Grantee Research Project Results
2016 Progress Report: Initial Annual CEMALB Progress Report: Human Health Effects of Environmental Pollutants
EPA Grant Number: CR835785Subproject: this is subproject number R835785 , established and managed by the Center Director under a main grant
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for Environmental Medicine, Asthma, lung biology
Center Director: Peden, David B
Title: Initial Annual CEMALB Progress Report: Human Health Effects of Environmental Pollutants
Investigators: Peden, David B , Jaspers, Ilona , Hernandez, Michelle L
Current Investigators: Peden, David B , Jaspers, Ilona , Hernandez, Michelle L , Alexis, Neil , Caughey, Melissa , Rebuli, Meghan E
Institution: University of North Carolina at Chapel Hill
EPA Project Officer: Schmitt, Michael
Project Period: April 1, 2015 through March 31, 2022
Project Period Covered by this Report: April 1, 2016 through March 31,2017
Project Amount: $9,800,000
RFA: Human Health Effects of Environmental Pollutants (2014) RFA Text
Research Category: Human Health
Objective:
- Discussion of the research performed during the reporting period and results (outputs/outcomes) that have been generated.
As originally proposed, this center is organized to be responsive to the research areas outlined in the funding announcement, which included: a) Multi-pollutant Interactions, b) Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, c) Susceptibility to Air Pollutants, d) Social Determinants of Health, e) Intervention Studies, and f) Biological Mechanisms.
As noted in the progress report (submitted 6/30/16) for the period beginning on 4/1/2015, this center has been revised and is focused on three projects. Project 1 is led by David Peden and is entitled Development of Interventions to Mitigate Inflammatory Response to Pollutants. Project 2 is led by Ilona Jaspers and is entitled Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, but has been revised during the reporting period to Development of Methodologies to Assess Health Effects Associated with Pollutant Exposures. Project 3 is led by Michelle Hernandez and is entitled Effect of bio-aerosols (LPS) on systemic and cardiovascular responses. These three projects respond to the areas Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources, Susceptibility to Air Pollutants, and Intervention Studies. It should be noted that while each project is led by Drs. Peden, Jaspers and Hernandez respectively, there is robust cross-collaboration by the PIs across each project.
Additionally, the funding announcement outlines the potential for additional program specific supplements to base funding to targeted program needs. During this initial year, three above base projects were proposed and agreed upon by the steering committee, all of which led by Dr. Jaspers (UNC) and Dr. Diaz-Sanchez (EPA). They are entitled Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects, Environmental Health Education, and Autophagy as a Key Determinant of Cell Fate in Air Pollution Health Effects Among Healthy and Type 2 Diabetics. Listed below are project summaries from year two. Detailed descriptions of each project are provided in the detailed project reports, which are provided with this overall report.
Progress Summary:
Project 1: Development of Interventions to mitigate Inflammatory Response to Pollutants:
The aims of Project 1 were modified in year 1, and outlined in the prior years project report. AS noted then, the primary activities of this project were to: 1.) to identify characteristics of people at risk for adverse response to pollutants; 2.) develop specific interventions to mitigate the inflammatory response to pollutants; 3.) to develop personalized wearable sensors to allow individuals to understand their personal exposures and physiological state (e.g. lung function, pulse, accelerometry) in conjunction with the ASSIST center at NCSU: and 4.) to develop programs in environmental precision medicine and health using big data approaches (with funding of an above base supplement to address some aspects of this aim). Each aim is outlined below, with progress in the protocols underway to address these goals are summarized below:
Progress in each aim:
Aim 1.) To identify characteristics of people at risk for adverse response to pollutants:
Protocol 15-1775 (D.Peden, PI): To identify persons who are susceptible to WSP-induced inflammation and examine the role of GSTM1 and other factors in this susceptibility. This is a single challenge protocol to identify responsive and non-responsive volunteers to 500 m g/m3 of woodsmoke particles (WSP). Healthy volunteers underwent exposure to 500 μg/m3 WSP for 2 hours with alternating 15-minute periods of exercise and rest to achieve minute ventilation of 20 L/min/m2. Induced sputum samples were obtained prior to and 6 hours after exposure for assessment of inflammatory cells and cytokines. Initial data were analyzed in 15 healthy volunteers have been studied and could provide qualifying sputum. On average, WSP exposure significantly increased mean sputum percent neutrophils (PMNs) [47% ± 18 (post) vs 31% ±18 (pre), n=15; p=.002] and PMNs/mg of sputum [370 ±152 (post) vs. 212 ±154 (pre), n=15; p=.003]. Sputum IL-8 concentration was significantly increased at 24 hours post-exposure [8714 pg/mL ± 9663 (post) vs. 3158 pg/mL ± 3151 (pre), n=14; p=0.05]. Using our established criterion that change in PMNs of at least 12% defined a responder, we observe that 25% of volunteers are non-responders, consistent with what we have observed for ozone and LPS. Overall, recruitment continues for GSTM1 analysis and 25 have completed the protocol, with 3 consented to enroll.
Protocol 15-2677 (D. Peden PI): Human biological responses to low level ozone: This study is designed to determine if exposed volunteers have cardiovascular, systemic and respiratory tract response to low level ozone which varies between 0.06 and 0.08 ppm O3 vs. filtered air. Additionally, ozone monitors developed in Aim 3 are being tested in this protocol. Planned enrollment is 16. To date, 13 have been consented, 6 have completed the study, and 5 are actively engaged in the study.
Data analyses of LPS response (D. Peden, N Alexis): We have currently reviewed data from 38 volunteers challenged with LPS and defined as responders (27) and non-responders (11) with regard to PMN influx into the airway. We had sputum mRNA from these volunteers. We observed that responders versus non-responders had significantly lower % PMN levels at baseline (29% vs. 62%) and greater post minus pre exposure changes (delta) in %PMN levels (delta: 30 vs 9). At baseline, 13 genes were identified as being differentially expressed in responders and non-responders. Ten of the 13 genes (77%) displayed increased expression in responders, among them cyclooxygenase 1 PTGS1, the enzyme that converts free arachidonic acid to prostaglandin H2. Three of the 13 genes (23%) displayed decreased expression in responders, including IL-8, a potent PMN chemoattractant, and IL18RAP, an IL-18 receptor binding enhancer that mediates downstream NF-kB activation. We are continuing RNA assessments and anticipate submission for publication soon.
Aim 2.) Develop specific interventions to mitigate the inflammatory response to pollutants;
Protocol 15-1938: Effect of gamma tocopherol enriched supplementation on response to inhaled O3 exposure (D. Peden, MD, PI). This is a double-blinded placebo controlled study of the effect of 1200 mg of oral gamma tocopherol for 4 doses over 48 hours on inflammatory response to 2-hour exposure to 0.25 ppm O3. To date 13 volunteers have been enrolled, with 8 completing the protocol, 2 in study and 3 failing to complete study for voluntary reasons. After 15 volunteers have been enrolled (and either completed for stopping study prematurely, a planned interim analysis will be undertaken. If there are definitive results (either there is a clear-cut effect of gT or study futility is recognized) the study will be terminated and results published.
Protocol 17-2303: (Allison Burbank, MD, PI). A phase II randomized, double blinded, placebo-controlled study of gamma tocopherol-enriched supplement on lower airway responses to inhaled wood smoke in healthy adults. This study will examine 20 volunteers exposed to 500 micrograms/m3 woodsmoke particles to determine if 2 doses of 700 mg of gamma tocopherol will mitigate the impact of WSP on airway inflammation. This protocol was the focus of substantial regulatory review, being submitted and approved by the FDA for an IND review , and the UNC Scientific Review Committee, and is now submitted for EPA and IRB review. Dr. Burbank completed her Allergy/Immunology and Clinical Pharmacology training and has joined the faculty of the Department of Pedoatrocs at UNC and is a new Investigator for the Center for Environmental Medicine, Asthma and Lung Biology.
Protocol 1529: Efficacy of Fish Oil or Olive Oil Supplementation on the Health Effects of Ozone Exposure in Healthy Young Subjects (James Samet, PhD, EPA, PI). As noted in last years report, CEMALB investigators are co-investigators in this study, and FDA approval was obtained for this protocol as an amendment to Dr. Pedens FDA IND for exposure to ozone (IND 71475) in 2/2017. The study is underway, but still relatively early in the study and no results are available
Aim 3.) To develop personalized wearable sensors to allow individuals to understand their personal exposures and physiological state
Protocol 14-1849 (D. Peden, PI): Exercise training and monitoring for environmental research This protocol is used to undertake rapid cycle improvement for testing of personal monitors and sensors for physiologic parameters (ECG, respiratory rate, accelerometry) developed by engineer-investigators at the NCSU-based assist center. To date, algorithms to estimate minute ventilation from accelerometry data are being developed, to be able to estimate the minute ventilation term in pollutant dosing in ambient settings. To date, 51 volunteers have completed this protocol, in which 2 sensor arrays have undergone development.
Additionally, Dr. Peden, is a key investigator in the UNC Biomedical Data Translator research team (led by Stan Ahalt of RENCI at UNC), which is part of a multi-site national consortium funded by the NIH (the National Center for Advancing Translational Sciences) to examine how various large data sets can be leveraged together to address medical, health and basic science questions. A unique element of the UNC proposal, which has now been adopted by the overall consortium, is inclusion of environmental data in big data assessments of health data. The UNCteam has done initial assessments with 10,000 asthma patients showing increased exposure to PM exposure in patients with increased acute episodes and severity. These data remain under analyses and publications are being developed. This project also led to an above base study by EPA and UNC scientists that is outlined under Above Base projects.
Project 2: Health Effects Associated with Inhaled Particulate Pollutants Derived from Specific Sources (now revised to Development of Methodologies to Assess Health Effects Associated with Pollutant Exposures): Previous studies conducted in close collaboration with investigators from EPA have demonstrated that exposure to DE prior to inoculation with live attenuated influenza virus (LAIV) increases markers of viral replication and allergic inflammation in allergic rhinitics. These responses were induced following exposure to two different sources of DE with different OC:EC ratios, suggesting that components other than organic carbon may be mediating the effects of DE on influenza infections. Similar to diesel exhaust (DE), oxidant pollutants derived from the incomplete combustion of organic matter, such as woodsmoke, are associated with increased respiratory infections. In addition, widespread use of organic matter, such as wood, for indoor heating and cooking, make exposure to woodsmoke and other biomass smoke an increasingly important global health issue. Direct cause-and-effect relationships between exposure to woodsmoke and increased risk for respiratory infections as well as potential mechanisms mediating these responses, are currently not well understood. To address this question, we used our well-established model of inoculation with LAIV as we model to mimic viral infections in humans in vivo.
To date, healthy nonsmoking young adult volunteers (n=39) were randomized to a 2-hr controlled chamber exposure to WSP (500 μg/cm3) generated from smoldering red oak, or clean air as control, then both groups were inoculated nasally with a standard vaccine dose of live attenuated influenza virus (LAIV). Nasal lavage was performed at pre-exposure baseline (day 0), and on day 1, day 2, and day 7 post-exposure. Nasal lavage fluid (NLF) cells were analyzed for inflammatory gene expression profiles and cell-free NLF were assayed for cytokines and chemokines by multiplex ELISA. In both the WSP (N=20) and control (N=19) exposure groups, LAIV induced expected transient increases in inflammatory (IL-6) and antiviral (IFNɣ) responses. Viral sequence quantity in NLF cells did not differ between WSP and control, but 4 of 20 WSP reported mild flu-like or upper respiratory symptoms, compared to only 1 of 19 controls. Among the panel of 30 cytokines and chemokines measured in NLF, more than half were significantly higher at baseline in males than in females. Only IL-10 was significantly affected by WSP exposure, with suppressed Day 2 response in WSP exposed subjects (median 0.9 fold change from baseline, interquartile 0.5-1.7) compared to controls (2.8 fold change, interquartile 0.9-6.2) (P=0.03). WSP-associated suppression of IL-10 receptor (IL10RB) was also noted in gene expression profiles from NLF cells (median 5.8 log2 fold decrease in WSP vs. control; P=0.001), and was more prominent in male subjects. Based on these observations we conclude that a 2-hour exposure to 500 μg/cm3 WSP was associated with suppression of post-LAIV IL-10 response in nasal secretions as well as IL10RB gene expression in NLF cells. Of note, we observed significant gender related differences in both baseline nasal mediators and in response patterns to LAIV and WSP. While the importance of these observations for human health is unclear, we speculate that WSP-induced suppression of IL-10 might delay resolution of virus-induced respiratory inflammation, resulting in enhanced symptoms and risk for post viral infection complications in susceptible individuals. Furthermore, these studies strongly indicate that gender should be considered as a variable in studies of particulate respiratory health effects. These findings were presented at the 2017 American Thoracic Society meeting and are currently being summarized for publication.
While the controlled exposure of humans to DE or woodsmoke facilitate establishing cause-and-effect relationships, these observations need to be translated into the community and populations naturally exposed to environmental contaminants. To address this gap, developed, optimized, and validated a novel non-invasive tools to sample the respiratory mucosa. The goal of these studies was to establish methodologies enabling investigators to assess markers of exposure and biomarkers of health effects in naturally exposed populations. This goal is a direct extension of our existing nasal lavage sampling technique, which is very well tolerated and can provide important information about mediator profiles and inflammatory cells lining the nasal mucosa. However, reproducibility, contamination with blood, variability of nasal lavage return, dilution of the nasal secretion, and need for laboratory space to process and store nasal lavage samples present experimental challenges especially for the types of studies proposed here. In an effort to improve the ease of non-invasively sampling nasal secretions, w e have adapted the technique of nasosorption of mucosal mediators using absorbent filter paper and Leukosorb (Pall Life Sciences) to collect nasal mucosal samples or epithelial lining fluid (ELF). This technique of ELF collection uses a strip of synthetic absorbant matrix cut to fit the nasal passage, which is inserted into each nostril, layered onto the inferior turbinate, and secured by a nasal clip. After 2 minutes, the strip is removed and stored until elution of the ELF material collected on the strip. Subjects can easily be trained to self-collect these samples without the need for clinical or laboratory type setting. Preliminary data suggest that drying the samples at room temperature (RT) or 37oC prior to elution does not affect the ability to recover and measure biomarkers of inflammation using this technique. In addition, the ELF sampling method enhances the ability to measure numerous biomarkers of inflammation and host defense responses with much greater efficiency than nasal lavage (data not shown). In addition to cytokines/chemokines, we could evaluate ELF samples for markers of specific immune cell activation, such as myeloperoxidase for neutrophils and monocytes, eosinophilic cationic protein for eosinophils, and granzyme B for cytotoxic lymphocytes. Furthermore, ELF could be assessed for specific pathogens or markers of specific pollutant exposure.
Activities to Optimize, Validate, and Apply this Methodology Conducted during the Reporting Period Include the Following:
- Compare Mediator Profiles in ELF, Induced Sputum, and BALF
ELF, induced sputum, and BALF collected from the same subject will be examined for the relative amount of cytokines/chemokines (using multiple ELISA platforms), neutrophil elastase, CC16, total protein as well as pH. Mediator profiles will be compared within each individual to determine whether there are respiratory tract region-specific mediators. These studies could be repeated in healthy versus diseased subjects (i.e. asthmatics) or used to determine demographic-dependent differences (i.e. sex, BMI, age, etc.) in these three different samples. For example, our preliminary data indicate that cytokines such as CXCL3/Fraktalkine correlate very well between ELF and sputum samples among different subjects, suggesting that that ELF CXCL3 levels could be used as a non-invasive indicator of effects in the lower airways.
- Assess Potential Health Disparities In Environmental Triggers Of Asthma
Dr. Hernandez (Co-I on this project) is currently enrolling African-American adolescent patients (age 12-18) with asthma into a clinical trial assessing asthma symptom control in her clinic in Raleigh. Based on symptom scores, lung function tests, environmental, and social history questionnaire, adjustments are made to the medication regimen. In addition, recommendations are made to reduce exposure to environmental triggers (i.e. exercise during certain times of the day, reduce allergen exposure, time spent outdoors, exposure to secondhand-smoker, etc.). Every patient is asked to return to the clinic 6-8 weeks later and undergoes the same tests to determine potential changes in asthma symptom severity. Using Dr. Hernandez patient population, we have added our non-invasive ELF sampling technique to the existing study to obtain biomarkers of disease before and after asthma control adjustment in adolescents from predominantly underserved communities. We will assess soluble markers indicative of 1) overall inflammation (IL-1β, IL-8, TNFα, IL-6, prostaglandin E2), 2) allergic inflammation (eosinophil cationic protein, IL-4, IL-13, mast cell tryptase), and 3) neutrophilic inflammation (neutrophil elastase, myeloperoxidase) before and after asthma control adjustments. ELF will also be analyzed for markers of tobacco smoke exposure (i.e. cotinine), a major trigger for asthma exacerbation. These data will be integrated with asthma symptom questionnaire data, to determine to what extend biomarkers are reflective of perceived symptoms in this at-risk population. We envision that data obtained from these subjects could also be integrated with ambient air pollution data, thus determining potential correlation between pollutant exposure, biological measures of respiratory inflammation, and asthma symptom scores.
- Determine Pollutant-induced Changes in ELF the non-invasiveness of the ELF collection, we envision including this methodology in all ongoing controlled exposure studies. ELF collection has already been added to ongoing portocols, such as SNOZ and GAMMOZ. Since the ability to retrieve mediators from ELF is not affected by repeated collection, we propose to include this methodology to obtain time-course measurements of pollutant-induced inflammatory mediator levels. For example, ELF could be collected just prior as well as every hour following a controlled pollutant exposure, thus yielding much more detailed data on the course and resolution of inflammation or injury following a defined exposure.
- Develop Rapid Response Protocol to Collect ELF Samples in Non-Laboratory Settings
We believe that collection of ELF is a valuable novel and non-invasive tool to gain information on biomarkers of exposure and disease severity. Similar to dried blood spots, we expect that collection of ELF is field-deployable and adaptable to studies needing the collection of biological samples in non-laboratory or clinical settings. With the goal of developing a rapid response protocol, we initiated discussions with investigators from NIEHS who have already developed the Rapid Acquisition of Pre- and Post-Incident Disaster Data (RAPIDD) study, which is a protocol template intended to minimize the time between environmental disaster and ability to collect health data and biological samples from disaster response workers.
Project 3: Establish whether LPS inhalation induces Systemic inflammation and CV inflammation (previously the project was entitled IL-1β and Anakinra in Modulation of O3-induced inflammation in Asthma):. As noted in the report from the prior year the Steering Committee agreed that Project 3 would redirect efforts to examination of the role of biological components of PM on cardiovascular outcomes. This led to to development of the following protocol:
Protocol 15-1458:Systemic inflammatory response to 20,000 EU Clinical Center Reference Endotoxin in Normal Adults (M. Hernandez, PI)
The goal of this study (also known as Endoscreen) is to assess 18 healthy volunteers with an inhaled LPS challenge to first establish responsiveness to inhaled LPS. It is estimated that up to 30% of the population may not be responsive to inhaled LPS. Inhaled LPS response will be established by detecting at least a 20% increase from baseline levels of neutrophils in the blood, and/or by a 10% increase from baseline levels of neutrophils in induced sputum samples. In addition, as secondary endpoints, we will evaluate inflammatory cytokine levels in systemic circulation and access for the presence of genes thought to be related to endotoxin response. Subjects will wear a cardiac monitor known as Faros 180 to monitor heart rate variability, an autonomic index that has been previously shown to be affected by high dose ozone exposure (Devlin RB et al, Circulation, 2012). The Endoscreen study will provide not only data on LPS responsiveness, but will also provide preliminary associations between changes in LPS-induced heart rate variability.
This study required us to submit an amendment (#55) to our CCRE IND: Protocol 15, Amendment #55 of IND BB-9998 Airway response to clinical center reference endotoxin in healthy adults. On 5/5/2016, we received notification from the FDA review coordinator no clinical hold on proceeding with this study, though minor revisions were requested to the document. We submitted the revised protocol on 5/23/16 to FDA, and an IRB application was submitted to UNC on 5/26/16. The IRB 15-1458 was approved on 6/28/2016. In the interim, the NIH chose to use a new source of endotoxin for inhalation challenge studies. NIH investigators then went through the FDA approval process to test the new endotoxin source. They received approvals in August 2017, and sent us new vials of endotoxin for inhalation in September 2017. Recruitment for this study began in November 2017.
While proceeding with this approval process, we also queried our Biorepository and Data Base and identified data from healthy volunteers and allergic asthmatics who participated in our past endotoxin studies using 20,000 EU CCRE within the past 10 years. We have previously undertaken 2 studies of a nutritional anti-inflammatory therapy, gamma tocopherol (γT), the dietary isoform of vitamin E, and have shown that it has anti-inflammatory properties against LPS-induced inflammatory responses. Biological data include neutrophil counts and cytokine levels in the blood and sputum at baseline and 6 hours after challenge. We used the data from both studies to address the role of specific risk factors (GSTM1 status and BMI) in response to LPS and effectiveness of gamma tocopherol
In these studies, a total of 28 subjects (13 healthy volunteers and 15 subjects with mild asthma) underwent cross-over studies where they received treatment 1200 mg gamma Tocopherol and placebo treatment. γT supplementation reduced post-challenge sputum neutrophilia compared to placebo in both HV and asthmatics (p=0.03 and p=0.04, respectively). Using linear regression modeling and Wilcoxon rank sum test, respectively, the effect of BMI and GSTM1 genotype on response to inhaled endotoxin and the reduction in endotoxin-induced sputum neutrophilia following γT treatment in each study was assessed. We found that neither BMI nor GSTM1 genotype had any effect on response to inhaled endotoxin, as measured by increase in sputum neutrophilia, in HV (p=0.17 and p=0.90, respectively) or asthmatics (p=0.81 and p=0.52, respectively). Similarly, GSTM1 genotype had no effect on the reduction in endotoxin-induced sputum neutrophilia following γT treatment in HV (p=0.42) or asthmatics (p=0.78).
However, higher BMI was associated with greater reduction in post-challenge sputum neutrophilia following γT treatment in HV (p=0.03) but not definitively in asthmatics (p=0.14). Response to inhaled endotoxin in HV and asthmatics is not affected by BMI or GSTM1 status. However, γT treatment reduces endotoxin-induced sputum neutrophilia regardless of GSTM1 status, with enhanced responses seen in those with higher BMI.
This work was accepted as a presentation for the AAAAI/WAO Congress meeting in March 2018 in Orlando, FL. A Sood, AJ Burbank, CG Duran, K Enders, H Zhou, DB Peden, ML Hernandez. Gamma Tocopherol (γT) Supplementation Reduces Endotoxin-Induced Sputum Neutrophilia in Healthy Volunteers and Asthmatics Regardless of BMI or GSTM1 genotype. The resulting manuscript is currently in preparation for submission to the Journal of Allergy & Clinical Immunology.
Protocol 12-1588: Observational assessment of baseline asthma control as a susceptibility factor for air pollution health effects in African-American children with persistent asthma (Teen AIRE Study)
We continued analysis of data from our observational panel study of African American adolescents, ages 12-17, with persistent asthma living in a defined geographical area of Wake County (Teen AIRE). Asthma status was assessed using NHLBI guideline criteria, with 14 volunteers having poorly controlled asthma and 11 having well- controlled asthma. These volunteers were followed over a course of 6-8 weeks through 6 visits. Endpoints included weekly measurements of pulmonary function, assessment of asthma control through the Asthma Control Questionnaire, autonomic control of heart rhythm and vascular markers of inflammation, and clotting/coagulation and exposure. We specifically focused on the health effects attributed to low levels of ozone in the 5 days preceding each participants clinic visits in their residential locations, controlling for exposure to ambient fine particle (PM2.5) and coarse particle (PM10) exposures. Because BMI has been previously associated with differential responses to ambient air pollution, we stratified health effects by BMI status (<25, normal weight v. >25, overweight).
All participants were exposed to low levels of ambient ozone (below the NAAQS of 70 ppb) throughout the course of the study and received a high level of clinical care, including stepping up of asthma controller medications as needed based on asthma control status. Despite this level of medical management, we still observed an association between increased ambient ozone concentration and reduced lung function measurements (FVC and FEV1). For %predicted FVC, the strongest effect was observed for ozone concentrations in the 24-hour period preceding clinic visits (lag 0), where there was a decrease of 2.7% predicted FVC (p =0.02). This decrement diminished for the preceding 24 to 48-hr period (lag 1) to 1.3%, and for the previous 5 day moving average a decrease of 2.9% was seen near significance (p=0.07). Similar results were observed for % predicted FEV1, where there was a 2.5% decrease at lag 0 (p=0.07) and a decrease of 1.6% at lag 1. In a two-pollutant model, we examined whether ozone effects were confounded by PM2.5. The effect estimates were minimally altered with a decrease of 2.5% and 1.4 % seen at lag 0 and lag 1, respectively.
Additionally, we provide what we believe is the first report of systemic changes by short-term ozone exposure in children. In particular, a highly significant (p<0.001) increase in total cholesterol levels of 5.56 mg/dL at lag 1, per IQR of ozone was observed. Changes in LDL followed the same pattern. At the same lag 1, an association with a 3.6 mg/dL increase in LDL was also observed (p=0.06). No changes in triglycerides or VLDL were observed. Additionally, cholesterol and LDL were elevated at lag 1 among those with high BMI.
Surprisingly, baseline levels of asthma control, rarely examined in pollutant studies, did not modify susceptibility to ambient air pollution. Our results suggest that low-level ozone can still impact respiratory outcomes regardless of baseline control status or daily controller treatment, and implies that environmental awareness or novel interventions that are not currently used in asthma may need to be employed in medical evaluation and treatment guidance for environmental asthma. Additionally, the cardiovascular effects of low level ozone in adolescents with asthma with elevated BMI, will need to be further examined in larger scale studies.
This work was accepted for inclusion as a presentation at the March 2018 AAAAI/WAO meeting in Orlando, FL, and the resulting manuscript, tentatively entitled Low level Ozone has both systemic and respiratory effects in African-American children with asthma is in the final stages of preparation for submission to the Journal of Allergy & Clinical Immunology, submission no later than 12/20/2017: Michelle L. Hernandez, MD, Radhika Dhingra, PhD, Allison J. Burbank, MD, Krista Todorich, MD, Celia E Loughlin, MD; Marcia Frye MD, Kelly Duncan, PhD, Carole Robinette, MS; Katherine Mills, BA, Robert B Devlin, PhD, David B. Peden, MD, David Diaz-Sanchez, PhD.
Additionally, we examined the performance characteristics of the Asthma Control Questionnaire compared to physician assessment of asthma control. The Asthma Control Questionnaire (ACQ) is of particular interest in research settings for determining the efficacy of asthma interventions or the impact of environmental exposures in adults and children, yet the cut points for well controlled and not well controlled asthma have not been validated in minority populations such as African-Americans. Given that African-Americans experience the highest rates of asthma-related morbidity and mortality, it is imperative that standardized asthma questionnaires be validated in this population. We found that a cut-off score of 1.0 demonstrated the highest area under the curve (AUC=0.836) with a sensitivity of 58.5% and specificity of 90.7% as well as the largest Cohens kappa (k= 0.5), indicating moderate agreement between ACQ and physician assessment of asthma control. These results were presented at the March 2017 AAAAI meeting in Atlanta, GA and are currently in preparation for submission to Annals of Allergy, Asthma, & Immunology.
Dr. Hernandez also completed data analysis for the protocol Broccoz: A randomized clinical trial of the NRF2 activator Sulforaphane against ozone-induced injury, initiatied in the previous cooperative agreement. This project follows on prior work by both EPA and UNC scientists that indicates that oral supplementation with Sulforaphane (SFN), an antioxidant compound derived from broccosprouts, upregulates expression of NRF2-regulated antioxidant enzymes in nasal cells which should protect against oxidant stress related responses induced by pollutants. We tested in vivo if SFN can suppress O3-induced decrements in lung function and inflammation in human volunteers. Sixteen healthy volunteers completed a double-blinded, placebo controlled crossover study in which they were treated with a SFN-rich broccosprout homogenate (BSH) vs. alfalfa sprout homogenate (placebo). After 3 days of daily supplementation, they underwent a 2-hour 0.4 part per million O3 exposure. Spirometry was performed immediately before and after the O3 exposures. Sputum induction was performed four hours after the O3 exposure. We observed that while three days of supplementation with BSH significantly increased plasma levels of SFN and its metabolites (p=0.001) compared to placebo, BSH did not significantly blunt O3-induced decrements in spirometry or increases in post-O3 sputum neutrophilia, sputum inflammatory cytokines, or nasal epithelial cell NRF2-regulated gene expression. Thus, three days of BSH supplementation successfully increased systemic SFN levels and its major metabolites in healthy volunteers, but did not confer protection against O3 -induced changes in lung function or airway inflammation in vivo. This manuscript was accepted and published: Duran CG, Burbank AJ, Mills KH, Duckworth HR, Aleman MM, Kesic MJ, Peden DB, Pan Y, Zhou H, Hernandez ML. A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respir Res. 2016 Jul 22;17(1):89
Above Base Project: Environmental Health Education : Both the EPA and CEMALB have a long and distinguished track record in support of activities that promote environmental public health education. Environmental Health is a fast moving field that encompasses toxicology, environmental medicine, microbiome, epidemiology, genomics, epigenetics, and many other fields. In addition, community engagement in public health research and in the dissemination of scientific facts is of increasing interest. Currently, CEMALB and UNC-CH at large has several initiatives to train students/postdocs by familiarizing them in the latest developments in these areas so as to enable them to understand better current and future environmental challenges. Linking state-of-the-art biomedical training with opportunities to actively engage in community-based public health research will better prepare our trainees for careers in Environmental Health.
In order to foster these initiatives, following goals are proposed:
To attract potential trainees to the field of Environmental Public Health.
To provide the opportunity for trainees to travel to meetings to further their education in Environmental Public Health
To provide the opportunity for trainees to interact with experts in Environmental Public Health
To enhance community-based research skills by supporting additional training opportunities
In pursuing these goals, we received applications from 5 trainees and awarded 1 travel award. All three applications were reviewed by a committee composed of the members of the Curriculum in Toxicology executive committee (which includes UNC and EPA Scientists) and ranked based on their merit. The awarded trainee traveled to the 2017 Society of Toxicology meeting to present his research and interact with other environmental health scientists. We also solicited applications for extramural training opportunities to further enrich education in Environmental Public Health outside of UNC and EPA in the RTP area. We reviewed 2 applications and awarded on extramural training award during the previous reporting period. Additionally, a committee composed of current Curriculum in Toxicology predoctoral and postdoctoral trainees identified 5-6 experts in environmental public health (usually 5-6) and ranks them based on interest of their research focus and reputation for mentoring young scientists. The top candidate is invited for a seminar at UNC-CH and discussions with local scientists. The committee organizes the invitation, the seminar, as well as the overall itinerary for the invited speaker. The attendance of the seminar usually exceeds 50 attendees, including many investigators from CEMALB and EPA. During the current reporting period, Dr. Terrance Kavanagh, PhD, Professor, University of Washington presented on the Genetic Determinants of Nanoparticle-Induced Lung Inflammation in Mice and Dr. Sasha Kaufmann, Associate Professor, University of CA, San Diego, Department of Reproductive Medicine presented on Steroid Hormone Regulation of Mammalian Reproductive Brain Circuits in Development and Adulthood.
Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects: Large datasets generated through emerging omics technology (epigenomics, metagenomics, genomics, proteomics, microbiomics and metabolomics) are increasingly being used to provide unbiased assessment of pollutant-induced adverse health effects, including identification of biomarkers of exposure, biomarkers of health effects, prediction of susceptibility and understanding biological mechanisms. Investigators in CEMALB have used these technologies to understand responsiveness to pollutants, such as ozone, investigate epigenetic markers of susceptibility, and identify novel biological pathways. In addition, utilizing metagenomic analyses of human samples, studies are proposed assessing the interplay between mucosal microbiota and inhaled pollutants in the mediating adverse health effects. This project facilitated large dataset analysis through SciOme, which is a technology consulting company supporting bioinformatics analyses of complex large datasets. This project also provided additional support for trainees to extend findings of projects they are undertaking using dataset analyses of omics data. Toxicology graduate students Emma Bowers and Kim Stratford , as well as Environmental Sciences and Engineering graduate student, Virginia Bass have been supported this year in this fashion. Previous trainees supported through this fashion also included Dana Walsh and Dr. Jaime Mirowsky. These projects have yielded 7 publications to date.
We have also expanded this above base project to leverage activity noted in Project1 to employ big data approaches to assess the impact of environmental agents on human health. These initiatives involve access to the Carolina Data Warehouse, a repository of electronic health records from >1,000,000 patients from UNC, Duke and Wake Forest. We have facilitated interaction between EPA & CEMALB investigators and biomedical informatics researchers based at the NC Translational and Clinical Sciences Institute and the UNC Biomedical Data Translator team based at RENCI, the Institute for the Environment, and NC TraCS. Dr. Peden plays a role in each of these projects and has facilitated access of Cavin Ward-Caviness of EPA (with David Diaz-Sanchez and Robert Devlin) to these data to facilitate assessment of PM 2.5 to cardiovascular outcomes from another large dataset.
Above Base Project: Title of Project: Autophagy as a Key Determinant of Cell Fate in Air Pollution Health Effects Among Healthy and Type 2 Diabetics:
This project supports Andres Henriquez working with Urmila Kodavanti (his EPA mentor). The original focus was the role that autophagy in mediating resolution (or lack of resolution) of ozone-induced lung inflammation and metabolic responses. However, while it was possible to reliably establish techniques for assessing critical markers of autophagy using Western blotting, it was problematic to find right the correct analytical tools antibodies that provided consistent results when performing repeat assessments. Also, after overcoming these difficulties, it was found that ozone-induced cellular changes in vitro did not involve autophagy changes that could be detectable. BEAS-2B cultures were used and highly variable results were obtained during each repeat led to difficulty in reliably assessing this process. As a result, the project was modified to assess the contribution of stress hormones in ozone-induced lung injury and inflammation. Since the other ongoing projects in the lab involving the role of stress hormones has resulted in novel insights, these are being further explored in relation to the roles of epinephrine and corticosterone in mediating ozone-induced lung injury and inflammation in this project. This project now consistent with the EPA program focus of Biological Mechanisms outlined in the Funding Announcement.
In pursuing the new focus, the involvement of immune cell changes and pulmonary inflammation were assessed at protein and gene expression levels in the lungs, BALF and serum samples from a study involving ozone exposure in rats with SHAM, adrenal demedullation or total bilateral adrenalectomy surgeries to examine the contribution of stress hormones. Andres made a presentation at the SOT 2017 meeting related to these data. Additional assessment of samples involving lung tissue gene expression profiling in SHAM and adrenalectomized rats using global RNASeq is completed as the specific aim 1. Studies proposed for specific aim 2A involving pharmacological means of intervening stress hormone receptors have been completed. Aim 2B study, which will include adrenalectomy in conjunction with pharmacological interventions, has also been completed. Andres Henriquez successfully defended his doctoral dissertation and this work has already resulted in 3 publications with another 2 publications currently submitted/under review.
- Discussion of difficulties the Center has encountered in carrying out its mission, and remedial actions taken. If the goals/hypotheses of any project funded under this Center have been modified from the original application, provide the revised goals and discuss the reason for the change. A discussion of any problems, delays, or adverse conditions which may materially impair the ability to meet the results (outputs/outcomes) specified in the application should also be provided.
Revised goals for any projects and discussion of the reason for the change: No further modifications were made for Projects 1 and 3. Revised goals for Project 2 were approved as outlined below.
Revised Goals for Project 2: Project 2 underwent revisions from the original proposal (focused on controlled exposures to woodsmoke and other combustion emission mixtures) to broaden the objectives to include population-based studies. While controlled laboratory exposure studies provide opportunities to establish clear exposure-effect relationships, they often lack the complexity of variables associated with ambient exposures in the community. On the other hand, large-scale population studies or cohort studies often lack the ability to non-invasively obtain respiratory bio specimens that could yield information about pulmonary health effects associated with specific ambient exposures. Project 2 was revised to address this gap by developing, optimizing, and validating non-invasive, field-deployable sampling techniques, allowing investigators to sample the respiratory mucosa for pulmonary biomarkers. Using a strip of synthetic absorbent matrix, we are developing a methodology of collecting nasal mucosal secretions from human volunteers, which can be analyzed for markers of inflammation, host defense responses, presence of potential pathogens, and markers of ambient exposures. Briefly, a strip of absorbent filter paper designed to fit with easy into in the nasal passages is inserted into each nostril, clamped with padded nose clips for 1-2 minutes, removed, and stored until analysis. Relevant to this proposed application is the fact that the ability to recover biomarkers of inflammation or immune responses is not affected by storage temperature, thus making it field-ready and suitable for the collection of biomarkers in a non-laboratory setting or community-based cohort. Moreover, the collection of nasal secretion is very non-invasive, reproducible, and easy-to-use, thus posing no restrictions on the population, including children or subjects with significant pre-existing conditions, that can be sampled for biomarkers. We envision that these samples can be used to determine markers of inflammation, injury, host defense, as well as markers of exposure, which can be integrated with additional exposure assessment data and health outcomes. Therefore, we hypothesize that non-invasive sampling of the nasal mucosa can yield biological samples representative of respiratory responses and that this technology is adaptable to community-based field studies.
Approval of Modification of Project 2: As documented in the minutes of the Steering Committee meetings on January 18th, 2017 and the final confirmation email from the Project Officer, Mike Schmitt, on January 19th, 2017, this change in broadening the goals was reviewed, discussed, and approved. The final modification of Project 2 has been added to the CEMALB Coop files on January 19th. 2017.
Difficulties the Center has encountered in carrying out its mission, and remedial actions taken: Protocol Activation: As noted in the project reviews, extensive regulatory reviews accompany each new and revised protocol. However, progress has been made accounting for these delays. Additionally, archived and database data and samples from prior EPA supported studies to address the goals of each project, as noted in each project description.
- Discussion of any absence or changes of key personnel involved in the individual projects or Center management.
There have been no changes or absences of Key Personnel. However, we do note the recruitment of Allison Burbank, MD, who recently completed training in Allergy and Immunology and has joined the CEMALB as a faculty investigator in the CEMALB and an Assistant Professor in the Department of Pediatrics. She is active in Project 1, Project 3, and Medical, Physiology and Study Coordination Core.
- Discussion of expenditures to date and an explanation of any costs which are significantly higher or lower than originally estimated.
A detailed financial report will accompany this annual report. Overall, actual expenditures are matching up appropriately with how these were budgeted.
- Discussion of how the quality assurance requirements of the following are being met in accordance with 40 C.F.R. Part 30, Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations.
The quality assurance requirements of the CEMALB are being met in the following manner: The CEMALB is part of the University of North Carolina, School of Medicine. Consequently, the CEMALB administrative structure and policies are typical of academic institutions in that it gives its investigators substantial independence in carrying out their research activities. Support staff working on a project are usually under the supervision of the investigator who leads the project. Therefore, Quality Assurance Program (QAP) for CEMALB research has traditionally been a responsibility delegated to individual investigators. Investigator control and responsibility for quality assurance (QA) have been maintained as central features of the CEMALB QAP. The QA/QC officer for CEMALB is Dr. Neil Alexis (neil_alexis@med.unc.edu) and access to the QAP can be arranged through contacting his office.
The CEMALB QAP exists to provide guidelines to its staff and assist investigators in dealing with issues that affect the quality of the data produced by CEMALB research activities, particularly, data accuracy and validity. In this regard, the QAP is in itself the implementation of a QA policy by the CEMALB. The QAP serves to prevent, detect and correct any deviations in data integrity and quality. In addition, the QAP acts to facilitate compliance with outside granting agency requirements for research grant proposals or potential audits. The main areas covered by the CEMALB QAP and therefore meeting the requirements of 40 C.F.R. Part 30, Grants and Agreements with Institutions of higher Education, Hospitals, and Other Non-Profit include: Organization and management; Quality Systems; Project or Component Specific QA; Documentation and Records. In addition to the CEMALB QAP, CEMALB investigators and staff preparing projects supported by US EPA follow relevant Quality Assurance Documents prepared by the US EPA Quality Staff. The complete list of US EPA QA documents can be accessed at the following website: https://www.epa.gov/quality/qa. Below are the most applicable documents that are accessible to CEMALB investigators.
These documents are located in G:\\Shared\CEMALB\QA\ directory for easy reference.
- EPA Requirements for Quality Management Plans (QA/R-2), EPA/240/B-01/002, March 2001. Provides specifications for Quality Management Plans (QMPs) for organizations that receive funding from EPA. These specifications are equivalent to chapter 3 of EPA Manual 5360.
https://www.epa.gov/quality/qs-docs/r2-final.pdf
- EPA Requirement for Quality Assurance Project Plans (QA/R-5), EPA/240/B-01/003, March 2001. Provides specifications for QA Project Plans prepared for activities conducted by or funded by EPA. These specifications are equivalent to chapter 5 of EPA Manual 5360.
https://www.epa.gov/quality/qs-docs/r5-final.pdf
- Data Quality Assessment: A Reviewers Guide (QA/G-9R), EPA/240/B-06/002, February 2006. General guidance to organizations on assessing data quality criteria and performance specifications for decision making. G-9R is non-technical document and shows a reviewer what constitutes an appropriate Data Quality Assessment (DQA).
https://www.epa.gov/quality/qs-docs/g9r-final
- Guidance for Quality Assurance Project Plans (QA/G-5), EPA/240/R-02/009, December 2002. Guidance on developing Quality Assurance Project Plans that meet EPA specifications.
https://www.epa.gov/quality/qs-docs/g5g-final.pdf
- Guidance for Preparing Standard Operating Procedures (QA/G-6), EPA/240/B-07/001, April 2007. Guidance on the development and documentation of Standard Operating Procedures.
https://www.epa.gov/quality/qs-docs/g6-final.pdf
The G:\\Shared\CEMALB\QA\SOP directory also contains the following files that may help the investigators to develop the QA and SOP/ROP for specific projects:
QMP for the EPHD US EPA National Health and Environmental Effects Research Laboratory-Health Divisions (NHEERL-H) Guidelines for Laboratory Record Keeping (NHEERL-H/QA-RK-95/00). QA_BALT.wpd is Quality Assurance Project Plan for 1998 Baltimore epi study, as an example of QMA. Furthermore, in addition to the CEMALB QAP the investigators and staff preparing a project sponsored by other granting agencies and funding entities follow QAPs issued by those institutions as appropriate. For example, each NIH Institute, FDA or HEI has its own QA guidelines with more specific guidelines for each research category or even specific studies. Documents listed below are used to develop a study-specific QAP.
The following NIH documents related to human research will be helpful in preparation, and conduct of a NIH sponsored studies, namely:
(a) Guidelines for the Conduct of Research Involving Human Subjects,
(b) Guidelines for Writing Research Protocols, and
(c) Assurance of Compliance with DHHS Regulations for the Protection of Human Subjects (45 CFR 46), published by the NIH Office of Human Subjects Research.
Future Activities:
- Discussion of difficulties the Center has encountered in carrying out its mission, and remedial actions taken. If the goals/hypotheses of any project funded under this Center have been modified from the original application, provide the revised goals and discuss the reason for the change. A discussion of any problems, delays, or adverse conditions which may materially impair the ability to meet the results (outputs/outcomes) specified in the application should also be provided.
Revised goals for any projects and discussion of the reason for the change: No further modifications were made for Projects 1 and 3. Revised goals for Project 2 were approved as outlined below.
Revised Goals for Project 2: Project 2 underwent revisions from the original proposal (focused on controlled exposures to woodsmoke and other combustion emission mixtures) to broaden the objectives to include population-based studies. While controlled laboratory exposure studies provide opportunities to establish clear exposure-effect relationships, they often lack the complexity of variables associated with ambient exposures in the community. On the other hand, large-scale population studies or cohort studies often lack the ability to non-invasively obtain respiratory bio specimens that could yield information about pulmonary health effects associated with specific ambient exposures. Project 2 was revised to address this gap by developing, optimizing, and validating non-invasive, field-deployable sampling techniques, allowing investigators to sample the respiratory mucosa for pulmonary biomarkers. Using a strip of synthetic absorbent matrix, we are developing a methodology of collecting nasal mucosal secretions from human volunteers, which can be analyzed for markers of inflammation, host defense responses, presence of potential pathogens, and markers of ambient exposures. Briefly, a strip of absorbent filter paper designed to fit with easy into in the nasal passages is inserted into each nostril, clamped with padded nose clips for 1-2 minutes, removed, and stored until analysis. Relevant to this proposed application is the fact that the ability to recover biomarkers of inflammation or immune responses is not affected by storage temperature, thus making it field-ready and suitable for the collection of biomarkers in a non-laboratory setting or community-based cohort. Moreover, the collection of nasal secretion is very non-invasive, reproducible, and easy-to-use, thus posing no restrictions on the population, including children or subjects with significant pre-existing conditions, that can be sampled for biomarkers. We envision that these samples can be used to determine markers of inflammation, injury, host defense, as well as markers of exposure, which can be integrated with additional exposure assessment data and health outcomes. Therefore, we hypothesize that non-invasive sampling of the nasal mucosa can yield biological samples representative of respiratory responses and that this technology is adaptable to community-based field studies.
Approval of Modification of Project 2: As documented in the minutes of the Steering Committee meetings on January 18th, 2017 and the final confirmation email from the Project Officer, Mike Schmitt, on January 19th, 2017, this change in broadening the goals was reviewed, discussed, and approved. The final modification of Project 2 has been added to the CEMALB Coop files on January 19th. 2017.
Difficulties the Center has encountered in carrying out its mission, and remedial actions taken: Protocol Activation: As noted in the project reviews, extensive regulatory reviews accompany each new and revised protocol. However, progress has been made accounting for these delays. Additionally, archived and database data and samples from prior EPA supported studies to address the goals of each project, as noted in each project description.
- Discussion of any absence or changes of key personnel involved in the individual projects or Center management.
There have been no changes or absences of Key Personnel. However, we do note the recruitment of Allison Burbank, MD, who recently completed training in Allergy and Immunology and has joined the CEMALB as a faculty investigator in the CEMALB and an Assistant Professor in the Department of Pediatrics. She is active in Project 1, Project 3, and Medical, Physiology and Study Coordination Core.
- Discussion of expenditures to date and an explanation of any costs which are significantly higher or lower than originally estimated.
A detailed financial report will accompany this annual report. Overall, actual expenditures are matching up appropriately with how these were budgeted.
- Discussion of how the quality assurance requirements of the following are being met in accordance with 40 C.F.R. Part 30, Grants and Agreements with Institutions of Higher Education, Hospitals, and Other Non-Profit Organizations.
The quality assurance requirements of the CEMALB are being met in the following manner: The CEMALB is part of the University of North Carolina, School of Medicine. Consequently, the CEMALB administrative structure and policies are typical of academic institutions in that it gives its investigators substantial independence in carrying out their research activities. Support staff working on a project are usually under the supervision of the investigator who leads the project. Therefore, Quality Assurance Program (QAP) for CEMALB research has traditionally been a responsibility delegated to individual investigators. Investigator control and responsibility for quality assurance (QA) have been maintained as central features of the CEMALB QAP. The QA/QC officer for CEMALB is Dr. Neil Alexis (neil_alexis@med.unc.edu) and access to the QAP can be arranged through contacting his office.
The CEMALB QAP exists to provide guidelines to its staff and assist investigators in dealing with issues that affect the quality of the data produced by CEMALB research activities, particularly, data accuracy and validity. In this regard, the QAP is in itself the implementation of a QA policy by the CEMALB. The QAP serves to prevent, detect and correct any deviations in data integrity and quality. In addition, the QAP acts to facilitate compliance with outside granting agency requirements for research grant proposals or potential audits. The main areas covered by the CEMALB QAP and therefore meeting the requirements of 40 C.F.R. Part 30, Grants and Agreements with Institutions of higher Education, Hospitals, and Other Non-Profit include: Organization and management; Quality Systems; Project or Component Specific QA; Documentation and Records. In addition to the CEMALB QAP, CEMALB investigators and staff preparing projects supported by US EPA follow relevant Quality Assurance Documents prepared by the US EPA Quality Staff. The complete list of US EPA QA documents can be accessed at the following website: https://www.epa.gov/quality/qa. Below are the most applicable documents that are accessible to CEMALB investigators.
These documents are located in G:\\Shared\CEMALB\QA\ directory for easy reference.
- EPA Requirements for Quality Management Plans (QA/R-2), EPA/240/B-01/002, March 2001. Provides specifications for Quality Management Plans (QMPs) for organizations that receive funding from EPA. These specifications are equivalent to chapter 3 of EPA Manual 5360.
https://www.epa.gov/quality/qs-docs/r2-final.pdf
- EPA Requirement for Quality Assurance Project Plans (QA/R-5), EPA/240/B-01/003, March 2001. Provides specifications for QA Project Plans prepared for activities conducted by or funded by EPA. These specifications are equivalent to chapter 5 of EPA Manual 5360.
https://www.epa.gov/quality/qs-docs/r5-final.pdf
- Data Quality Assessment: A Reviewers Guide (QA/G-9R), EPA/240/B-06/002, February 2006. General guidance to organizations on assessing data quality criteria and performance specifications for decision making. G-9R is non-technical document and shows a reviewer what constitutes an appropriate Data Quality Assessment (DQA).
https://www.epa.gov/quality/qs-docs/g9r-final
- Guidance for Quality Assurance Project Plans (QA/G-5), EPA/240/R-02/009, December 2002. Guidance on developing Quality Assurance Project Plans that meet EPA specifications.
https://www.epa.gov/quality/qs-docs/g5g-final.pdf
- Guidance for Preparing Standard Operating Procedures (QA/G-6), EPA/240/B-07/001, April 2007. Guidance on the development and documentation of Standard Operating Procedures.
https://www.epa.gov/quality/qs-docs/g6-final.pdf
The G:\\Shared\CEMALB\QA\SOP directory also contains the following files that may help the investigators to develop the QA and SOP/ROP for specific projects:
QMP for the EPHD US EPA National Health and Environmental Effects Research Laboratory-Health Divisions (NHEERL-H) Guidelines for Laboratory Record Keeping (NHEERL-H/QA-RK-95/00). QA_BALT.wpd is Quality Assurance Project Plan for 1998 Baltimore epi study, as an example of QMA. Furthermore, in addition to the CEMALB QAP the investigators and staff preparing a project sponsored by other granting agencies and funding entities follow QAPs issued by those institutions as appropriate. For example, each NIH Institute, FDA or HEI has its own QA guidelines with more specific guidelines for each research category or even specific studies. Documents listed below are used to develop a study-specific QAP.
The following NIH documents related to human research will be helpful in preparation, and conduct of a NIH sponsored studies, namely:
(a) Guidelines for the Conduct of Research Involving Human Subjects,
(b) Guidelines for Writing Research Protocols, and
(c) Assurance of Compliance with DHHS Regulations for the Protection of Human Subjects (45 CFR 46), published by the NIH Office of Human Subjects Research.
Journal Articles: 50 Displayed | Download in RIS Format
Other center views: | All 83 publications | 50 publications in selected types | All 50 journal articles |
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Bowers EC, McCullough SD. Linking the epigenome with exposure effects and susceptibility:The epigenetic seed and soil model. Toxicological Sciences 2016;155(2):302-14 |
CR835785 (2016) CR835785 (2017) CR835785 (2020) |
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Hickman E, Smyth T, Cabos-Uribe C, Immormino R, Rebuli M, Moran T, Alexis N, Jaspers I. Expanded characterization of in vitro polarized M0, M1, and M2 human monocyte-derived macrophages: Bioenergetic and secreted mediator profiles. PLOS ONE 2023;18(3):e0279037 |
CR835785 (Final) |
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Kobernick AK, Peden DB, Zhou H, Zhou Q, Dillon MA, Alexis NE. Reproducibility of the inflammatory response to inhaled endotoxin in healthy volunteers. Journal of Allergy and Clinical Immunology. 2016;138(4):1205-7 |
CR835785 (2015) CR835785 (2020) |
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Martin WK, Tennant AH, Conolly RB, Prince K, Stevens JS, DeMarini DM, Martin BL, Thompson LC, Gilmour MI, Cascio WE, Hays MD. High-throughput video processing of heart rate responses in multiple wild-type embryonic Zebrafish per imaging field. Scientific reports 2019;9(1):1-4. |
CR835785 (2019) CR835785 (2020) |
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McCullough SD, Bowers EC, On DM, Morgan DS, Dailey LA, Hines RN, Devlin RB, Diaz-Sanchez D. Baseline chromatin modification levels may predict interindividual variability in ozone-induced gene expression. Toxicological Sciences. 2015;150(1):216-24 |
CR835785 (2015) CR835785 (2017) CR835785 (2020) |
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McCullough SD, On DM, Bowers EC. Using Chromatin Immunoprecipitation in Toxicology:A Step‐by‐Step Guide to Increasing Efficiency, Reducing Variability, and Expanding Applications. Current protocols in toxicology 2017;72(1):3-14 |
CR835785 (2016) CR835785 (2017) CR835785 (2020) |
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Miller DB, Snow SJ, Henriquez A, Schladweiler MC, Ledbetter AD, Richards JE, Andrews DL, Kodavanti UP. Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats. Toxicology and applied pharmacology 2016;306:47-57 |
CR835785 (2016) CR835785 (2017) CR835785 (2020) |
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Mirowsky JE, Peltier RE, Lippmann M, Thurston G, Chen LC, Neas L, Diaz-Sanchez D, Laumbach R, Carter JD, Gordon T. Repeated measures of inflammation, blood pressure, and heart rate variability associated with traffic exposures in healthy adults. Environmental Health. 2015;14(1):66 |
CR835785 (2015) CR835785 (2020) |
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Mirowsky JE, Devlin RB, Diaz-Sanchez D, Cascio W, Grabich SC, Haynes C, Blach C, Hauser ER, Shah S, Kraus W, Olden K. A novel approach for measuring residential socioeconomic factors associated with cardiovascular and metabolic health. Journal of Exposure Science and Environmental Epidemiology 2017;27(3):281 |
CR835785 (2016) CR835785 (2020) |
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Perryman A, Kim H, Payton A, Rager J, McNell E, Rebuli M, Wells H, Almond M, Antinori J, Alexis N, Porter N, Jasters I. Plasma sterols and vitamin D are correlates and predictors of ozone-induced inflammation in the lung: A pilot study. PLOS ONE 2023;18(5):e285721 |
CR835785 (Final) |
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Walsh DM, McCullough SD, Yourstone S, Jones SW, Cairns BA, Jones CD, Jaspers I, Diaz-Sanchez D. Alterations in airway microbiota in patients with PaO2/FiO2 ratio≤ 300 after burn and inhalation injury. PloS one 2017;12(3):e0173848 |
CR835785 (2016) CR835785 (2020) |
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Zetlen H, Cao K, Schichlein K, Knight N, Maecker H, Nadeau K, Rebuli M, Rise M. Comparison of multiplexed protein analysis platforms for the detection of biomarkers in the nasal epithelial lining fluid of healthy subjects. JOURNAL OF IMMUNOLOGICAL METHODS 2023;517(113473). |
CR835785 (Final) |
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Thurston GD, Balmes JR, Garcia E, Gilliland FD, Rice MB, Schikowski T, Van Winkle LS, Annesi-Maesano I, Burchard EG, Carlsten C, Harkema JR. Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society 2020;17(4):387-98. |
CR835785 (2019) CR835785 (2020) |
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Bass V. San Antonio Oleic acid induces acute pulmonary injury and inflammation in vivo. Society of Toxicology, 2017;10(1):34 |
CR835785 (2017) CR835785 (2020) |
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Miller DB, Karoly ED, Jones JC, Ward WO, Vallanat BD, Andrews DL, Schladweiler MC, Snow SJ, Bass VL, Richards JE, Ghio AJ. Inhaled ozone (O3)-induces changes in serum metabolomic and liver transcriptomic profiles in rats. Toxicology and applied pharmacology 2015;286(2):65-79. |
CR835785 (2017) CR835785 (2020) |
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Pawlak EA, Noah TL, Zhou H, Chehrazi C, Robinette C, Diaz-Sanchez D, Müller L, Jaspers I. Diesel exposure suppresses natural killer cell function and resolution of eosinophil inflammation:a randomized controlled trial of exposure in allergic rhinitics. Particle and fibre toxicology. 2015;13(1):24 |
CR835785 (2015) CR835785 (2020) |
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Cascio WE, Gilmour MI, Peden DB. Ambient air pollution and increases in blood pressure:role for biological constituents of particulate matter. Hypertension. 2015;66(3):469-71. |
CR835785 (2015) CR835785 (2020) |
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Mirowsky J, Gordon T. Noninvasive effects measurements for air pollution human studies:methods, analysis, and implications. Journal of Exposure Science and Environmental Epidemiology. 2015;25(4):354 |
CR835785 (2015) CR835785 (2020) |
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Rebuli ME, Speen AM, Clapp PW, Jaspers I. Novel applications for a noninvasive sampling method of the nasal mucosa. American Journal of Physiology-Lung Cellular and Molecular Physiology 2016;312(2):L288-96 |
CR835785 (2016) CR835785 (2020) |
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Duran CG, Burbank AJ, Mills KH, Duckworth HR, Aleman MM, Kesic MJ, Peden DB, Pan Y, Zhou H, Hernandez ML. A proof-of-concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respiratory Research 2016;17(1):89. |
CR835785 (2016) CR835785 (2020) |
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Mirowsky JE, Dailey LA, Devlin RB. Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells. Inhalation toxicology. 2016;28(8):374-82 |
CR835785 (2015) CR835785 (2016) CR835785 (2020) |
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Snow SJ, Gordon CJ, Bass VL, Schladweiler MC, Ledbetter AD, Jarema KA, Phillips PM, Johnstone AF, Kodavanti UP. Age-related differences in pulmonary effects of acute and subchronic episodic ozone exposures in Brown Norway rats. Inhalation toxicology 2016;28(7):313-23. |
CR835785 (2017) CR835785 (2020) |
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Dieffenderfer J, Goodell H, Mills S, McKnight M, Yao S, Lin F, Beppler E, Bent B, Lee B, Misra V, Zhu Y. Low-power wearable systems for continuous monitoring of environment and health for chronic respiratory disease. IEEE journal of biomedical and health informatics. 2016;20(5):1251-64. |
CR835785 (2015) CR835785 (2020) |
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Henriquez A, House J, Miller DB, Snow SJ, Fisher A, Ren H, Schladweiler MC, Ledbetter AD, Wright F, Kodavanti UP. Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation. Toxicology and applied pharmacology 2017;329:249-58 |
CR835785 (2016) CR835785 (2017) CR835785 (2020) |
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Snow SJ, McGee MA, Henriquez A, Richards JE, Schladweiler MC, Ledbetter AD, Kodavanti UP. Respiratory effects and systemic stress response following acute acrolein inhalation in rats. Toxicological Sciences 2017;158(2):454-64 |
CR835785 (2016) CR835785 (2017) CR835785 (2020) |
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Miller CN, Dye JA, Ledbetter AD, Schladweiler MC, Richards JH, Snow SJ, Wood CE, Henriquez AR, Thompson LC, Farraj AK, Hazari MS. Uterine artery flow and offspring growth in long-evans rats following maternal exposure to ozone during implantation. Environmental health perspectives 2017;125(12):127005 |
CR835785 (2017) CR835785 (2020) |
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Mirowsky JE, Carraway MS, Dhingra R, Tong H, Neas L, Diaz-Sanchez D, Cascio W, Case M, Crooks J, Hauser ER, Dowdy ZE. Ozone exposure is associated with acute changes in inflammation, fibrinolysis, and endothelial cell function in coronary artery disease patients. Environmental Health 2017;16(1):126 |
CR835785 (2016) CR835785 (2020) |
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Zhou S, Behrooz L, Weitzman M, Pan G, Vilcassim R, Mirowsky JE, Breysee P, Rule A, Gordon T. Secondhand hookah smoke:an occupational hazard for hookah bar employees. Tobacco control. 2017;26(1):40-5 |
CR835785 (2015) CR835785 (2020) |
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Burbank AJ, Peden DB. Assessing the impact of air pollution on childhood asthma morbidity:how, when, and what to do. Current opinion in allergy and clinical immunology2018;18(2):124-31 |
CR835785 (2018) CR835785 (2020) |
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Henriquez AR, Snow SJ, Schladweiler MC, Miller CN, Dye JA, Ledbetter AD, Richards JE, Mauge-Lewis K, McGee MA, Kodavanti UP. Adrenergic and glucocorticoid receptor antagonists reduce ozone-induced lung injury and inflammation. Toxicology and applied pharmacology 2018;339:161-71 |
CR835785 (2017) CR835785 (2020) |
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Snow SJ, Henriquez AR, Costa DL, Kodavanti UP. Neuroendocrine regulation of air pollution health effects:emerging insights. Toxicological Sciences 2018;164(1):9-20 |
CR835785 (2017) CR835785 (2020) |
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Huang MC, Douillet C, Dover EN, Stýblo M. Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner. Archives of toxicology 2018;92(6):1925-37 |
CR835785 (2017) CR835785 (2020) |
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Hazari MS, Stratford KM, Krantz QT, King C, Krug J, Farraj AK, Gilmour MI. Comparative cardiopulmonary effects of particulate matter-and ozone-enhanced smog atmospheres in mice. Environmental science & technology 2018;52(5):3071-80. |
CR835785 (2017) CR835785 (2020) |
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Stratford K, Haykal-Coates N, Thompson L, Krantz QT, King C, Krug J, Gilmour MI, Farraj A, Hazari M. Early-life persistent vitamin D deficiency alters cardiopulmonary responses to particulate matter-enhanced atmospheric smog in adult mice. Environmental science & technology 2018;52(5):3054-61. |
CR835785 (2017) CR835785 (2020) |
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Snow SJ, Cheng WY, Henriquez A, Hodge M, Bass V, Nelson GM, Carswell G, Richards JE, Schladweiler MC, Ledbetter AD, Chorley B. Ozone-induced vascular contractility and pulmonary injury are differentially impacted by diets enriched with coconut oil, fish oil, and olive oil. Toxicological Sciences 2018;163(1):57-69 |
CR835785 (2017) CR835785 (2020) |
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Henriquez AR, Snow SJ, Schladweiler MC, Miller CN, Dye JA, Ledbetter AD, Richards JE, Hargrove MM, Williams WC, Kodavanti UP. Beta-2 adrenergic and glucocorticoid receptor agonists modulate ozone-induced pulmonary protein leakage and inflammation in healthy and adrenalectomized rats. Toxicological Sciences 2018;166(2):288-305. |
CR835785 (2019) CR835785 (2020) |
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Egorov AI, Converse R, Griffin SM, Styles J, Klein E, Sams E, Hudgens E, Wade TJ. Environmental risk factors for Toxoplasma gondii infections and the impact of latent infections on allostatic load in residents of Central North Carolina. BMC infectious diseases 2018;18(1):421. |
CR835785 (2019) CR835785 (2020) |
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Lyerly HK, Peden DB. Health and the Environment in North Carolina. North Carolina medical journal2018;79(5):302-5 |
CR835785 (2018) CR835785 (2020) |
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Peden DB. The Unexpected Health Effects of Air Pollution. North Carolina medical journal2018;79(5):309-11 |
CR835785 (2018) CR835785 (2020) |
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Brooks JL, Berry DC, Currin EG, Ledford A, Knafl GJ, Fredrickson BL, Beeber LS, HAPPI Community Partnership Committee, Peden DB, Corbie‐Smith GM. A community‐engaged approach to investigate cardiovascular‐associated inflammation among American Indian women:A research protocol. Research in nursing & health201942(3):165-75 |
CR835785 (2018) CR835785 (2019) CR835785 (2020) |
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Fecho K, Pfaff E, Xu H, Champion J, Cox S, Stillwell L, Peden DB, Bizon C, Krishnamurthy A, Tropsha A, Ahalt SC. A novel approach for exposing and sharing clinical data:the Translator Integrated Clinical and Environmental Exposures Service. Journal of the American Medical Informatics Association 2019;26(10):1064-1073 |
CR835785 (2018) CR835785 (2020) |
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Bass VL, Snow S, Soukup J, Schladweiler M, Ghio A, Kodavanti U, Madden MC. 12-hydroxy oleic acid impairs endothelium-dependent vasorelaxation. Journal of Toxicology and Environmental Health, Part A 2019;82(5):383-6. |
CR835785 (2019) CR835785 (2020) |
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Cromar KR, Duncan BN, Bartonova A, Benedict K, Brauer M, Habre R, Hagler GS, Haynes JA, Khan S, Kilaru V, Liu Y. Air Pollution Monitoring for Health Research and Patient Care. An Official American Thoracic Society Workshop Report. Annals of the American Thoracic Society 2019;16(10):1207-14. |
CR835785 (2019) CR835785 (2020) |
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Miller CN, Kodavanti UP, Stewart EJ, Schaldweiler M, Richards JH, Ledbetter AD, Jarrell LT, Snow SJ, Henriquez AR, Farraj AK, Dye JA. Aspirin pre-treatment modulates ozone-induced fetal growth restriction and alterations in uterine blood flow in rats. Reproductive Toxicology 2019;83:63-72. |
CR835785 (2019) CR835785 (2020) |
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Stevens EL, Rosser F, Forno E, Peden D, Celedón JC. Can the effects of outdoor air pollution on asthma be mitigated?. Journal of Allergy and Clinical Immunology 2019;143(6):2016. |
CR835785 (2019) CR835785 (2020) |
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Corteselli EM, Gibbs-Flournoy E, Simmons SO, Bromberg P, Gold A, Samet JM. Long chain lipid hydroperoxides increase the glutathione redox potential through glutathione peroxidase 4. Biochimica et Biophysica Acta (BBA)-General Subjects 2019;1863(5):950-9. |
CR835785 (2019) CR835785 (2020) |
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Zhang XA, Yates A, Vasilevsky N, Gourdine JP, Callahan TJ, Carmody LC, Danis D, Joachimiak MP, Ravanmehr V, Pfaff ER, Champion J. Semantic integration of clinical laboratory tests from electronic health records for deep phenotyping and biomarker discovery. NPJ digital medicine 2019;2(1):1-9. |
CR835785 (2019) CR835785 (2020) |
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Hargrove MM, Kim YH, King C, Wood CE, Gilmour MI, Dye JA, Gavett SH. Smoldering and flaming biomass wood smoke inhibit respiratory responses in mice. Inhalation Toxicology 2019;31(6):236-47. |
CR835785 (2019) CR835785 (2020) |
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Sood AK, Burbank AJ, Lawson M, Zhou H, Wells HB, Peden DB, Hernandez ML. Systemic inflammatory response to inhaled endotoxin does not correlate with airway response. Respiratory research 2019;20(1):1-4. |
CR835785 (2019) CR835785 (2020) |
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Kim YH, King C, Krantz T, Hargrove MM, George IJ, McGee J, Copeland L, Hays MD, Landis MS, Higuchi M, Gavett SH. The role of fuel type and combustion phase on the toxicity of biomass smoke following inhalation exposure in mice. Archives of toxicology 2019;93(6):1501-13. |
CR835785 (2019) CR835785 (2020) |
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Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2020 Progress Report
- 2019 Progress Report
- 2018 Progress Report
- 2017 Progress Report
- 2015 Progress Report
- Original Abstract
50 journal articles for this center