was followed by Fisher’s Least Significant Difference (LSD) post hoc testing to determine specific differences among the groups. Data presented are the means±standard error (SE) from n=8−11 dams for each CAPs exposure period and n=26 dams for the pooled FA controls. Bars with different letters are significantly different from one another (p<0.05). Note: AGD, anogenital distance; CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); CRL, crown-to-rump length; FA, filtered air; PND, postnatal day.

Compared with the FA-exposed controls, offspring from mothers exposed to CAPs during early and mid-pregnancy (i.e., periods 1 and 2) had significantly (p=0.0088) shorter AGDs (10.8%) at PND10. The reduction in AGD for male offspring born to dams exposed to CAPs throughout pregnancy (period 4) was slightly less dramatic (8.8%), although the reduction remained significant (Figure 6C). The CAPs-induced reduction in AGD observed in male offspring at PND10 persisted (p=0.0063) until PND21, but only for those offspring whose mothers were exposed either before implantation or throughout gestation (periods 1 and 4), in which case AGDs were reduced by 5.4% and 4.3%, respectively (Figure 6D).

Similar to that observed for male offspring, maternal CAPs exposure caused significant (p=0.0403) decreases in female CRL. Exposure during period 1 decreased CRL in female offspring on PND10 by 2.4% (Figure 7A). However, by weaning on PND21, female CRL was indistinguishable (p=0.2519) from that of their sex-matched control offspring (Figure 7B). The differences in anogenital distance in female offspring in response to maternal CAPs exposure were more dramatic than those observed in their age-matched male counterparts because AGD was significantly (p=0.0001) reduced by exposure during all exposure periods (Figure 7C). However, AGDs reached control values by PND21, but only in female offspring exposed to CAPs during mid- and late pregnancy (periods 2 and 3); CAPs-induced changes in AGD in offspring exposed during early pregnancy (period 1) and throughout gestation (period 4) persisted (p=0.0490) over time (Figure 7D).

Bar graphs A and B with confidence intervals plotting body length in millimeters ranging from 36 to 44 (in 7A) and from 46 to 58 (in 7B), respectively, (y-axis) across exposure to filtered air and four gestational exposure periods (x-axis). Bar graphs C and D with confidence intervals plotting anogenital distance in millimeters ranging from 1 to 4 (in 7C) and 7.5 to 10 (in 7D) (y-axis) across exposure to filtered air and four gestational exposure periods (x-axis).
Figure 7. Exposure of pregnant mice to CAPs during different pregnancy periods results in alterations in CRL and AGD in female offspring on PND10 and PND21. CRLs of female offspring were measured on PND10 and PND21 (A, B), and AGDs were measured at these same time points (C, D). The results from analysis of variance (ANOVA) showed significant differences (p<0.05) among the groups for each endpoint; ANOVA was followed by Fisher’s Least Significant Difference (LSD) post hoc testing to determine specific differences among the groups. Data presented are the means±standard error (SE) from n=8−11 dams for each CAPs exposure period and n=26 dams for the pooled FA controls. Bars with different letters are significantly different from one another (p<0.05). Note: AGD, anogenital distance; CAPs, concentrated ambient PM2.5 (fine-sized particulate matter); CRL, crown-to-rump length; FA, filtered air; PND, postnatal day.

Discussion

There were two main goals of these studies: a) Provide experimental evidence to support the human epidemiologic literature linking both PTB and LBW to inhalation exposure of PM2.5 during pregnancy at concentrations relevant to many urban centers; b) determine whether CAPs-induced PTB, LBW, or both were linked to exposure during a specific gestational period. The 24-h National Ambient Air Quality Standard (NAAQS) for PM2.5 concentration established in 2012 by the U.S. Environmental Protection Agency (EPA) is 35 μg PM2.5/m3 (U.S. EPA 2012, 2013). Although the time-weighted average (TWA) CAPs concentrations used in some of these experiments exceeded the U.S. EPA standard (the concentration in experiment 1 was 41 μg/m3 and that in experiment 3 ranged from 42.8–48.2 μg/m3 over the designated periods), the CAPs levels are nevertheless relevant to many U.S. and global cities that often exceed the NAAQS. In 2006, >200 U.S. counties were surveyed, and of these, 53 had 24-h PM2.5 levels that exceeded the standard (Yip et al. 2011). Many cities throughout the world also have documented levels of PM2.5 far exceeding the U.S EPA standard. For example, the daily average PM2.5 concentration for Beijing, China in 2013 was 90 μg PM2.5/m3 (Huang et al. 2014), and >10 other Chinese cities registered even higher concentrations.

In addition to respiratory and cardiovascular health concerns associated with exposure to elevated PM2.5 levels, epidemiologic data demonstrate an association between exposure to ambient PM2.5 and obstetric consequences including PTB and LBW (Lewandowski et al. 2013; Li et al. 2014). Given the numbers of women of reproductive age worldwide who are exposed daily to elevated PM2.5 levels, studies such as these are critical for informing health policy and for better understanding the mechanisms behind these comorbidities.

The gestational time frames selected for PM2.5 exposures in these studies were based on recommendations by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) testing guidelines (http://www.ich.org) for predicting reproductive/developmental toxicity in animals. These same time points are highly translatable to humans and represent times during human pregnancy when the developing offspring is most vulnerable to toxic insult (Figure 8). Each specific gestational period of mouse development/growth selected for study represents a critical time period during pregnancy, including a) fertilization and implantation (period 1); b) placental development/vascularization/nutrient transport and embryonic organogenesis (period 2); and (c) placental maturation and rapid fetal growth (period 3). A fourth gestational exposure period that covered all three of the abovementioned periods was also included in experiment 3. In the studies here, period 1 (i.e., GD0.5–GD5.5) corresponds to GD0–GD7–12 in humans, which is the time period during which preimplantation events occur. Period 2 in the mouse (GD6.5–GD14.5) encompasses postimplantation events, including formation and maturation of the placenta and the completion of organogenesis, that occur in humans through the 12th–14th week of gestation, defining the first trimester. The second and third trimesters of human pregnancy align with period 3 (GD14.5 to parturition range) in mice as rapid fetal growth occurs, and the lungs become fully functional.

Tabular representation of mice gestational days, events, and human gestational days for the first, second, and third trimester.
Figure 8. Alignment of mouse reproductive timeline to that of humans from the beginning of pregnancy through parturition. This table is based on Theiller stages of mouse development (Theiler 1989) and Carnegie stages of human development (O’Rahilly and Müller 2010).

Normal gestation in humans is 38–40 wk, and birth is considered preterm if it occurs before 37 wk. For the particular mouse strain used here, normal term is approximately 19–19.5 days. Shortening the mouse gestational term by 0.5 d, as seen following maternal exposure to PM2.5 during the entire gestational period, corresponds to an approximately 1-wk decrease in humans, thus placing them into the preterm category.

The magnitude of decreases in pregnancy duration and birth weight observed in the summer exposures (experiments 1 and 3) compared with that observed in the winter exposure (experiment 2) suggests that particle concentration and relative compositions are important. In this study, the metal composition (both absolute and relative) and the particle mass differed depending on the season in which the mice were exposed. Schwab et al. (2004) reported that PM2.5 concentrations from various regions in the state of New York vary throughout the year. Early studies by Thurston et al. (1994) also reported that metal components of PM2.5 can show seasonal fluctuations between winter and summer.

Many of the PM2.5-associated metals identified in the present study have been implicated as risk factors for LBW in the northeastern and mid-Atlantic regions of the United States. Positive associations have been shown with each interquartile increase of Al, Ca, Ni, Ti, and Zn, with risk ratios ranging from 3.0 for Ca {46 ng/m3 [95% confidence interval (CI): 1.36–4.3]} to 5.7 for nickel (Ni) [6 μg/m3 (95% CI 2.7–8.8)] (Ebisu and Bell 2012). In full-term infants, LBW was associated with maternal exposure to PM2.5 with the following average levels of metallic components: vanadium (V) (4.3 ng/m3), S (0.83 μg/m3), Fe (0.16 μg/m3), Ti (10 ng/m3), manganese (Mn) (3.3 ng/m3), Br (4.4 ng/m3), Zn (15 ng/m3), and Cu (9 ng/m3) (Basu et al. 2014). In our toxicological study, the aforementioned metal concentrations associated with epidemiological studies were exceeded in all experiments (with the exception of V in experiment 2), suggesting that PM-associated metals could be playing a role in the observed toxicity. However, further research is necessary to better understand the role of PM-associated metals in causing LBW in the present scenario.

In this study, PTB was associated not only with CAPs exposure throughout pregnancy but also with exposure during particular gestational periods. When CAPs exposure occurred only prior to blastocyst implantation, no effects were observed on gestational duration compared with the control. This result supports epidemiologic findings suggesting that PM2.5-induced PTB is associated with exposure occurring later in pregnancy (i.e., during the second or third trimester) (Ha et al. 2014). However, these findings are in contrast to those of Symanski et al. (2014) who demonstrated that exposure to a 10 μg/m3 increase in PM2.5 concentration during the first 4 wk of pregnancy, the time of human blastocyst implantation, was associated with a 73% increased risk for PTB. A study by Rapazzo et al. (2014) revealed that risk for PTB was most closely associated with exposure to PM2.5 during the fourth week of gestation (i.e., just after implantation, corresponding to the early part of period 2 in the present study); exposure to PM2.5 during the week of birth and during the last two weeks before birth in that study also resulted in early delivery. The authors concluded that exposures to PM2.5 around the time of implantation or near birth were the highest risk for PTB.

In the present study, maternal exposure to PM2.5 during any gestational period other than the fetal growth phase (period 3) resulted in LBW. Harris et al. (2014) correlated PM2.5 concentrations with LBW and found that U.S. states with the highest PM2.5 concentrations such as New York (average PM2.5 concentration of 13 μg/m3) also had the highest rates of LBW (2.6%). In contrast, Utah and Minnesota (average PM2.5 concentration of 9 μg PM2.5/m3) had the lowest rates of LBW (2.1% and 1.9%, respectively). The same study also showed that in New York State, LBW was linked to PM2.5 exposure levels during each of the three trimesters as well as to full-term exposure. For all states examined, the highest risk for LBW was associated with exposure during the first trimester [odds ratio (OR)=1.018 (95% CI 1.013, 1.022)] and full-term exposure [OR=1.030 (95% CI 1.022, 1.037)], with exposure during the second and third trimesters resulting in a lower risk. Our experimental animal data support the human epidemiologic studies demonstrating that maternal exposure to high PM2.5 levels between implantation and the end of the second trimester in humans is the most sensitive time frame for suppressing birth weight.

Following implantation, placentation is the next major milestone during fetal development. In the present study, placental weight was decreased significantly with maternal exposure to PM2.5 during the gestational window of rapid fetal growth (i.e., period 3). In contrast, exposure to PM2.5 throughout gestation increased placental weight compared with FA controls. To our knowledge, these findings are the first to demonstrate that PM2.5-induced changes in placental weight are based upon the timing of exposure in an animal model. In a study by Veras et al. (2008), whole-body exposure of mice to PM2.5 (24-h average level of 27.5 μg/m3) from traffic in São Paulo, Brazil, before breeding (exposed 24 h/d from 20 d of age to 6 wk of age) or during pregnancy alone decreased fetal weight (∼23%) on GD18. In that study, decreased fetal weight was associated with reduced vasculature volumes, luminal diameters, and surface areas of the blood spaces on the maternal face of the placenta. The authors suggested that exposure to traffic-related PM2.5, either before conception or immediately after breeding, caused restrictions in maternal blood circulation through the placenta, which led to reduced birth weights. Increased fetal capillary surface area observed in that study was considered by the authors to be a result of the release of fetal “factors” that enhanced blood circulation through the placenta or enlargement of the surface areas available for nutrient exchange, or a combination of the two, to compensate for maternal vasoconstriction that may have resulted from PM2.5-induced inflammation (de Melo et al. 2015). Because the mouse placenta continues to grow throughout fetal development, mechanisms similar to those described above may have been responsible for the placental changes observed in our study. It is possible that maternal blood circulation to the placenta experienced greater restriction in mice that began their exposure in period 3 owing to increased amounts of maternal systemic inflammatory mediators.

In contrast to our observations from period 3, placentas from dams exposed to PM2.5 throughout pregnancy (i.e., period 4) were heavier than those recovered from their FA control counterparts on GD17.5. As suggested by Veras et al. (2008), increased placental weight could have resulted from signals received from the fetus leading to an increased size of the nutrient exchange domains and an increased perfusion rate from the dam’s circulation as a mechanism to prevent intrauterine growth restriction.

Alternatively, many PM2.5 components contribute to oxidative stress that may have an impact on the function of the placenta. A recent study by Saenen et al. (2016) showed that exposure to a 7.5 μg/m3 increase in PM2.5 concentration during the second trimester in human pregnancies was associated with a 1.4% decrease in placental leptin gene methylation. Decreased methylation generally results in increased transcription of the methylated gene. Because leptin is a hormone involved in the proliferation and survival of placental trophoblast cells (Maymó et al. 2011), it may play a role in the alterations in placental weight observed in periods 3 and 4 (GD14.5–16.5 and GD0.5–16.5, respectively) in the present study. Additional studies are required to determine the potential role of leptin in this model.

Given that maternal exposure to PM2.5 resulted in both PTB and LBW in this study, the observed subsequent lack of effects on postnatal growth rate was surprising. Human studies have shown that small-for-gestational-age size at birth is associated with increased risk of cardiovascular disease and type 2 diabetes in adulthood (Barker et al. 1989; Barker et al. 1990; Barker et al. 1993a, b; Phipps et al. 1993). In utero exposure to PM2.5, which has independently been shown to predispose children to these same later-life outcomes (Johnson and Breslau 2000; Lewandowski et al. 2013; Li et al. 2014), could, in combination with small-for-gestational-age size, pose a synergistic increase in risk for these same obstetric consequences. A recent study by Janssen et al. (2016) showed a link between human exposure to an 8.2 μg/m3 increase in PM2.5 exposure levels in the third trimester and decreased thyroid stimulating hormone (TSH) levels and free thyroxine to triiodothyronine ratio (T4/T3) in cord blood. The decrease in free T4 in cord blood was linked to a 56-g decrease in average birth weight. This finding differs from those in the present study, where exposure that occurred before the equivalent of the third trimester was associated with LBW. However, GD17.5 fetuses from dams exposed either throughout gestation or only during the third trimester analog were significantly lighter. Additional studies are warranted to determine the possible role for thyroid hormones in LBW due to PM2.5 exposure.

In the present study, AGD in male offspring was reduced on PND10 and PND21 following maternal exposure to PM2.5 throughout and early during gestation. In males, AGD is an indirect measure of total androgen exposure (both endogenous and exogenous) during fetal development; typically, the greater the exposure in utero to androgens, the greater the AGD (McIntyre et al. 2001). Shortening of the AGD, as was observed in this study following exposure during specific periods of development, has been used as an indicator of developmental exposure to antiandrogens such as phthalates (Foster 2006; Gray et al. 2006; Swan 2008). In humans, a shorter AGD in males has been linked to reductions in semen quality as defined by alterations in sperm morphology, motility, and total sperm per ejaculate (Mendiola et al. 2011; Swan et al. 2005). Interestingly, it has been observed in this laboratory (J.L.B. et al. 2013, unpublished work) that sperm numbers/motility were decreased in adult offspring in response to CAPs exposure throughout gestation at similar inhaled concentrations.

Increased AGD in females is also regulated by the secretion of androgens in utero (Wolf et al. 2002). In the present study, maternal exposure to CAPs early in and throughout pregnancy resulted in decreased AGD in females on PND10 that persisted through PND21. Although the underlying mechanism (or mechanisms) for such a finding is as yet unknown, AGD has been positively associated with the number of recruited ovarian follicles in women (Mendiola et al. 2012). In rat litters, female siblings with longer AGDs had greater pituitary responsiveness to gonadotropin releasing hormone than their sisters with shorter AGDs (Faber et al. 1993). The results from those studies suggest that changes associated with altered AGD in females brought about by in utero exposure to PM2.5 may result in reduced fertility in the female offspring.

The present study has several limitations. In our study, the mice were exposed to higher PM2.5 concentrations than would ordinarily be observed in human epidemiology studies, and it is not clear if the effects seen with short-term high-concentration exposures emulate those seen in constant, long-term exposures that could be experienced under conditions of pregnancy. However, when concentration is calculated based on the breathing rates of both species, the dose to the lung was only ∼5 times greater in the mouse than in pregnant women. Additionally, PM2.5 composition has been shown to vary from place to place with possible temporal variations within a single location. This study attempted to account for seasonal variation by performing experiments only in the summer and winter and to limit temporal effects by exposing the mice during all exposure periods at the same time so there would not be a bias in the event of a particularly high ambient air pollution day. Thus, although the confines of the study are recognized, the results of this animal study represent an important step forward in understanding the effects of maternal exposure to particulate air pollution across the gestational time span.

Conclusions

The study described herein presents biological feasibility for the epidemiologic studies demonstrating the adverse effects of inhaled particulate matter from air pollution on pregnancy-related outcomes. Moreover, these studies demonstrate the usefulness of a pregnant mouse model for studying the developmental consequences of exposure to PM2.5. Such a model eliminates many confounding variables that often cloud human studies; it also provides the opportunity to confine exposures to a particular gestational time period, making data interpretation easier. The results of this study also contribute to a better understanding of how and to what extent exposure periods play a role in predicting gestational outcomes.

Based on the findings here, exposure to PM2.5 before implantation is not related to PTB, whereas maternal exposure postimplantation appears to pose a credible risk. In contrast, LBW appears to be linked with PM2.5 exposure that occurs any time before the completion of embryogenesis. These animal studies suggest that exposure to high levels of inhaled PM2.5 during pregnancy poses a risk for obstetric consequences during most gestational periods. Although it is difficult to avoid exposure to air pollution during pregnancy, certain interventions including the use of home air filters and air conditioners could help mitigate the risk for adverse pregnancy outcomes.

Acknowledgments

The authors wish to acknowledge the contributions of C. Hoffman-Budde for assistance with the animal exposures and necropsies and M. Zhong for assistance with the X-ray fluorescence spectroscopy (XRF) analysis. Funding was provided by the March of Dimes (21-F12-13) and the New York University National Institutes of Health/National Institute of Environmental Health Sciences (NYU NIEHS) Center (ES000260).

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Department Press Briefings : Department Press Briefing – July 27, 2017

Heather Nauert

Spokesperson

Department Press Briefing

Washington, DC

July 27, 2017


Index for Today’s Briefing

  • DEPARTMENT
  • REPUBLIC OF KOREA
  • ISRAEL/PALESTINIANS
  • DPRK
  • JAPAN
  • CHINA
  • REPUBLIC OF KOREA / DPRK
  • YEMEN
  • IRAN
  • QATAR
  • DEPARTMENT
  • DPRK
  • AFGHANISTAN
  • TURKEY
  • SYRIA
  • MEXICO
  • VENEZUELA

    TRANSCRIPT:


    2:51 p.m. EDT

    MS NAUERT: Hi. Hi, everybody. How are you?

    QUESTION: In a supposedly good mood —

    MS NAUERT: You may be wondering why you all have cookies today. And I can assure you if I were trying to bribe a bunch of journalists, I would bring booze and cigarettes. (Laughter.)

    QUESTION: Money. Money is fine.

    MS NAUERT: Or money. You all probably make enough money, though. So today is – for historians in the room, anyone know what today is?

    QUESTION: (Off-mike.)

    QUESTION: (Off-mike.)

    QUESTION: (Off-mike.)

    MS NAUERT: It’s the State Department’s 228th birthday. So Happy Birthday, State Department. And that’s where I’m going to begin today, with a little history lesson.

    In 1789, the first Congress established the Department of Foreign Affairs on this day. It succeeded the department that had existed under the Articles of Confederation. The name of the department was changed to the Department of State in September of that year, in recognition of the domestic duties assigned to the department which have been reallocated over the succeeding years. Our mission is to shape and sustain a peaceful, prosperous, just, and democratic world, and foster conditions for stability and progress for the benefit of the American people and people everywhere.

    Two hundred and twenty-eight years the department remains strong and relevant and dedicated to U.S. national security, economic prosperity, and the safety and security of our citizens as it has ever been.

    Earlier this year, the Secretary asked all employees of the department to share their opinions of the department and its activities with him. The report compiled from the listening tour survey showed that the department employees – more than 36,000 of them who responded – view their work as a calling, a duty, and an obligation to represent what is best about America to the world. Department employees experience their work with great pride, with honor, and a calling on behalf of our country.

    I can tell you that that has been my experience as I’ve gotten to know my colleagues from every part of the building and the world over the last few months. I’m personally honored and humbled to have the opportunity to join them here every day and speak on their behalf at this podium.

    So Happy 228th Birthday to the Department of State, and I hope you like the cookies.

    Okay, now a little bit of news for you. The Secretary spoke with the foreign minister of the Republic of Korea, Foreign Minister Kang, earlier today to reaffirm the strength of the U.S. and ROK alliance. The Secretary told Foreign Minister Kang that the United States remains firmly and fully committed to the defense of the ROK and other allies in the region. The leaders agreed to continue our close coordination in response to North Korea’s destabilizing violations of UN Security Council resolutions and hold North Korea accountable for its unlawful actions. The two pledged to work closely together to strengthen U.S.-ROK cooperation, and they reaffirmed our joint commitment to a stable, peaceful, and denuclearized Korean Peninsula.

    And with that, I’ll take your questions.

    QUESTION: Thanks, Heather.

    MS NAUERT: Hey, Josh.

    QUESTION: Why don’t we start with the developments over the last 24 hours or so in Jerusalem —

    MS NAUERT: Okay.

    QUESTION: — with the Temple Mount. I wanted to get your take on the latest outbreak of violence and what you think might be behind that. And also, specifically on this decision to remove the cameras that had been put up, does the U.S. support that decision to take down those cameras as the Muslim worshipers had wanted?

    MS NAUERT: Yeah. Well, let me start out by mentioning to you that our special presidential envoy, Jason Greenblatt, still remains in the region. He is there today as he continues to conduct meetings with people from both sides on this issue. We continue to monitor that situation very closely. I’m going to again be cautious in what I say. Our firm position is that we don’t want to do or say anything that would escalate tensions in the region. We all know that it’s a fragile part of the world, and we want to be very careful and cautious about that.

    Israel’s security is our top priority – among our top priorities. We would never pressure Israel, to get to your question, into making a security decision for political purposes. So the Trump administration has been and will remain engaged in that situation as Mr. Greenblatt, Mr. Kushner, backed by our State Department folks, will remain involved. And we also recognize that it’s going to take some space and some time to get this to a better place.

    QUESTION: So are you saying that they did make that decision for political purposes?

    MS NAUERT: No, did not. We would not – we would not do that for – we would not get involved in a decision like that. It’s their decision. We recognize that the sides have to be willing to work together on this.

    QUESTION: So how is that working out for you? I mean, for the last few weeks or so, the U.S. has really been trying to keep some distance from the situation, and it doesn’t seem like us giving them room to do that is leading to this resolving in any more effective of a way. Is there any consideration about the U.S. trying to —

    MS NAUERT: I think we have all seen in this part of the world that there have been ebbs and flows, developments where there has been more tension and where there have been periods of less tension. So we’re taking the long view on this and recognizing that it’s going to take some time for both sides to be able to work together to start to rebuild trust in perhaps a smaller fashion, and then try to build upon that. And that’s what Mr. Greenblatt is there for, so that he could help facilitate that.

    Okay?

    QUESTION: Can I follow up on that?

    MS NAUERT: Certainly. Go right ahead.

    QUESTION: Okay. But you do adhere to your own principle that the status quo must be maintained. So you will push for that, without – without applying any political pressure.

    MS NAUERT: We have not —

    QUESTION: What position is that, the status quo must remain the same?

    MS NAUERT: We have not changed our position on that.

    QUESTION: Right.

    MS NAUERT: And that the status quo must be maintained.

    QUESTION: Now, a quick follow-up also on Mr. Greenblatt’s meeting. Now, today it is – the Israeli press is saying – or the 10th Channel on Israeli television – saying that Mr. Netanyahu informed Mr. Greenblatt that they want to keep all the settlements on the West Bank in exchange for the Wadi Ara. I don’t know if you know the area, but in exchange for Wadi Ara. Is that something that you can confirm or refute or deny?

    MS NAUERT: I cannot. I have not spoken to Mr. Greenblatt. Again, he’s in the region. If I have anything for you from those meetings, I’ll certainly bring it to you if I can.

    QUESTION: So your position remains on the settlements that these settlements are illegal and they should be taken down?

    MS NAUERT: I think I’ve been clear about our position on settlements and the administration’s position on the settlements, so I don’t want to get into that all over again, okay? Okay.

    QUESTION: Can you comment on the —

    MS NAUERT: Hi, how are you?

    QUESTION: Hi.

    MS NAUERT: Yeah, good to see you.

    QUESTION: Fine, thanks. So to go back to the – to Aqsa Mosque, is the mediation to de-escalate limited between you as the State Department and the Israelis and the Palestinians, or is it expanding to other Arab countries like Jordan, for example, or Saudi Arabia? Has it been in contact with you trying to de-escalate the situation?

    MS NAUERT: So I know that other nations have been in contact with us. I know we’ve spoken to some other countries. In terms of the specifics of those countries and the exact words that were exchanged in those calls and meetings, I can’t get into those specifically. But I know there have been a lot of countries that have expressed their concern, and we’ve expressed our concern as well.

    QUESTION: Were there any specific demands, especially to remove these gates from the —

    MS NAUERT: I just can’t get into that right now. Okay? Thank you.

    Hey, Oren.

    QUESTION: Can you comment on the tactics that were employed by, I guess, the crowds in this particular incident? There have been a lot of – like hundreds of thousands of people have – hundreds and thousands of people have shown up to pray in the streets of the Old City of Jerusalem using basically nonviolent tactics, and it seems to me like this may have been the first. And is this the first time that those kinds of tactics were effective in changing an Israeli policy?

    MS NAUERT: I’m not sure about that. That’s a good question. I’m going to, again, be cautious about this against – cautious about weighing really in on too much on that matter. We want to keep things as calm as possible.

    QUESTION: Do you have a comment on the tactics in general, though?

    MS NAUERT: I do not, no. Anything else on Israel right now?

    QUESTION: But you’re not opposed to protesting and so on at —

    MS NAUERT: Sorry?

    QUESTION: You are not opposed to people protesting what they perceive to be a grievance, correct?

    MS NAUERT: In terms of —

    QUESTION: I mean, they have – people have a right to protest —

    MS NAUERT: We —

    QUESTION: — any kind of grievance that is perceived.

    MS NAUERT: As the American Government long recognizes the power of peaceful protest, and we would not back away from something like that. But again, I’m going to be cautious. Our priority is not escalating tensions. We want both sides to be able to work together, all parties to be able to work together on this and come to some sort of eventual agreement and some sort of peaceful situation.

    Anything else on Israel?

    QUESTION: Nothing.

    MS NAUERT: No?

    QUESTION: On North Korea?

    MS NAUERT: Okay, all right. Shall we go to North Korea? Okay. Hi, Janne.

    QUESTION: Thank you, Heather. North Korea threatened to destroy United States with merciless missile strikes this morning. The comment come after CIA Director Michael Pompeo said Kim Jong-un needs to be separated from his weapons. What is your comment?

    MS NAUERT: Well, that would combine two things that we wouldn’t comment on. And one would be threats, and the other would be potential intelligence. I’ll leave it at that. Okay?

    QUESTION: So how did you respond to his threatening with that weapons, like their new ICBM missile test?

    MS NAUERT: That’s an intelligence matter. If that were to be the case – and I’m just not going to get into that – but it’s, again, a hypothetical and a threat, and we just aren’t going to get into that.

    Okay? Anything else on North Korea?

    QUESTION: On North Korea.

    MS NAUERT: Okay. Hi.

    QUESTION: During – yes, thank you. So during the meeting this morning between Secretary Tillerson and his counterpart from Korea, was this addressed, the potential ICBM test, this afternoon? I mean it’s – the source – information saying that it could be done around 5:00 p.m., 6:00 p.m.

    MS NAUERT: Yeah. Again, that would be an – and I know you all have a lot of questions about this type of thing. That would be a matter for – two issues – one, intelligence; and then that would be considered just a private diplomatic conversation, and some of those I’m not going to comment on. Okay?

    QUESTION: Is it still the position —

    MS NAUERT: Hi, Carol.

    QUESTION: — at least of the – hi. Is it still the position of the State Department that the United States does not seek regime change in North Korea?

    MS NAUERT: The United States seeks – and this is the top thing that we look for there – a denuclearized Korean Peninsula. That is a priority that the United States shares not only with our regional partners such as the Republic of North – excuse me, the Republic of Korea in that phone call today, but also people from around the globe – other nations that understand the importance of trying to denuclearize the Korean Peninsula and get North Korea to a place where we could potentially have some kind of a better situation with them.

    QUESTION: What did he say about regime change?

    MS NAUERT: I’m not going to comment on that, okay?

    Hi.

    QUESTION: Has the geographical travel restriction gone to the Federal Register yet?

    MS NAUERT: So, yeah, I know a lot of people are very curious about that. And that’s something we’ve given our guidance to the – to prepare for the Federal Register. That then goes to OMB. It’s a legal process. It takes a little bit of time to get from here to there and get all the paperwork and everything in order. So I don't have an exact date for you as to when that will be delivered. I know a lot of people were expecting that soon – today, in fact, some were. But I don't know that that’s going to happen today, but it will happen soon.

    QUESTION: And can you give us any more details on the humanitarian or special purposes, other purposes, that Americans could use as a reason to travel there?

    MS NAUERT: I know we touched on that a little bit. Again, this is still new. Some of this stuff is still being worked out. People have the ability to apply for waivers to be able to travel to North Korea once this new system or the travel restriction is put in place. That will – journalists can apply, for example; certain people under humanitarian – on humanitarian grounds can apply as well. Again, we don’t encourage you to go to North Korea. That is the reason that we have this travel ban that is going into effect. But we also recognize that journalists need to get the ground and need to be able to report the facts on the ground. But we certainly caution you. It’s not considered a safe country to go to.

    Anything else on North Korea?

    QUESTION: Staying in the region?

    MS NAUERT: Yeah. Okay. Yeah, go ahead.

    QUESTION: So —

    MS NAUERT: Hi. How are you?

    QUESTION: There’s been media reports that State Department officials are removing the word “genocide” in documents —

    MS NAUERT: Let me get back to you on that. I mean, ask me that later. Let’s stick on North Korea for now, and I’ll get back —

    QUESTION: Okay.

    MS NAUERT: — I’ll call on you again for that.

    QUESTION: Okay.

    MS NAUERT: Okay. Go right ahead.

    QUESTION: Yeah. So Japanese Defense Minister Inada announced her resignation earlier. And there’s been a U.S.-Japan 2+2 dialogues that has been expected to take place this summer or fall, a major topic of which is supposed to be North Korea. Are you concerned that her resignation is going to impact the timing of the dialogue or more generally discussions over North Korea with Japan?

    MS NAUERT: Yeah. Regarding that, as you know, we have a close relationship with Japan and we have talked about having meetings. And I just don’t have any meetings or any travel to read out for you at this time. When I do, I will let you know though. But I can’t see that our relationship with Japan would change based on the political change there.

    Okay. Anything else on DPRK? Hi. How are you? Good to see you.

    QUESTION: So on Tuesday, Assistant Secretary Susan Thornton said the secondary sanction on Chinese company will be coming very soon. Are you still talking to China so they can avoid this announcement coming? Or are you going to announce anyway?

    MS NAUERT: So we regularly have conversations with the Chinese and other countries about secondary sanctions. Susan has the ability to speak more to those things than I do. We don’t forecast sanctions, but we retain the right and the ability to impose sanctions, whether it’s secondary sanctions or primary sanctions. Okay?

    QUESTION: Thank you.

    MS NAUERT: Okay. Anything else on DPRK?

    QUESTION: Just quickly out of curiosity —

    MS NAUERT: Yeah.

    QUESTION: — did they talk about the possibility of talks between North and South Korea on the call today? And if so, can you give a sense of what input the Secretary gave?

    MS NAUERT: So in terms of the call today, what I provided you as the readout is what I can give you right now. My understanding is that when the Republic of North Korea[1] said that it would be potentially willing to meet with the DPRK, my understanding is that the DPRK has not gotten back to South Korea at this point. But that question would have to be answered between those two nations.

    QUESTION: Just a quick clarification on what you said.

    MS NAUERT: Hi.

    QUESTION: You don’t forecast sanctions. Does that mean you don’t expect them or that you don’t expect them to be implemented?

    MS NAUERT: Good – we don’t look ahead and predict sanctions, and we usually don’t talk about sanctions, if it’s something on the horizon or if it’s not something on the horizon. That’s what I mean.

    QUESTION: So you just don’t talk about them?

    MS NAUERT: That’s what I mean by that. Yeah.

    QUESTION: Can we go to Yemen?

    MS NAUERT: Okay. Yeah. Sure.

    QUESTION: Okay. There are some reports that Yemen is facing problems, the worst humanitarian disaster right at the present time, and it seems to be completely off your radar screen. What is your position on Yemen? What should be done? What are you doing in terms to end the violence in Yemen?

    MS NAUERT: So, Said, you know that we have talked about Yemen. We’ve talked about food insecurity in African nations here in this briefing room and elsewhere. That is something that is a top priority for USAID. I’ve recently talked about the amount of money that the United States and its taxpayers have provided in humanitarian assistance to Yemen. So I would disagree with your characterization that it is off our radar. If more of you want to ask me about Yemen or any of the other countries affected by food insecurity, I’d be more than happy to answer those questions. I’m glad that you brought it to our attention today. So again, it is not off our radar, as you well know.

    Since you asked, let me just give you a little bit of updated information on that matter. Yemen is facing the world’s largest cholera outbreak at this time. The recent resurgence of disease has now resulted in nearly 1,900 deaths since April 27th of this year alone – 409,000 suspected cases of cholera. The UN estimates that more than 75 percent of Yemen’s entire population is in need of aid. Children are also falling victim to the cholera. The rates of malnutrition in children under five are rising throughout that country; 1.8 million children are now experiencing acute malnutrition, 400,000 experience severe, acute malnutrition. That’s according to UNICEF.

    The United States so far has provided more than $467 million to date this fiscal year to alleviate the humanitarian crisis in Yemen and in the region. And if we have any updates on those numbers – I believe those numbers are the most up to date, but if any of our USAID folks write in and say that they have a more recent update, please do let me know during the briefing.

    QUESTION: Are there any diplomatic efforts by the State Department, by Secretary Tillerson himself, to see that somehow the situation ends up – it’s not a political solution?

    MS NAUERT: So Said, what I can tell you – without getting too much into some of the diplomatic conversations, I can say that I’ve been in the room with the Secretary when he’s spoken with other foreign ministers about the importance of that issue there. It’s something that he consistently raises with other foreign ministers around the world. Among the issues there – not just cholera, but also food insecurity. And part of the problem with that is not for any weather-related reason, but rather the military situation, the fighting on the ground there. And being able to get food and aid in and out of the port there has been a major issue. That’s something that the Secretary has talked about a lot.

    Anything else related to Yemen?

    QUESTION: Go to Iran?

    MS NAUERT: Iran. We can go to Iran.

    QUESTION: So the Iranians say they launched a satellite into space on a rocket. Does the U.S. consider that long-range rocket to be essentially an ICBM that would violate UN resolutions prohibiting such activity by the Iranians?

    MS NAUERT: So we would consider that a violation of UNSCR 2231. We would consider it that. We saw the reports that Iran launched a rocket into space early this morning Eastern Time. So we’re looking into the nature of those reports; some of the specifics I’m not going to be able to confirm or address with you here today. Perhaps in the future, but as of right now, this is still considered sort of a developing situation, but we consider that a violation of a UN Security Council resolution.

    QUESTION: So it’s just about (inaudible)? So you consider what took place this morning a violation of that resolution, or if it turns out that it is what it’s purported to be, then it would be a violation?

    MS NAUERT: Yeah. Good point. We consider that to be continued ballistic missile development. We’re – also remain very concerned about Iran’s support for terrorism. We consider this to be a provocative action, and a provocative action that undermines the security, the prosperity of those in the region and around the world as well.

    QUESTION: Thanks.

    MS NAUERT: Okay.

    QUESTION: On Russia?

    MS NAUERT: Okay. Iran?

    QUESTION: Just real quick on Iran. Is the administration entering a new phase on the JCPOA where it’s asking for stricter enforcement of the JCPOA? And in the larger context of the Iran review, is the administration taking action on – even though the review’s not completed yet, is the administration moving in a different direction than, let’s say, the previous administration?

    MS NAUERT: So I’m not going to get ahead of the President and the overall review of that, so I’m going to be careful on that matter. Again, we believe that what happened overnight and in the early morning hours here in Washington is inconsistent with the Security Council resolutions.

    You mentioned the JCPOA. Even though the JCPOA was put together to address nuclear issues, not necessarily ballistic missiles, we believe that what happened overnight and into the morning is in violation of the spirit of the JCPOA. So that hasn’t changed.

    QUESTION: But separately – separately from the launch, just in general with the JCPOA, is the U.S. looking for stronger enforcement of – within the current framework?

    MS NAUERT: We have a lot of respect and regard for the IAEA, and the IAEA has done a terrific job of working toward inspections. And we value what they have done in that fashion. So we respect what they have; I’m just not going to forecast where we’re going from there. Okay.

    QUESTION: No, but the suggestion from the White House is that more inspections are needed, so beyond, I guess, what is the amount of inspections that are taking place now.

    MS NAUERT: Yeah. On that matter, I would just refer you to the White House on that. Okay? Anything else on Iran? Okay. Let’s —

    QUESTION: Can I ask about Qatar?

    MS NAUERT: Sure.

    QUESTION: Yesterday the Secretary met with the foreign minister of Qatar, and was not much in the statement that we saw.

    MS NAUERT: Yeah.

    QUESTION: Are we – is this any development in terms of mediation of ending this crisis? Is there any point of view that the Qataris has brought to you? And is any new contact with the other four countries?

    MS NAUERT: Let me just mention, sometimes when we provide information on the meetings, there isn’t always a ton of detail in that, and that’s largely because these are private conversations and we don’t want to – we just don’t want to provide too much because they’re private, sensitive diplomatic conversations.

    The Secretary met with the foreign minister yesterday. They talked a lot about the situation as it unfolds there. We believe now that the dispute is at a standstill. We’ve gone between periods where we have said that it is at an impasse at one point and then there was some movement; well, now it appears to be at a standstill. So that naturally concerns us. We are urging direct talks between all of the parties because we believe that in order for the situation to be resolved – and it does need to be resolved – but they have to sit down together and have some direct dialogue about it. We are willing to help as they have called upon us for our advice and counsel. We support the emir of Kuwait and his efforts at a mediation and resolution. We’re thankful to him for doing that and taking that on, and we’re just hoping that those countries will get together and start having conversations.

    QUESTION: So in other words, are you frustrated by the lack of progress?

    MS NAUERT: I wouldn’t use the word “frustrated.” We would like to see this come to a resolution. We believe that all of these nations working together are going to be a lot more effective at what is one of our top priorities, and that is defeating terrorism and defeating ISIS. So we hope that they’ll come together and work this out. It may take some time. We’re hopeful that they’ll eventually be able to get it done.

    QUESTION: Heather?

    QUESTION: Is there a difference between a standstill and an impasse?

    MS NAUERT: Well – (laughter) – a standstill and an impasse. I don’t know. Let’s look that up and see if the definition is actually different.

    QUESTION: I guess what I’m saying is do you see this as at more of an intractable place than you did a few weeks ago when you said it was at an impasse.

    MS NAUERT: I think a few weeks ago it was so incredibly tense – not to say that it is not tense right now, but I think the parties are getting – and we’re hoping – getting closer to working together on this. We asked them to do it. We hope that they will do it. A few weeks ago we didn’t have Kuwait involved in the mediation efforts. This is a – not a new development, but they’ve taken a strong role. The Secretary did his trips over there in his – the shuttle, which many of you were along for as well, so we’re hoping that they will get to a point of resolution on that.

    QUESTION: Is the U.S. ready to play any role in those direct talks, Heather, like —

    MS NAUERT: I haven’t asked the Secretary about that. I know that we have said to the parties we’re willing to help out in pretty much whatever way they might need, but it has to work for them, and the ultimate resolution has to be able to work for all of those parties.

    Okay, anything else on Qatar?

    QUESTION: Yeah, yeah, one more, please.

    MS NAUERT: Yes, hi.

    QUESTION: Do you urge – I mean, you urging both parties to have a private conversation, but based on what? Did you propose any framework for the – based on what?

    MS NAUERT: There have been different ideas proposed, and I’m not going to outline what exactly those are.

    QUESTION: Yesterday?

    MS NAUERT: No, no, no, no. I’m not saying that at all. In – since this first started six weeks ago or so, there have been different proposals that have gone back and forth. Where that exactly stands now, I’m just not going to characterize that.

    Okay, anything else on Qatar?

    QUESTION: Russia and Ukraine?

    QUESTION: Turkey?

    MS NAUERT: Okay. Okay. Okay, go right ahead to your question, ma’am.

    QUESTION: Someone —

    MS NAUERT: I’m sorry, your name is?

    QUESTION: I’m Penny Starr.

    MS NAUERT: Hi Penny, how are you?

    QUESTION: Hi, nice to meet you.

    MS NAUERT: And you’re from?

    QUESTION: Breitbart.

    MS NAUERT: Breitbart. Welcome.

    QUESTION: Thanks. There’s been media reports that State Department officials are removing the word “genocide” from documents. There’s been – human rights activists have spoken out about it. Can you address that?

    MS NAUERT: Yeah. I can tell you I have seen an article that indicates that the United States has allegedly taken that word – the State Department, in fact, an article said, has taken that word “genocide” out of some documents, and I can tell you that that is categorically false. We have looked through documents ourselves. The word “genocide” is in fact in there. That has not been removed. When we look at Iraq and we look at what has happened to some of the Yezidis, some of the Christians, we – the Secretary believes and he firmly believes that that was genocide, okay, and I’m – that’s all I’m going to have to say about that, okay? I hope I’ve been clear.

    QUESTION: Okay, yeah. Thank you so much.

    MS NAUERT: Okay, thank you. Anything else on that matter? While we’re on it, anything else on Iraq?

    QUESTION: I have something kind of related.

    MS NAUERT: Okay, hi.

    QUESTION: This is a birthday question.

    MS NAUERT: How you doing? Oh, a birthday question, okay.

    QUESTION: Some former diplomats are expressing concern about the possible impact on morale of budget cuts and some offices, such as the global war crimes office, reportedly slated for closing. Could you comment on that and what is the status of that?

    MS NAUERT: So I do have some information for you on that, so let me go to this, okay? A lot of people have asked about what is going to happen with our reorganization. As you all know, that is still under review right now. It’s something that when our note went out to our employees – 75,000 or so employees – I think it’s 40-some percent participated in this, which is a really good figure for people to have participated. And you all work in the private sector; I’ve worked in the private sector. I have never once been asked to fill out a survey at any job that I have had where my company has asked how do you feel about this, how do you feel about your position, where do you think we could cut the fat. And so what the State Department did is really incredible. I mean, you’ve never heard of a government agency, I’m willing to bet, that has actually asked its employees how it feels about their mission, how it feels about their job, and where there might be waste, or where there might be positive areas. So first, I want to start out by saying this is a really incredible feat that we undertook and that our employees were involved with.

    You ask about the Global Criminal Justice Office, and that office will remain – the functions of that office will remain here at the State Department. They continue to operate and handle issues related to war crimes, crimes against humanity, and as you brought up, Penny, genocide as well. So that function is not going away. I have a little more information for you on that if you’d like me to give it to you. We have a special coordinator, Todd Buchwald. His detail to the Global Criminal Justice one will soon come to an end, but it doesn’t mean that that won’t – that function won’t be carried on by somebody else. It will. The Department remains committed to working closely with other governments, international institutions, and nongovernmental organizations, including domestic and criminal prosecutions, on all of that. So it’s important to us. That is not going to change. Okay?

    QUESTION: So his position will stay?

    MS NAUERT: My understanding is that he will – he will no longer be a part of that, but the position will remain. Now, whether – and we talked about this the other day – whether the office remains or not – and guys, step in if I’m misspeaking or anything – but whether the actual office – I think that is all still under review, as are many of our envoys in some of those special offices. But those functions will still remain here at the State Department. That will not change.

    QUESTION: But he – so when you said the envoys are under review, that – his envoy-ship would also be under review or could it be divided up into other areas? That’s what I’m asking.

    MS NAUERT: Well, some of the envoys are congressionally mandated. Others have come in over the years.

    QUESTION: That’s my – I mean, my question is: There will be another person appointed to his position is what you’re saying?

    MS NAUERT: I am – I am not sure, and maybe we can check on this before we finish up because I want to get you the correct information on this. The function will still remain. Whether or not that actual title will remain, I’m not sure at this moment. If I can get you anything more on this before the end of our briefing or right after, I will let you know. Okay?

    Anything else on this matter?

    QUESTION: A related question?

    QUESTION: Afghanistan?

    QUESTION: Yeah, a related question.

    MS NAUERT: Okay, okay. Hey.

    QUESTION: Last night, the White House announced the administration’s intent to nominate Governor Brownback as the ambassador-at-large for international religious freedom. But that comes, as you said, as a lot of these other positions are either vacant or filled by someone in an acting capacity, including really important policy ones, including the assistant secretaries of state, Diplomatic Security. Why fill that role and leave these other roles empty?

    MS NAUERT: This is all a work in progress. So there are a lot of people who are in the pipeline for assistant secretary positions. That all takes some time. As you know, they have to go through the various security screenings and Office of Government Ethics and financial disclosure forms, all of that. And then it goes to Congress and the Senate deals with those actual appointments and the hearings and all that. That takes – that takes some time.

    QUESTION: So was he named first months ago internally and that’s why his name has come out first?

    MS NAUERT: I’m not sure about that because the White House announced his name. I can tell you that I know we’re looking forward to having him on board. He will be involved with our Religious Freedom Report and that, we anticipate, will be coming out sometime soon. I don’t have an exact date for you at this point, but we’re looking forward to having him on board.

    QUESTION: What would you say to critics saying – who say it shows a lack of urgency on these other issues, whether it’s policy on different bureaus or Diplomatic Security?

    MS NAUERT: I’d say we can walk and chew gum at the same time. I mean, we have the ability to have somebody fulfilling the duties of that role while we work to get other people coming in in other roles. So it’s not mutually exclusive. Okay?

    QUESTION: On that Religious Freedom Report —

    MS NAUERT: Yeah.

    QUESTION: — I believe that was due to Congress several months ago.

    MS NAUERT: Yeah.

    QUESTION: Do you know what the reason for that delay is?

    MS NAUERT: I do not. I do not. I can tell you that it’s an important matter to us. We recently had the trafficking report. My understanding is that sometimes these reports don’t get to Congress on the – on a certain date, that they sometimes take a little extra time with that. Okay?

    QUESTION: Afghanistan?

    QUESTION: Can I —

    MS NAUERT: Okay. Hold on. Hey. I’m sorry, just one second.

    QUESTION: Can I just clarify? Back to North Korea briefly, I was just thinking that since the Secretary had prior indicated that he was not seeking or not interested in regime change in North Korea, why no comment now?

    MS NAUERT: If the Secretary had previously said that, I just didn’t have his words right in front of me. So if the Secretary has previously said that, I would just refer you to those statements.

    QUESTION: Okay. So it doesn’t indicate a change in —

    MS NAUERT: No, I just – I just don’t have his words right in front of me —

    QUESTION: Okay.

    MS NAUERT: — and so I don’t want to misstate something —

    QUESTION: That’s okay.

    MS NAUERT: — or misquote the Secretary on that. I hope you understand.

    QUESTION: Just making sure. And do you mind if we switch to Russia?

    MS NAUERT: Sure. Hold on with – let’s go to Afghanistan first and then we’ll go to Russia.

    QUESTION: Sure.

    MS NAUERT: Hi.

    QUESTION: Yeah, do you have – yeah, do you have anything on reports that the United States is considering efforts to capitalize minerals in Afghanistan and is sending envoys to meet with the mineral officials over there.

    MS NAUERT: So I’ve seen the report that you are talking about, and as you know – we’ve talked about this before – the Afghan review process is still underway. So what exactly will take place in Afghanistan, the final decisions that will be made, I’m not going to get ahead of that. I’m not going to get ahead of the President. The President is still in consultations with the National Security Council as well as Secretary Tillerson and Secretary Mattis. They’ll come to a conclusion about that, and when they do, I’ll bring you whatever I have on that, okay?

    QUESTION: What is U.S. position regarding capitalizing Afghans’ natural resources?

    MS NAUERT: Again, that is an issue – anything related to Afghanistan would be under review at this time, and so I’m just going to hold off until they come to a decision on that, okay?

    Okay.

    QUESTION: Turkey.

    MS NAUERT: Hi, Ilhan. How are you?

    QUESTION: Thank you. On Turkey, Heather, tomorrow there will be interim verdict – some kind of verdict for journalists who have been tried since Monday. These journalists from Cumhuriyet daily have been behind bars over nine months now and accused of different charges. Across the world, human right groups and press institutions have been condemning the indictment and what has been happening. I am wondering whether the U.S. Government is following the case and if – do you have any comment on that?

    MS NAUERT: Yeah. I’ve got a bit for you on this here today. The United States remains seriously concerned about the widespread arrest and pretrial detention that’s taking place of individuals in Turkey who have been critical of that government. You mentioned the trial of 17 newspaper reporters. I know you are very familiar with this case, and many of us here have followed those cases as well. We continue to urge the Government of Turkey to respect and ensure freedom of expression, fair trial guarantees, judicial independence, other human rights and fundamental freedoms, and to also release the journalists and others who we believe are being held arbitrarily under the government’s state of emergency.

    I spoke today with our ambassador, our Ambassador Bass, who serves in Turkey, and he’s done a wonderful, wonderful job over there. He tells me that our embassy personnel have joined colleagues from other missions to observe some of those trial proceedings. Ambassador Bass has previously visited the newspaper – I don’t want to mispronounce it – Cumhuriyet? Is that how I say —

    QUESTION: Cumhuriyet. Yes.

    MS NAUERT: Cumhuriyet. Thank you. He’s gone there, and that really shows our level of concern, the fact that he has gone there to express his support for journalists there, his support for our belief in freedom of expression, including freedom of expression that other governments and other individuals might find uncomfortable. So he continues to underscore our support for free, independent media, important work that they do in democratic societies. If I have anything more on you – on that for you, I will certainly bring it to you, but we are following the cases of those individuals.

    QUESTION: Thank you.

    MS NAUERT: Thank you. Okay. Anything else on Turkey?

    QUESTION: Can I get a follow-up on that?

    MS NAUERT: Yes. Hi.

    QUESTION: Hi.

    MS NAUERT: Tell me your name, please.

    QUESTION: Cansu Camlibel from Hurriyet in Turkey.

    MS NAUERT: Oh, welcome.

    QUESTION: Hi.

    MS NAUERT: Thanks.

    QUESTION: So on the same case, you said Ambassador Bass went to the newspaper headquarters before, and some personnel from the embassy, I understand, followed the court case this week.

    MS NAUERT: Yes.

    QUESTION: I remember last year in a similar court case, some other diplomats, European diplomats, because they’d been to the courtroom, were personally attacked by the Turkish president. So since you said that you had a conversation with Ambassador Bass, does he have concerns that he might be subject to that kind of reaction from the Turkish Government because he – because of the U.S. mission’s close interest in the matter?

    MS NAUERT: I can certainly check with him. I’m not sure I would have anything for you on that. It’s kind of a hypothetical question, and so we typically don’t get into hypotheticals. But I know that he remains committed to the ideals of freedom of speech and also democracy.

    Okay. I think we’re about done.

    QUESTION: No.

    MS NAUERT: Okay.

    QUESTION: Let me ask about Syria.

    MS NAUERT: Okay. You want to ask about Syria? Okay.

    QUESTION: Could you update us on the situation —

    MS NAUERT: Last thing and then we’ve got to go.

    QUESTION: — on Syria? I know there has been a statement by your allies, the Democratic Syria forces, that they have liberated half of Raqqa so far. Could you update us? What is the situation and how are you coordinating with the Russians on the ground?

    MS NAUERT: Okay. So some of that would be a DOD matter, so I’m not going to get too much into how much ground has been taken. We know overall that the progress continues in Raqqa by the Syrian Democratic Forces backed by the U.S. and its coalition partners in that. That is an area where we know that ISIS has been heavily dug in. For folks who don’t follow this that closely, that is basically one of the areas where – well, it’s not basically; it is an area where ISIS had planned some of its plots – Nice, for example; Brussels. So ISIS was dug in there. They used that location in which to come up with those plots and activate those plots from that area.

    So our coalition allies have been hard at work in trying to get ISIS out of there, contain it. They have left a lot of explosive material behind. One of our missions will certainly have to be to work with our partners to de-mine some of those areas and get those explosives out so that eventually some of the civilians can come back in. Beyond that, I’d have to refer you to DOD.

    QUESTION: If the – this disarming or taking out these explosives required more American technical teams and so on, would the U.S. be willing to send in more teams?

    MS NAUERT: I’m not sure exactly who is on the ground doing that. I know that that is part of our humanitarian support for that area so that people can get back in.

    Okay, guys, we’re going to have to —

    QUESTION: Can you just speak quickly to —

    QUESTION: Russia-Ukraine.

    QUESTION: (Off-mike.)

    MS NAUERT: Yeah, sure.

    QUESTION: And in regard to the new safety security assessment that you guys put out, is the U.S. Government or the State Department investigating any of these cases?

    MS NAUERT: So the cases that you’re referring to – and I know Michele has asked some questions about this regarding Mexico and concerns about tainted alcohol – we’ve put an update on our website about that because we have seen the media reports and concerns that people have about tainted alcohol at some resorts and clubs and things of that sort in Mexico.

    So the United States wouldn’t be involved in an investigation. That would be an internal matter for the Government of Mexico. They have a regulatory body that, from my understanding, that they are involved in in looking into some of this.

    QUESTION: Can you say whether you – the U.S. Government consulted the Mexican Government before it changed the language, or is it just because of the media reports?

    MS NAUERT: Well, this is because of – because of media reports, that is in part how we learned about it. I know it remains something that we’re watching carefully, but I’m just not going to get ahead of anything on that.

    QUESTION: So you can’t —

    MS NAUERT: Okay.

    QUESTION: The U.S. Government hasn’t verified any of the reports? It’s just the fact that they’re out there?

    MS NAUERT: We have simply – one of the things we do is we will update our website just so visitors have information that they need just so they can be aware. This isn’t an increase in any kind of travel warnings, because you know that’s actually a technical thing, a travel warning. We’re not increasing that level as a result of this, but we want people to be able to have information that this is an issue. We’re aware of that through the media reports. It is an issue, so we just want our citizens and others to be aware of that and be careful.

    Okay? All right.

    QUESTION: Just one more on the region, Heather.

    MS NAUERT: Yeah.

    QUESTION: Just real quick before the expected vote in Venezuela on Sunday —

    MS NAUERT: Oh yeah, I’m so glad you asked. Yeah.

    QUESTION: Just Secretary watching – the United States earlier and the Trump Administration earlier had warned against holding that vote. Before that occurs on Sunday, is there any change in position?

    MS NAUERT: In terms of —

    QUESTION: From the – from the U.S. or otherwise.

    MS NAUERT: No, not at all. I mean, in fact, we had a really big news day yesterday, as you know, about the Treasury Department and sanctioning 13 Venezuelan individuals directly implicated in the political, economic, and also the social crises that are currently unfolding in Venezuela.

    We are prepared to continue taking strong and swift economic actions if the Government of Venezuela insists on holding those July 30th constituent assembly elections. It’s an area of major concern of ours. We have asked them not to do it. They have a constitution that is in place. The United States has consistently asked the Government of Venezuela to uphold its constitution and not hold the constituent elections, because we see these constituent elections as just a way to further the Maduro regime, and we’ve seen what has happened to the people of Venezuela. We have seen food shortages. We’ve seen children and families not being able to get the medical care and attention that they need. And we’re very concerned about the situation there. Venezuela crumbles and we don’t – is crumbling right now, and we don’t want to see that happening.

    Okay. Nikki Haley has also spoken out about this, as you all are very well aware, and one of the things that she has said and Secretary Tillerson has said as well, that we’ll keep our promise to the people of Venezuela, sanctions on individuals who are associated with corruption and violence against the Venezuelan people.

    Okay, all right. Gotta go.

    QUESTION: Russia?

    MS NAUERT: We’re – I’m done with Russia. We’re done with that for today. Thank you, everybody, and Happy Birthday to State Department.

    (The briefing was concluded at 3:33 p.m.)

    DPB # 40


    [1] Republic of Korea



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Ambient Coarse Particulate Matter and the Right Ventricle: The Multi-Ethnic Study of Atherosclerosis

Author Affiliations open

1Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA

2Department of Medicine, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

3Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington, USA

4Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington, USA

5Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa, USA

6Department of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA

7Radiology and Imaging Sciences, National Institute of Biomedical Imaging and Bioengineering, Bethesda, Maryland, USA

8Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

9Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA

10Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA

11Department of Civil and Environmental Engineering, University of Washington College of Engineering, Seattle, Washington, USA

PDF icon PDF Version (353 KB)

  • Background:
    Coarse particulate matter (PM10–2.5) is primarily mechanically generated and includes crustal material, brake and tire wear, and biological particles. PM10–2.5 is associated with pulmonary disease, which can lead to right ventricular (RV) dysfunction. Although RV characteristics have been associated with combustion-related pollutants, relationships with PM10–2.5 remain unknown.
    Objectives:
    To quantify cross-sectional associations between RV dysfunction and PM10–2.5 mass and components among older adults and susceptible populations.
    Methods:
    We used baseline cardiac magnetic resonance images from 1,490 participants (45–84 y old) from the Multi-Ethnic Study of Atherosclerosis and assigned 5-y residential concentrations of PM10–2.5 mass, copper, zinc, phosphorus, silicon, and endotoxin, using land-use regression models. We quantified associations with RV mass, end-diastolic volume, and ejection fraction after control for risk factors and copollutants using linear regression. We further examined personal susceptibility.
    Results:
    We found positive associations of RV mass and, to a lesser extent, end diastolic volume with PM10–2.5 mass among susceptible populations including smokers and persons with emphysema. After adjustment for copollutants, an interquartile range increase in PM10–2.5 mass (2.2 μg/m3) was associated with 0.5 g (95% CI: 0.0, 1.0), 0.9 g (95% CI: 0.1, 1.7), and 1.4 g (95% CI: 0.4, 2.5) larger RV mass among former smokers, current smokers, and persons with emphysema, respectively. No associations were found with healthy individuals or with ejection fraction.
    Conclusions:
    Alterations to RV structure may represent a mechanism by which long-term PM10–2.5 exposure increases risks for adverse respiratory and cardiovascular outcomes, especially among certain susceptible populations. https://doi.org/10.1289/EHP658
  • Received: 14 June 2016
    Revised: 24 February 2017
    Accepted: 16 March 2017
    Published: 27 July 2017

    Address correspondence to S. D. Adar, University of Michigan School of Public Health, 1415 Washington Heights, SPH II-5539, Ann Arbor, MI 48109 USA. Telephone: (734) 615-9207; Email: sadar@umich.edu

    Supplemental Material is available online (https://doi.org/10.1289/EHP658).

    S.M.K. receives nonfinancial support from the American College of Clinical Pharmacology and the American Thoracic Society; personal fees from the European Respiratory Journal; and grants from Actelion, Gilead, GeNO, and Bayer that are unrelated to the submitted work.

    All other authors declare they have no actual or potential competing financial interests.

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    Note to readers with disabilities: EHP has provided a 508-conformant table of contents summarizing the Supplemental Material for this article (see below) so readers with disabilities may determine whether they wish to access the full, nonconformant Supplemental Material. If you need assistance accessing journal content, please contact ehponline@niehs.nih.gov. Our staff will work with you to assess and meet your accessibility needs within 3 working days.
    PDF icon Supplemental Table of Contents PDF (92 KB)

Introduction

Air pollution is a well-established risk factor for adverse respiratory outcomes, including chronic lung diseases (Andersen et al. 2011; Karakatsani et al. 2003; Lindgren et al. 2009; Schikowski et al. 2005; Sunyer 2001), hospitalizations (Chen et al. 2005) and death (Dockery et al. 1993; Pope et al. 2002). Most recently, it has been estimated that for 2013 worldwide ambient particulate matter (PM) pollution accounts for nearly 170,000 deaths and nearly 4 million disability-adjusted life years (DALYs) due to chronic respiratory disease (Forouzanfar et al. 2015; IHME 2016).

A common sequela of chronic lung disease is the development of pulmonary hypertension and impairments to the heart, including right ventricular (RV) dysfunction (Freixa et al. 2013). The right ventricle pumps blood through the lungs to allow for its oxygenation. Then the oxygen-rich blood flows to the left ventricle for subsequent distribution to all tissues of the human body. Changes in RV structure and function can therefore result in many similar clinical sequelae of left ventricular (LV) changes, including dyspnea, exercise intolerance, lower-extremity edema, and (at advanced stages) severe heart failure (Voelkel et al. 2006). Although the left ventricle is vulnerable to increased pressures during ejection due to systemic hypertension or valvular disease, reduced blood supply, and hypoxia, the right ventricle may be similarly affected by changes in lung function [e.g., chronic obstructive pulmonary disorder (COPD)], LV function, and hypoxia (e.g., sleep disordered breathing). The RV has been thought to respond to this increased load through structural changes such as hypertrophy (i.e., thickening of the ventricle leading to increased mass), chamber dilation leading to greater end-diastolic volume, and lowered pumping efficiency (i.e., reduced ejection fraction) (Polak et al. 1983; Shah et al. 1986). Although these three manifestations of RV dysfunction are most likely in severe stages of lung disease, the right ventricle can also be affected early in lung disease (Hilde et al. 2013). RV dysfunction has public health importance because it has been linked to poor outcomes among persons with and without preexisting disease, such as COPD and cardiovascular disease (Burgess et al. 2002; France et al. 1988; Kawut et al. 2012).

Long-term exposures to air pollution are believed to affect the same biological mechanisms that lead to COPD and cardiovascular disease. There is evidence that air pollution is associated with greater inflammation (Adar et al. 2015b) and reduced vessel compliance (Brook et al. 2014; Krishnan et al. 2013; Mills et al. 2005); such evidence suggests a plausible link to RV function. In fact, two studies from the Multi-Ethnic Study of Atherosclerosis (MESA) recently linked long-term exposures to two combustion-related air pollutants: nitrogen dioxide (NO2) (Leary et al. 2014) and fine PM (aerodynamic diameter <2.5 μm, PM2.5) (Aaron et al. 2016) to greater RV hypertrophy and lower function. Although PM in the coarse fraction (aerodynamic diameter between 2.5 and 10 μm, PM10–2.5) has also been associated with adverse respiratory end points (Adar et al. 2014; Brunekreef and Forsberg 2005), no study has investigated associations between PM10–2.5 and RV characteristics. Understanding the health impacts of PM10–2.5 independent of other pollutants, including PM10–2.5 and NO2 has importance, given that the U.S. Environmental Protection Agency (EPA) is interested in regulating PM10–2.5 levels but has struggled with insufficient data in the general population as well as among susceptible individuals (U.S. EPA 2009). Because PM10–2.5 is generated by very different diverse processes, ranging from crustal material to brake and tire wear, a lack of information on associations between health and indicators of different PM10–2.5 sources represents another important gap in the literature.

To expand the literature on the health implications of PM10–2.5 and to better understand environmental risk factors of RV dysfunction, we aimed to quantify cross-sectional associations between PM10–2.5 and measures of RV function among older adults and susceptible subpopulations. We approached this goal using individual-level long-term estimates of PM10–2.5 mass and selected source-specific components with multiple measures of RV structure (mass, end-diastolic volume) and function (ejection fraction) in participants of MESA. Some of these results have been previously reported in the form of an abstract (Adar et al. 2015a).

Methods

Study Population

Initiated in 2000, MESA is a multicenter, prospective study examining the progression of subclinical cardiovascular disease among an ethnically diverse population of 6,814 subjects (45–84 y old) who were free of known cardiovascular disease at baseline (Bild et al. 2002). In this analysis, we restricted reporting to participants from Chicago, Illinois, St. Paul, Minnesota, and Winston-Salem, North Carolina, who were part of the MESA Coarse ancillary study (n=3,295). The MESA Coarse study conducted intensive sampling of PM10–2.5 concentrations in three of the MESA sites chosen to reflect PM10–2.5 variability. We further restricted to those who had cardiac magnetic resonance images (MRI) interpreted for RV morphology as part of the MESA RV ancillary study (n=1,851). After excluding those with missing exposures and covariates, our final sample was 1,490 persons (Figure S1).

All protocols described herein received approval from local and national institutional review boards. Participants also provided informed consent.

Right Ventricle Characteristics

The MESA RV study obtained measures of RV function using cardiac MRIs performed at the baseline exam (Natori et al. 2006). These measures include RV mass at end-diastole, end-diastolic volume, and ejection fraction (Bluemke et al. 2008; Chahal et al. 2010). These measures were estimated by two independent analysts using QMASS software (version 4.2; Medis), is described elsewhere (Chahal et al. 2010). Based on random, blinded rereads from approximately 230 scans, the inter-reader intraclass correlation coefficients were 0.89, 0.96, and 0.80 for RV mass, end-diastolic volume, and ejection fraction, respectively (Kawut et al. 2011).

Exposure Assessment

We used site-specific land-use regression spatial prediction models derived from project-specific PM10–2.5 measurements and geographic data to predict concentrations of PM10–2.5 at subjects’ residences. Details of these models have been previously published (Zhang et al. 2014). Briefly, we conducted two spatially intensive 2-wk monitoring campaigns of integrative PM10 and PM2.5 samples using paired Harvard Personal Exposure Monitors (HPEMs) in each of three MESA Coarse sites. In each city, approximately 60 locations were targeted to cover the greatest geographic space. Additionally, the locations were selected to capture the variability of hypothesized characteristics associated with PM10–2.5 mass and components (e.g., vegetation, distance to roads). All samples were weighed in a temperature- and relative humidity-controlled chamber, analyzed for elements by X-ray fluorescence spectroscopy, and total PM10–2.5 mass and that of chemical components were calculated by difference (U.S. EPA 2009). The specific components of interest were copper, zinc, phosphorus, and silicon as consistent indicators for motor vehicle brake wear, tire wear, fertilized soil/agriculture, and crustal material across all study sites, respectively (Sturtz et al. 2014). We also examined a fifth component of PM10–2.5, endotoxin, a major component of the outer membrane of Gram-negative bacteria. Endotoxin was chosen due to its capability to induce inflammation and modulate immune responses (Hadina et al. 2008) and its association with airway disease (Schwartz et al. 1995). We separately derived spatial prediction models for PM10–2.5 mass and each component using many geographic variables, including land use, population density, vegetation, impervious surface, roadways, railways, and airports, as well as spatial correlation. The cross-validated (CV) R2 for the site-specific models of PM10–2.5 and chemical species ranged from 0.3 to 0.9. As described elsewhere (Zhang et al 2014), the models performed best for copper (CV R2, 0.5–0.9) and generally worse for endotoxin (CV R2=0.3–0.4). For our statistical modeling, we selected 5–y average concentrations weighted according to subjects’ residential history preceding subjects’ MRI.

Exposures to PM2.5 and NO2 were also estimated for each participant using spatiotemporal models derived from project-specific measurements, land-use characteristics, as well as regulatory monitoring data in the MESA Air study (Gill et al. 2011; Szpiro et al. 2010).

Covariates

All covariates, with the exception of airflow limitation, were assessed at baseline. These included sociodemographic and behavior information obtained via interview, and anthropometric measurements, left ventricle function, and laboratory data from the clinical exam. Comorbidities of hypertension and diabetes were also defined based on blood pressure or glucose measurements, respectively, self-reported medication use, and doctor diagnosis (Genuth et al. 2003; JNC 1997). Through the MESA Lung ancillary study, we had data on percent emphysema from computed tomography (CT) scans (Hoffman et al. 2009) and spirometry (Hankinson et al. 2010). The MESA Neighborhood Study developed a neighborhood socioeconomic scale (NSES) for each participant based on a principal components analysis of 2000 census tract data (U.S. Census Bureau 2002), including median household income, percent of persons in tract with at least a high school degree and median home value (Hajat et al. 2013).

Statistical Analysis

Multivariable linear regression models were used to quantify adjusted cross-sectional associations between PM10–2.5 and continuous measures of our RV outcomes. All models were adjusted for age, race/ethnicity (White, Chinese, Black, and Hispanic), sex, education (less than high school, high school/some college, college or more), NSES, height, weight, cigarette smoking history (never, former, current), pack-years of smoking (0 pack-y, 0<pack-y≤10, 10<pack-y≤20, greater than 20), second-hand smoke exposure, hypertension (JNC 1997), diabetes (according to the 2003 American Diabetes Association Fasting Criteria Algorithm: normal, impaired fasting glucose, untreated diabetes, treated diabetes), cholesterol, study site, and an interaction of study site with NSES. Age, height, weight, NSES, and cholesterol were modeled as continuous; all other variables were modeled as categorical. In secondary models, we examined the linearity of these associations using splines and the robustness of our results to adjustment for PM2.5 and NO2 in two pollutant models. In secondary models of the chemical species of PM10–2.5 we also adjusted for total mass as a covariate using a constituent residual model (Mostofsky et al. 2012). We used interaction terms to assess effect modification by age, sex, race/ethnicity, smoking status, emphysema (defined as percent of emphysema-like lung based on CT scans that were greater than the upper limit of normal (Hoffman et al. 2014)), and airflow limitation (FEV1/FVC<0.7). All reported estimates were scaled to the interquartile range (IQR) for each pollutant/species: PM10–2.5 (2.2 μg/m3), copper (4 ng/m3), zinc (11 ng/m3), phosphorous (6 ng/m3), silicon (0.13 μg/m3), endotoxin (0.08 EU/m3), NO2 (7.0 ppb), and PM2.5 (3.8 μg/m3).

In sensitivity analyses, we restricted our analyses to participants who were residentially stable (lived at their current residence for 10 y or longer) and examined additional control for hypertension, diabetes, and cholesterol, as well as measures of LV function and lung disease as potential mediators.

The data analysis for this paper was generated using SAS (version 9.4; SAS Institute Inc.) and R (version 3.3.2; R Development Core Team).

Results

The mean age of the sample at baseline was 61 y; nearly 9% had physician-diagnosed asthma, and 7% had emphysema based on their CT scans (Table 1). Although participants in this sample were more likely to be Chinese, less likely to be black, and more likely to have a graduate degree than the full MESA Coarse cohort, these individuals were otherwise quite similar. Importantly, they did not differ with respect to their air pollution levels for all pollutants except zinc, which was approximately 10% lower in the study sample (Table S1).

Table 1. Descriptive characteristics of the MESA Coarse participants at the baseline examination (2000–2002), by study site.
Characteristics Total Winston-Salem St. Paul Chicago
n 1490 457 536 497
61.1±10.0 62.4±9.6 59.4±10.0 61.9±10.1
Age (y, %)
 45–54 477 (32%) 124 (27%) 196 (37%) 157 (32%)
 55–64 437 (29%) 128 (28%) 173 (32%) 136 (27%)
 65–74 404 (27%) 150 (33%) 119 (22%) 135 (27%)
 75–84 172 (12%) 55 (12%) 48 (9%) 69 (14%)
Female 795 (53%) 253 (55%) 278 (52%) 264 (53%)
Race/ethnicity
 White 828 (56%) 277 (61%) 327 (61%) 224 (45%)
 Chinese 158 (11%) 0 (0%) 0 (0%) 158 (32%)
 Black 293 (20%) 178 (39%) 0 (0%) 115 (23%)
 Hispanic 211 (14%) 2 (0%) 209 (39%) 0 (0%)
Education
 <High school 400 (27%) 128 (28%) 205 (38%) 67 (13%)
 High school/some college 440 (30%) 135 (30%) 191 (36%) 114 (23%)
 ≥College 650 (44%) 194 (42%) 140 (26%) 316 (64%)
Smoking status
 Never 744 (50%) 225 (49%) 255 (48%) 264 (53%)
 Former 556 (37%) 171 (37%) 200 (37%) 185 (37%)
 Current 190 (13%) 61 (13%) 81 (15%) 48 (10%)
≥10 y in neighborhood 1033 (69%) 281 (61%) 381 (71%) 371 (75%)
Health
 BMI (kg/m2) 27.7±5.0 28.2±5.0 28.9±4.9 26.0±4.7
 Cholesterol (mg/dl) 195.3±36.0 189.1±34.7 201.5±38.9 194.2±32.7
 Hypertension 584 (39%) 232 (51%) 167 (31%) 185 (37%)
 Diabetic 2.3 (1.0) 1.4 (1.0) 2.0 (1.0) 3.8 (1.0)
 % Emphysema (−950 HU)a 81% (0) 37% (0) 71% (0) 134% (0)
 Airflow limitationb 220 (22%) 66 (26%) 57 (19%) 97 (22%)
 Emphysema 97 (7%) 15 (3%) 46 (9%) 36 (7%)
 Asthma 130 (9%) 36 (8%) 51 (10%) 43 (9%)
 Left Ventricular end-diastolic Mass (g) 147.5±39.0 145.7±38.5 154.6±38.5 141.4±38.8
RV Outcomes
 RV mass (g) 21.6±4.7 21.2±4.3 22.7±4.9 20.8±4.5
 RV ejection fraction (%) 70.3±6.7 69.1±7.0 70.2±6.3 71.4±6.5
 RV end-diastolic volume (mL) 127.6±33.2 122.9±30.5 135.1±35.0 123.9±32.2
Pollutants
  PM10–2.5 (μg/m3) 4.9±1.6 3.7±1.2 5.3±1.8 5.5±1.2
  Copper (ng/m3) 4.4±2.5 2.5±0.8 3.5±0.8 7.1±2.4
  Zinc (ng/m3) 9.0±9.6 3.1±1.6 5.1±1.2 18.5±11.5
  Silicon (μg/m3) 0.4±0.1 0.4±0.0 0.5±0.1 0.4±0.1
  Phosphorous (ng/m3) 15.9±3.6 19.7±2.2 12.9±1.9 15.6±2.7
  Endotoxin (EU/m3) 0.1±0.1 0.0±0.0 0.1±0.0 0.0±0.1
  PM2.5 (μg/m3) 14.6±2.1 15.5±0.9 12.3±1.4 16.1±1.4
  NO2 (ppb) 14.7±5.1 10.3±2.5 13.5±2.2 20.2±4.1
Note: Values given as n (%) or mean±standard deviation. BMI, body mass index; NO2, nitrogen dioxide; PM2.5, particulate matter <2:5 μm in diameter; PM10–2.5, particulate matter between 2.5 and 10 μm in diameter; RV, right ventricular.

aEmphysema is defined as the percent emphysema via computed tomography scan greater than the upper limit of normal.

aAirflow limitation is defined as an FEV1/FVC<0.7 and was available on only 974 participants.

Average PM10–2.5 mass concentrations were lowest for Winston-Salem (3.7 μg/m3) but similar in St. Paul (5.3 μg/m3) and Chicago (5.5 μg/m3). St. Paul had the largest intracity variation (standard deviation: 1.8 μg/m3 in St. Paul vs. 1.2 μg/m3 for Chicago and Winston-Salem). With respect to the chemical components, the highest average concentrations of the two traffic-related markers of copper and zinc were in Chicago, whereas Winston-Salem had the highest concentrations of phosphorus. Mean endotoxin levels were generally low (≤0.1 EU/m3) across all locations. In all locations, we observed modest to high correlations (0.46–0.89) between the traffic-related pollutants of copper, zinc, and NO2. In addition, PM2.5 and NO2 were also correlated (>0.6) in all locations. Although the other pollutants did not demonstrate consistent patterns across sites, there were notable (>0.6) correlations between most pollutants in Chicago (Table S2).

Among all participants, RV mass was positively associated with PM10–2.5 mass, copper, phosphorus, and silicon in single-pollutant models (Table 2). After controlling for PM2.5 and NO2, however, which were themselves associated with RV mass, the association with copper was eliminated and associations with PM10–2.5 mass, phosphorus, and silicon were blunted. Apart from copper, adjustment for PM10–2.5 mass did not strongly affect associations with any chemical components (Figure S2). Results were also robust to more and less control for potential intermediate factors such as hypertension, cholesterol, diabetes, emphysema, airflow limitation, and LV mass and function (Figure S3).

Table 2. Associations between PM10–2.5 mass and RV structure and function in single and multipollutant models.
Mass (g) Volume (mL) Ejection Fraction (%)
Model Difference 95% CI p–Value Difference 95% CI p–Value Difference 95% CI p–Value
PM10–2.5
 Single Pollutant Model 0.3 0.0, 0.5 0.06 0.4 −1.3, 2.2 0.63 −0.1 −0.6, 0.4 0.75
 + PM2.5 0.2 −0.1, 0.5 0.14 0.3 −1.5, 2.2 0.74 −0.1 −0.6, 0.4 0.76
 + NO2 0.2 −0.1, 0.5 0.22 0.4 −1.5, 2.3 0.68 −0.1 −0.6, 0.4 0.72
Cu
 Single Pollutant Model 0.3 −0.2, 0.8 0.20 0.6 −2.5, 3.6 0.71 0.1 −0.7, 1.0 0.75
 + PM2.5 0.0 −0.5, 0.5 0.93 0.0 −3.4, 3.3 0.99 0.5 −0.5, 1.4 0.32
 + NO2 −0.2 −0.8, 0.5 0.56 −0.1 −4.3, 4.1 0.96 0.4 −0.8, 1.6 0.56
Zn
 Single Pollutant Model 0.0 −0.3, 0.3 0.90 −0.6 −2.6, 1.3 0.51 −0.1 −0.6, 0.5 0.81
 + PM2.5 −0.2 −0.5, 0.1 0.16 −1.1 −3.2, 0.9 0.27 0.1 −0.5, 0.6 0.85
 + NO2 −0.3 −0.7, 0.0 0.09 −1.4 −3.6, 0.9 0.24 −0.1 −0.7, 0.6 0.81
P
 Single Pollutant Model 0.5 0.0, 1.0 0.03 0.5 −2.6, 3.6 0.75 −0.1 −0.9, 0.8 0.87
 + PM2.5 0.2 −0.3, 0.7 0.41 −0.4 −3.6, 2.9 0.83 0.0 −0.9, 1.0 0.93
 + NO2 0.3 −0.2, 0.8 0.25 0.0 −3.4, 3.4 0.99 −0.1 −1.0, 0.9 0.91
Si
 Single Pollutant Model 0.4 0.1, 0.7 0.01 0.8 −1.1, 2.8 0.41 −0.2 −0.7, 0.4 0.54
 + PM2.5 0.2 −0.2, 0.5 0.36 0.2 −2.0, 2.4 0.86 0.0 −0.6, 0.6 0.95
 + NO2 0.3 −0.1, 0.6 0.19 0.7 −1.8, 3.1 0.59 −0.2 −0.9, 0.4 0.49
Endotoxin
 Single Pollutant Model −0.1 −0.5, 0.2 0.49 −0.2 −2.4, 1.9 0.82 −0.1 −0.7, 0.5 0.67
 + PM2.5 0.1 −0.3, 0.4 0.64 0.1 −2.1, 2.4 0.91 −0.4 −1.0, 0.3 0.26
 + NO2 0.0 −0.4, 0.3 0.89 −0.1 −2.4, 2.1 0.90 −0.2 −0.8, 0.5 0.59
NO2
 Single Pollutant Model 0.5 0.1, 0.9 0.01 0.8 −1.8, 3.5 0.54 0.0 −0.8, 0.7 0.93
 + PM10–2.5 0.4 0.0, 0.9 0.06 0.6 −2.2, 3.5 0.66 0.0 −0.8, 0.8 0.96
 + PM2.5 0.2 −0.3, 0.8 0.38 0.3 −3.1, 3.8 0.84 0.3 −0.7, 1.3 0.53
PM2.5
 Single Pollutant Model 1.0 0.4, 1.6 0.001 1.8 −2.0, 5.6 0.36 −0.6 −1.7, 0.4 0.25
 + PM10–2.5 0.9 0.3, 1.5 0.003 1.7 −2.3, 5.6 0.41 −0.6 −1.7, 0.5 0.28
 + NO2 0.8 0.0, 1.5 0.043 1.5 −3.4, 6.4 0.56 −0.9 −2.3, 0.5 0.19
Note: All models adjusted for age, race, gender, height, weight, neighborhood socioeconomic scale (NSES), NSES, education, smoking status, pack-years, second-hand smoke exposure, hypertension, diabetes, total cholesterol, study site, and site by NSES interaction. Associations scaled to interquartile range (IQR) IQR of pollutant: PM10–2.5 (2.2 μg/m3), Cu (4 ng/m3), Zn (11 ng/m3), P (6 ng/m3), Si (0.13 μg/m3), endotoxin (0.08 EU/m3), PM2.5 (3.8 μg/m3), NO2 (7.0 ppb). CI, confidence interval; Cu, copper; NO2, nitrogen dioxide; P, phosphorous; PM2.5, particulate matter <2:5 μm in diameter; PM10–2.5, particulate matter between 2.5 and 10 μm in diameter; Si, silicon; Zn, zinc.

Analysis of effect modification suggested that associations between PM10–2.5 and RV mass were present in several susceptible populations. These subgroups included: former and current smokers in comparison with nonsmokers (p-value for interaction=0.02), persons with emphysema in comparison with persons without emphysema (p-value for interaction=0.02), and residentially stable participants in comparison with participants who had lived at their residences for less than 10 y (p-value for interaction=0.15). These associations remained even after adjustment for PM2.5 and NO2 concentrations (Figure 1) and after adjustment for emphysema (results not shown).

Forest plot indicating RV mass in grams per IQR increase in PM sub 10-2.5 for the following categories: overall, race/ethnicity (White, Chinese, AA, and Hispanic), age categories (45-54, 55-64, 65-74, and 75-84), smoking status (Never, Former, and Current), airflow limitation (No and Yes), emphysema (No and Yes), and greater than 10 years in neighborhood (No and Yes).
Figure 1. Effect modification of associations between PM10–2.5 concentrations and RV end-diastolic mass after control for PM10–2.5 and NO2 [g per interquartile range (IQR) of pollutant, 95% confidence interval (CI)].

*Interaction was statistically significant (p<0.05). Note: PM2.5, particulate matter with aerodynamic diameter between 2.5 and 10 μm; NO2, nitrogen dioxide.

Although the size and direction of the associations between PM10–2.5 mass and silicon with RV end-diastolic volume were consistent with RV mass, the confidence intervals were very wide and indistinguishable from no association (Table 2). As with RV mass, associations with RV end-diastolic volume were strongest among current smokers, participants with emphysema, and particpants who were residentially stable, although the precision of these estimates remained large (Figure S4). No associations were observed with ejection fraction in the full cohort or in any subpopulation evaluated.

Discussion

Among a population-based cohort from three U.S. metropolitan areas, we found suggestive evidence of associations between PM10–2.5 and RV structure after adjustment for confounding by PM2.5 and NO2. Positive associations between total PM10–2.5 mass concentrations and RV hypertrophy and, to a lesser extent, dilation were driven by relationships among former and current smokers, persons with advanced emphysema, and participants who were residentially stable. Associations were not found among other participants. No associations were found with RV ejection fraction among any group.

This study adds to the literature by expanding our understanding of the health implications of PM10–2.5 and the environmental risk factors for RV dysfunction. After adjustment for other risk factors such as smoking, height, weight, and co-pollutants previously associated with RV dysfunction, we observed the most robust associations for PM10–2.5 mass with a 1.4 g (95% CI: 0.4, 2.5) and 0.9 g (95% CI: 0.1, 1.7) larger RV mass among persons with emphysema and current smokers, respectively, per 2.2 μg/m3. These associations were on the same order of magnitude as those reported for PM2.5 in the full cohort (Aaron et al. 2016) and in the MESA Coarse cities. These differences are also comparable to differences in RV mass for participants 5 kg/m2 apart in BMI (Chahal et al. 2012) and may be clinically relevant, given that MESA participants with RV hypertrophy have double to triple the risk of heart failure or cardiovascular death (Kawut et al. 2012).

Mechanisms through which PM10–2.5 exposures might likely affect the right ventricle (Voelkel et al. 2006) include the restructuring of the pulmonary vasculature, increases in RV load (Zangiabadi et al. 2014), hypoxia, inflammation (Chaouat et al. 2009), and autonomic dysfunction (Wensel et al. 2009; Wrobel et al. 2012). Support for these mechanisms comes from a previous study of healthy Mexican children that reported greater pulmonary arterial pressures and serum levels of the vasoconstrictive protein endothelin-1 with larger long-term PM concentrations (Calderón-Garcidueñas et al. 2007). Toxicological research has similarly demonstrated enhanced vasoconstriction and impaired vasodilation of pulmonary arterioles in healthy animals and in animals with chronic bronchitis exposed to PM (Faustini et al. 2012; Peel et al. 2005). Interestingly, the associations with RV mass were robust to control for hypertension, emphysema, airflow limitation, and LV mass and function, suggesting that these factors may not be critical intermediates of our observed associations. However, it is difficult to conclusively assess mediation in this study given our cross-sectional design and the possibility that only advanced cases of emphysema or airflow limitation are critical intermediates, which are limited in number in this population. Our overall null associations with RV ejection fraction were similar to findings in a previous analysis (Kawut et al. 2012) where only RV mass was independently associated with cardiovascular death. These data could suggest that RV hypertrophy is an earlier indicator of increased pressure in the RV than RV ejection fraction, though this has yet to be clearly demonstrated.

Although the observed association between PM10–2.5 and RV appeared to be independent of PM10–2.5-associated lung damage, the interaction with emphysema suggests that individuals with preexisting lung damage may be more susceptible to long-term PM10–2.5 exposures. This susceptibility is plausible, given that persons with COPD have greater deposition and less mucociliary clearance of particles from their lungs relative to healthy individuals (Bennett et al. 1997; Brown et al. 2002). It is also consistent with epidemiological evidence of enhanced vulnerability of persons with respiratory conditions to short-term air pollution exposures (Faustini et al. 2012; Peel et al. 2005; Sacks et al. 2011), though the findings of the few studies to examine chronic lung disease as an effect modifier of long-term exposures to air pollution have been mixed (Andersen et al. 2012; Jerrett et al. 2009).

We also observed positive associations between RV mass and PM10–2.5 concentrations among participants who smoke or who have a history of smoking, independent of their emphysema status. One possible explanation may be that individuals who smoke or have smoked are more susceptible to the effects of air pollution because of smoking’s ability to increase inflammation and vasoconstriction (Akishima et al. 2007) and alter immune function, among other effects. However, epidemiologic evidence has also been mixed regarding the interaction between smoking and air pollution (Pope et al. 2011), suggesting that more research is necessary to understand this relationship. In addition, some caution is warranted about the generalizability of these findings as the smokers in MESA are generally healthier than the average smoking population due to our restriction to older adults without cardiovascular disease at baseline.

Our study is not without limitations. First, due to its cross-sectional design, our findings only provide evidence of potential associations that warrant further evaluation. Reverse causality is unlikely, however, and we have adjusted our models for a rich set of personal characteristics to account for between-person differences. Second, despite the highly innovative exposure assessment used, our exposure models are entirely spatial in nature and are assumed to capture the key differences in concentrations across space at different times. Our finding that associations were larger and more precise among persons living at their residences for >10 y may, however, suggest that our overall results may be biased towards the null due to inaccuracies in long-term exposures for some participants. On the other hand, compared with individuals who lived in their neighborhood for <10 y, residentially stable participants were more likely to be older, have hypertension, and have advanced emphysema, suggesting that these individuals may have been susceptible for other reasons. Another issue is that our models varied in predictive power by pollutant. Thus, differences in the observed strength of association between pollutants may be causal or could simply reflect different measurement errors. For example we found significant associations with PM2.5 and NO2, which, compared with PM10–2.5, had substantially better predictive ability due to a greater number of measurements that were collected over a longer period of time. In contrast, no associations were found with endotoxin, which had the lowest CV R2 in our prediction models. This finding may be the result of smaller errors for PM2.5 and NO2 that make them less likely to be biased toward the null in individual pollutant and multipollutant models. Finally, although the exposure estimation methods used in this study allow for individual assessment of outdoor concentrations, we do not have estimates of indoor or personal concentrations.

Despite these limitations, this work has many important strengths. The MESA cohort is an extremely well-characterized population with detailed and standardized measures of outcomes and covariates. The availability of RV measures is unique in such a large sample. Another distinction in this study is our exposure assessment, which improves on existing epidemiology studies of long-term exposures to PM10–2.5 in the United States. Our model predicts fine-scale spatial variability in exposures using a model derived from intensive air pollution monitoring campaigns in each study community. This methodology is in contrast to previous studies that have relied exclusively on data from relatively sparse national monitoring networks to estimate exposures to PM10–2.5 (Lipfert et al. 2006; McDonnell et al. 2000; Pope et al. 2002; Puett et al. 2009; Puett et al. 2011). We were also able to control for copollutants (PM2.5 and NO2) and demonstrated independent associations with PM10–2.5. The availability of chemical component data has particularly important implications for regulatory purposes, given that PM10–2.5 is generated by both natural and anthropogenic sources. This inclusion has important implications for regulatory purposes, given that PM10–2.5 is generated by both natural and anthropogenic sources.

Conclusion

This cross-sectional study provided some evidence of a positive association between long-term residential PM10–2.5 concentrations and RV mass among persons with a history of tobacco-smoke exposures and persons with severe emphysema. If replicated by future work, our findings could suggest a possible mechanism for observed associations between PM10–2.5 exposures and mortality from respiratory disease.

Acknowledgments

This work was supported by supported by grants RD 833741010 and RD 83169701 from the U.S. Environmental Protection Agency (EPA) and the National Institutes of Health (NIH) (R01 HL086719). MESA was further supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-RR-025005 from NCRR. MESA RV was funded by NIH R01-HL086719. MESA Lung was supported by NIH-R01-HL077612 and RC1 HL100543. MESA Neighborhood was supported by 2R01 HL071759. One author (P.S.T.) was supported by NIH P30 ES005605 and another (J.D.K.) by P30 ES07033 and K24 ES013195. Although funded by the U.S. EPA, this publication has not been formally reviewed by the U.S. EPA, and the views expressed in this document are solely the views of the authors. The U.S. EPA also does not endorse any products or commercial services mentioned in this publication.

The authors acknowledge the other investigators, staff, and participants of MESA and MESA Air for their valuable contributions to this work. A full list of MESA investigators and institutions is located at http://www.mesa-nhlbi.org.

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Alternative Test Methods for Developmental Neurotoxicity: A History and Path Forward (OECD EFSA workshop)

Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characterizing potential chemical hazards for the thousands of untested chemicals currently in commerce. Thus, research efforts over the past decade have endeavored to develop cost-effective alternative DNT testing methods. These efforts have begun to generate data that can inform regulatory decisions. Yet there are major challenges to both the acceptance and use of this data. Major scientific challenges for DNT include development of new methods and models that are “fit for purpose”, development of a decision-use framework, and regulatory acceptance of the methods. It is critical to understand that use of data from these methods will be driven mainly by the regulatory problems being addressed. Some problems may be addressed with limited datasets, while others may require data for large numbers of chemicals, or require the development and use of new biological and computational models. For example mechanistic information derived from in vitro DNT assays can be used to inform weight of evidence (WoE) or integrated approaches to testing and assessment (IATA) approaches for chemical-specific assessments. Alternatively, in vitro data can be used to prioritize (for further testing) the thousands of chemicals used in commerce for which there is no data at all on their potential to cause DNT. The focus of this problem-dictated strategy is that testing is driven by decision-making needs, and the amount of resource utilization is adjusted to provide efficient and timely data to address the needs. As the health and environmental impacts of the decision increase, data needs increase, resource use increases, and the need increases for reduced scientific uncertainty in estimates of risk. Recent advances in testing methods and models hold great promise for the development and use of efficient testing strategies for DNT that are capable of initial prioritization and screening, hazard characterization, and hazard prediction. This abstract does not necessarily reflect U.S. EPA policy.

Commercial Spectrum Enhancement Act Annual Progress Report for 2016

Topics: 
Spectrum ManagementAWS-1 Transition
Spectrum ManagementAWS-3 Transition
July 27, 2017

NTIA submits this report pursuant to Section 207 of the Commercial Spectrum Enhancement Act (CSEA), Title II of Pub. L. 108-494, which requires annual reporting on federal agencies’ progress to relocate radio communications systems from spectrum or share spectrum that has been reallocated to commercial use. This report provides details on two separate spectrum auctions conducted by the Federal Communications Commission (FCC) that included: 1) the 1710 to 1755 megahertz (MHz) band, and 2) the 1695-1710 MHz and 1755-1780 MHz bands.

Projected precipitation increases are bad news for water quality

An extensive algae bloom in Lake Erie in August, 2011 resulted from record-breaking nutrient loads.

Increased precipitation from a changing climate could pollute U.S. waterways with excess nitrogen, increasing the likelihood of severe water quality impairment from coast to coast, according to a new study by scientists Eva Sinha and Anna Michalak of the Carnegie Institution for Science and Venkatramani Balaji of Princeton University.

The results are published in this week’s issue of the journal Science.

The effects will be especially strong in the Midwest and

More at https://www.nsf.gov/news/news_summ.jsp?cntn_id=242494&WT.mc_id=USNSF_51&WT.mc_ev=click


This is an NSF News item.