2019 Progress Report: Initial Annual CEMALB Progress Report: Human Health Effects of Environmental Pollutants Year 1, period beginning 4/1/15

EPA Grant Number: 83578501
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 Year 1, period beginning 4/1/15
Investigators: Peden, David B , Jaspers, Ilona , Hernandez, Michelle L , Alexis, Neil , Smith, Judith , Noah, Terry , Bennett, William D , Robinette, Carole
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, 2019 through March 31,2020
Project Amount: $9,800,000
RFA: Human Health Effects of Environmental Pollutants (2014) RFA Text
Research Category: Human Health

Objective:

Project 1: Development of Interventions to mitigate Inflammatory Response to Pollutants:

The aims of Project 1 were modified in year 1 and outlined in previous years project report. As noted at the time of modification in year 1, the primary activities of this project are 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).

Project 2 Development of Methodologies to Assess Health Effects Associated with Pollutant Exposures

Oxidant pollutants derived from the incomplete combustion of organic matter, such as burning of biomass or woodsmoke, are of increased global public health concern and associated with increased susceptibility to respiratory infections, including viral infections in children. More than two billion people in the world use biomass (including indoor wood burning) as their main source of energy for domestic heating and cooking. Epidemiological evidence suggests that reducing exposure to biomass smoke exposure is associated with a decrease in upper and lower respiratory tract infections. Collaborative studies among investigators from UNC and EPA developed a human in vivo exposure and viral challenge study to translate these findings into human. These studies were built on human in vivo experimental models developed by investigators at UNC using the FDA-approved live attenuated influenza virus (LAIV) vaccine as a model for viral infections in human volunteers. Inoculation with LAIV causes a self-limiting replicative infection, which induces similar cytokine and antiviral host defense responses as community-acquired infections. This human LAIV inoculation model was previously used to assess interactions between exposure to diesel exhaust (DE) and viral infections, which demonstrated that underlying allergy rhinitis enhances the interaction between DE and viral infection, leading to increased viral replication and markers of allergic inflammation.

Project 3: Establish whether LPS inhalation induces Systemic inflammation and CV inflammation”

There is a growing body of literature supporting that short term exposure to LPS, a biological constituent of particulate matter, is associated with increased blood pressure in controlled human exposures (Zhong et al, Endotoxin and β-1,3-D-Glucan in concentrated ambient particles induce rapid increase in blood pressure in controlled human exposures, Hypertension 2015).  The innate immune protein IL-1β, a byproduct of LPS-induced inflammation, appears to serve as a central mediator of systemic and CV responses.  Short-term changes in air pollution are also associated with changes in stiffness of the conduit arteries and with exacerbations of heart failure.  Moreover, inhibition of IL-1β activity with anakinra improves vascular endothelial function and left ventricular contractile function in patients with chronic inflammatory diseases. Thus, it is plausible that through IL-1β release, LPS adversely affects CV outcomes by modifying heart rate variability through autonomic control of heart rate, impairing endothelial function, increasing vascular stiffness, and depressing myocardial contractility.

Project 4: Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects

Increasingly, large datasets generated through emerging “omics” technology, including epigenomis, metagenomics, genomics, proteomics, and metabolomics are used to provide unbiased assessment of pollutant-induced adverse health effects. These technologies can identify biomarkers of exposure, biomarkers of health effects, predict susceptibility, understand biological mechanisms, and indicate preventative strategies. 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. The trainees supported through this project are Meghan Rebuli, and Virginia Bass

Project 5: Above Base 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.

Project 6: 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.

Project 7: Above Base Project: Efficacy of Fish Oil or Olive Oil Supplementation on the Health Effects of Ozone Exposure in Healthy Young Subjects

A growing body of epidemiological data suggests an increased risk of cardiovascular events associated with air pollution. One of the common air pollutants, ozone, has been shown to induce oxidative stress and inflammation in the cardiovascular and respiratory systems. This proposal is to examine the efficacy of fish oil and olive oil in protecting cardiovascular and pulmonary functions after ozone exposure. The objective is to understand the mechanistic basis for the health effects of ozone in relation to previously studied particulate matter. Healthy young adults will be given dietary supplementation of fish oil, olive oil, or placebo for 4 weeks, then exposed to ozone for 2 hours in an exposure chamber. Cardiac rhythm, pulmonary function, vascular responses, endothelial function, and markers of coagulation and airway inflammation pre- and post- ozone exposure will be measured. This study is designed to build on the previous nutritional supplement interventions PM studies OMEGACON (IRB # 07-0190) and CAPTAIN (IRB # 11-1807), in order to understand the mechanism of action of particulate pollutants in comparison to that of ozone, a known oxidant air contaminant.Participants: Sixty healthy 18-35 year-old male and female subjects will be involved in the study. Methods: The subjects will be exposed to clean air for 2 hours on the first day, then ozone (0.3ppm) for 2 hours on the second day after being randomly supplemented for four weeks with omega-3 fatty acids, olive oil, or placebo. 

Project 8:The influence of stress, neighborhoods and the built environment on environmental health

There is an increasing interest in how social factors, chronic stress, the built environment and neighborhood conditions interact to affect susceptibility to the adverse health effects of environmental contaminants. Increasing evidence indicates complex interactions between host and community factors such as the environmental microbiome (soil, air), the host microbiome (gut, nasal, salivary, skin) and the epigenome also play a role in individual and community susceptibility. In order to enhance research in this area, community-based studies are needed to assess how these factors vary across individuals, and neighborhoods as well as the long-term impact of how these factors interact with chronic stress to affect health outcomes.

Project 9:  Above Base Project: Effect of fuel and combustion conditions on pulmonary toxicity of smoke emissions

Every day we breathe billions of particles in air which are deposited in various locations of the respiratory tract depending on the size, density, shape, and surface properties. The focus of this research program is to determine how the chemistry of particles affects development of subsequent health outcomes. Specifically, emissions from combustion sources such as biomass from domestic woodburning or wildland fires, diesel exhaust or samples from military burn pits will be analyzed for physicochemical characteristics. Samples collected under various conditions will be applied to a standard battery of toxicity assays including human cells at the air liquid interphase and selected in vivo animal (mouse) models of disease. A relative potency matrix will be developed against standardized samples in order to rank the potential for the various materials for their ability to alter cellular signaling, increase oxidative stress and pulmonary injury and cause detrimental effects on immune function.

COVID Project 1: Effectiveness of UNC Hospital Facemask Alternatives for the COVID-19 Pandemic

  • Due to limited national supplies of N95 facemasks, UNC hospitals have accepted public and private company donations of personal protective equipment, including many types of face masks. With so many options, infection prevention experts at the UNC Medical Center asked CEMALB, in collaboration with the EPA HSF and TRC contractors, if they could measure the protectiveness of various types of masks and alternative options, including sterilized N95 masks, expired N95 masks, foreign-sourced masks, as well as surgical and homemade masks. To achieve these ends, an EPA exposure chamber was filled with airborne particles (50nm NaCl) to measure how many of those particles were able to penetrate each mask type fitted on an adult male and female subject, i.e. fitted filtration efficiency for each mask type.
  • To date we have found that gas sterilized (hydrogen peroxide and ethylene oxide) N95 masks have maintained their filtration capacity to greater than 98% efficiency, i.e. less than 2% penetration beyond the mask into the subjects breathing space.  With regards to expired masks, these studies have also shown that 11-year-old expired 3M N95 masks were still greater than 95% effective. Future studies include continued efficiency assessment of new masks for both the UNC Medical Center and students/staff/faculty at UNC Chapel Hill.

COVID Project 2: Protocol 20-0937-ScreenNC: Screening seroprevalence of IgG antibody to SARS-CoV2 virus in asymptomatic UNC Health Patients (Aim 4 of Project 1)

  • This is a SARS-CoV2 seroprevalence study supported by the UNC School of Medicine, UNC Health, NIEHS and this Cooperative Agreement. This study is a multi-site study in which persons asymptomatic for COVID-19 are recruited for screening for IgG antibody to the SARS-CoV2 virus. Volunteers must be UNC patients and test results are entered into the Epic UNC electronic health record data system, curated in the Carolina Data Warehouse for Health. Investigators have permission to analyze data from recruited volunteers as well as any UNC patients who have been tested for this antibody. Volunteers are recruited at the UNC Family Medicine Center, CTRC, the UNC Emergency Department, the Rex Emergency Department, Nash Medical Center, and UNC Physician Network. This catchment area (counties in which each recruitment site is located and adjoining counties) represents 44% of the regions in which SARS-CoV2 infection has been reported.
  • Recruitment began on 4/28/2020 and to date, data from 4,617 patients has been acquired, with data on 3,101 patients who were positive by viral swab also being available. Our initial report focuses on our initial 3,035 volunteers recruited into the study, to determine the seroprevalence of IgG to SARS-CoV2 in asymptomatic people. However, subsequent analyses and studies using this data set will focus on the impact of environmental factors (PM2.5, O3, SES factors, geocoded locations) on likelihood of being exposed and severity of disease in those who are seropositive.

 

Progress Summary:

Project 1: Development of Interventions to mitigate Inflammatory Response to Pollutants:

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 mg/m3 of woodsmoke particles (WSP). Fifty-five volunteers, 38 of whom are healthy volunteers and 17 of whom have allergic asthma. They have each undergone 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.
  • 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
  • Protocol 16-1776: Inflammatory Markers, Hazardous Air Pollutants, and Psychosocial Factors (J. Brooks, PI, Peden DB) Dr. Brooks is an Assistant Professor in the School of Nursing who is supported by a NIEHS K 23 award to develop this environmental research. The primary goal of this research is to determine how particulate matter and psychosocial states are associated with inflammation and whether positive psychosocial states moderate the effect of particulate matter on objectively assessed biomarkers in American Indian women

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, A. Burbank, 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.  There is no change from last year’s report. The manuscript is currently under review for publication.
  • 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.
  • 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 year’s report, CEMALB investigators are co-investigators in this study, and FDA approval was obtained for this protocol as an amendment to Dr. Peden’s FDA IND for exposure to ozone (IND 71475) in 2/2017. The study remains active, but still blinded and thus, no results are available This protocol is currently in hiatus due to the COVID-19 related halt in human studies.

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.  A total of 57 volunteers have completed this protocol, in which 2 sensor arrays have undergone development. At present, a report demonstrating that minute ventilation can be estimated from ECG and wrist motion sensors is under review. 

Aim 4.) To develop programs in environmental precision medicine and health using big data approaches

  • 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 final example of assessing the effect of real-world pollutant exposure on health outcomes derives from our efforts in applying “big data” approaches to environmental health, noted above from the Biomedical Data Translator project with the resulting development of the data analysis tool the Integrated Clinical and Environmental Exposures Service (ICEES).

  • Protocol 20-0937: ScreenNC-Screening seroprevalence of IgG antibody to SARS-CoV2 virus in asymptomatic UNC Health Patients: Another use case actively being pursued is recruitment of the ScreenNC cohort (described above in special COVID projects) in which we will ultimately assess environmental and social determinants of health (e.g. PM2.5, proximity to heavily traveled roads, poverty) on COVID-19 outcomes in the ScreenNC cohort. (see preamble)

Project 2 Development of Methodologies to Assess Health Effects Associated with Pollutant Exposures

Using our established model combining human in vitro and in vivo models of viral infections, we propose to address this hypothesis with the following aims:

Objective 1: Determine the Effects of Controlled Woodsmoke exposures on markers of viral replication and mucosal immune responses in healthy human volunteers.

Objective 2: Develop, Optimize, and Validate Non-invasive, Field-deployable Sampling Techniques, Allowing Investigators To Sample The Respiratory Mucosa For Pulmonary Biomarkers

  • Compare Mediator Profiles in ELF, Induced Sputum, and BALF
  • Assess Potential Health Disparities In Environmental Triggers Of Asthma
  • Determine Pollutant-induced Changes in ELF

Project 3: Establish whether LPS inhalation induces Systemic inflammation and CV inflammation”

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”) was 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
  • As both we and others have demonstrated increased circulating neutrophils following inhaled endotoxin challenges, we sought to determine whether this systemic inflammatory response correlated with endotoxin-induced increases in airway inflammation and could thus serve as an adequate biomarker. We found that increases in endotoxin-induced circulating neutrophils do not correlate with airway responses and cannot be used as adequate biomarkers, necessitating further investigation.  

Protocol 17-3351: Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) versus placebo on systemic and cardiovascular inflammatory responses in mild asthmatics and healthy volunteers (aka EndoHeart protocol, M. Hernandez, PI)

  • Individuals who exhibited a systemic inflammatory response to inhaled LPS (identified in EndoScreen) were recruited for this study.  Fifteen participants from the Endoscreen study completed both the LPS and placebo (saline) exposures in the EndoHeart study.
  • Cardiovascular outcomes:  The HRV data from EndoScreen and EndoHeart were analyzed in conjunction with RTI (K Gilchrist) to examine if there are any detectable changes in HRV associated with neutrophilic airway inflammation.  Dr. Gilchrist and her team were not able to generate a robust enough detection algorithm for the immune response.  We suspect that the cardiac response to inhaled LPS is highly variable and quite subtle in some subjects, so development of a generalizable algorithm was a challenge.  In the upcoming months, we will finish analyses of the remaining CV data (BP, FMD, and LVS).

Protocol 18-2425: Effects of low dose ozone on airway inflammatory responses in adults with asthma, AsthmaSnoz (M Hernandez, PI)

  • We developed a new study named Asthma SNOZ.  The objective of this study is to examine if low level ozone exposure (compared to a clean air exposure), reflective of a typical metropolitan summer day, will cause decrements in lung function and measurable upper and lower airway inflammation in mild asthmatics (who are not on asthma controller medications) while performing typical daily activities.
  • This project was recruiting through early March 2020.  The recruitment goal is 18 subjects.  Staff remain blinded to the exposures. Eleven (11) subjects have enrolled in the study so far. Clinical data, sputum samples and nasal epithelial lining fluid have been collected at 24h post exposure for 3 subjects for both exposures, and 5 subjects for one exposure so far. Cell differentials have been performed on all qualifying slides. We had to cancel exposure sessions in early March 2020 due to the COVID-19 pandemic

Project 4: Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects

By creating linkages of existing medical records and environmental datasets, we will investigate the impact of in utero and childhood exposure to air pollutants and wildfire smoke on childhood atopic and respiratory diseases including asthma, infant wheeze, etc. These investigations propose to use medical records data, such as those available through the prescription data from MarketScan and Medicare databases and North Carolina state birth registry data. These datasets will be used to examine the impact of the 2008 peat wildfire in eastern North Carolina and the November 2016 Great Smoky mountains wildfire, whose smoke drifted as far east as central North Carolina. We will compare incidence and severity of respiratory and atopic disease as well as related ER admissions among those exposed in critical periods of childhood and gestation to those who were not exposed to wildfire. Disease and/or severity will be defined via diagnostic codes recorded in medical records as well as prescription histories. Birth records will be used to assess representativeness of electronic medical records and prescription datasets. For this project, Dr. Rebuli and Dr. Dinghra (ESE, SoPH) are currently developing an IRB protocol.

Oleic acid (OA) is frequently used as a representative fatty acid, found for example in meat-cooking fumes or biodiesel exhaust.  Vascular damage and acute lung injury has been observed with OA infusion in models of acute respiratory distress, but it is not yet established whether OA deposited in the lung is able to produce adverse pulmonary and cardiovascular effects associated with exposure to ambient air pollution.

Using human in vitro models, this research will examine the role of OA on pulmonary and cardiovascular endpoints. For this project, the following goals have been accomplished (Virginia Bass):

  • OA exposure inhibited relaxation of rings to the vasodilator acetylcholine (which acts via endothelial cell mechanisms).  This inhibition of vasodilation is similar to the finding that exposure of volunteers to either diesel or biodiesel exhaust attenuated the response of endothelial cell mediated vasodilation.
  • OA changed lung function parameters in rats in vivo, increased markers of inflammation and lung injury

OA increase iron load in lung macrophages in vivo and co-administration of OA and ferric ammonium citrate (FAC) tended to increase the responses (neutrophilia, cytokines) relative to oleic acid alone

Project 5: Above Base Project: Autophagy as a Key Determinant of Cell Fate in Air Pollution Health Effects Among Healthy and Type 2 Diabetics

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. 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 7 publications with additional publications currently submitted/under review.

Project 6: Above Base Project: Environmental Health Education

  • Opportunities for trainees to travel to meetings to further their education in Environmental Public Health
  • Opportunities for trainees to interact with experts in Environmental Public Health
  • Enhance community-based research skills by supporting additional training opportunities

  • Research and training support for trainees interested in conducting research in the field of Environmental Public Health

Project 7: Above Base Project: Efficacy of Fish Oil or Olive Oil Supplementation on the Health Effects of Ozone Exposure in Healthy Young Subjects

While working on Omegoz, Ms. Corteselli (student in Dr. Samet’s lab) optimized a protocol to analyze the bioenergetic profile of induced sputum samples using the Seahorse Extracellular Flux Analyzer. The analysis measures several aspects of both mitochondrial and glycolytic function. Following optimization, Ms. Corteselli processed the post-air and post-ozone exposure sputum samples (N= 4) collected from four Omegoz subjects. Seahorse analysis requires a minimum number of viable sputum cells for successful analysis. Sputum cell recovery has been variable to date with Omegoz and thus has presented a challenge with this part of the study.

Project 8:The influence of stress, neighborhoods and the built environment on environmental health ​​​​​​​

Jennifer Styles, a graduate student with the Department of Environmental Sciences and Engineering, is currently conducting experiments assessing differences in the microbiome of community-based samples. Experimental parameters and protocols have been established, and data are being collected/analyzed. Specifically, since May 2019, the primary samples (air microbiome samples) for this project have been collected and analyzed. Jennifer Styled developed and defended her dissertation proposal in March 2020.  During the current reporting period, this work has resulted in 2 manuscripts with 2 additional papers currently under review. 

Project 9:  Above Base Project: Effect of fuel and combustion conditions on pulmonary toxicity of smoke emissions

Dr. Yong Ho Kim, was hired as a Senior Research Associate for CEMALB working under the supervision of Dr. Jaspers. He has been instrumental in developing experimental models and combustion systems to generate samples mimicking the emissions from burning biomass fuel sources (e.g. wood) as well as waste disposed in military burn pits (e.g. plastics, plywood, carboard, etc.). These samples have been used for laboratory animal in vivo and human cell culture in vitro exposures to examine relative toxicities of these emission mixtures. Chemical analyses of these samples have been partially completed, which will be integrated with the biological toxicity matrix to rank the materials and resulting emission components for their ability to induce adverse health effects. Data from this project was used to support a newly funded NIEHS/NIH R21 application, which started 05/01/2020 with Dr. Kim as a collaborator on this project. In addition, one manuscript is currently being prepared summarizing the initial computational analysis identifying chemical classes in combustion emission mixtures driving biological responses.

Future Activities:

Project 1: Development of Interventions to mitigate Inflammatory Response to Pollutants:

  1. ICEES can also be employed to assess pollutant impacts on clinical outcomes to achieve policy changes. An example of an immediate policy outcome from this project builds on ongoing collaborative environmental informatics research currently underway by CEMALB and EPA scientists exploring environmental impacts on cardiovascular disease using patient data from the CDWH. ICEES would allow these analyses to occur in a fashion in which personal identifiers are modified, so that primary data may be reviewed by federal reviewers in such a way that individual privacy is guaranteed. This approach has regulatory application for periodic assessment of the NAAQS of each pollutant mandated by the Clean Air Act.
  2. We will apply ICEES to explore environmental impacts on temporally discreet public health events. In addition to ScreenNC above, we anticipate undertaking an assessment of health outcomes in the UNC Health population due to PM2.5 increases caused by the 2008 NC Wildland Fires.
  3. We will use ICEES to explore the effect of the GSTM1 null genotype on asthma exacerbation and other clinical outcomes, guided by our published reports and leveraging our prior work.
  4. Note that the ICEES tool developed by this project and the subsequent use cases are also available to the studies outlined in Above Base Projects 4 and

Project 2 Development of Methodologies to Assess Health Effects Associated with Pollutant Exposures

Objective 1:Initial in vitro studies comparing woodsmoke exposure to emissions generated by burning plastics, plywood, cardboard, and mixtures thereof are underway and biological responses and toxicities will be compared to those seen after woodsmoke exposures. Computational analyses will be used to identify potential classes of chemicals within woodsmoke or other combustion emission mixtures driving biological responses.

Objective 2: Focus on implementing the sampling technique to other ongoing studies and expand the scope of sample analyses. As described above, we have conducted initial pilot experiments to determine exposure-dependent changes in the nasal microbiome as well as chemical analyses, which could be used to determine exposures, including components and concentrations. Several studies led by Dr. Rebuli are implementing nasal ELF collection to determine biomarkers of disease and exposure in a variety of different cohorts

Objective 3: Our non-invasive nasal mucosal sampling technique is currently part of 4 ongoing COVID-19 cohort studies at UNC. These samples will be analyzed for viral load as well as nasal biomarkers of immune responses. Data will be stratified based on demographic information, potential co-exposures, and other risk factors

Project 3: Establish whether LPS inhalation induces Systemic inflammation and CV inflammation”

EndoScreen Study: Using the multiplex protein data from serum and sputum as well as mRNA data, we will identify mediators that are associated with an airway or systemic response to inhaled LPS challenge.

EndoHeart Study:  In the upcoming months, we will finish analyses of the remaining CV data (BP, FMD, and LVS).  We will also analyze sputum and serum mediators for inflammatory cytokines; specifically, we will focus on examining the role of LPS-induced IL-1β on airway and systemic cardiovascular responses on CV outcomes.  This work will be prepared for publication.

AsthmaSnoz: When the O3 chambers are permitted to reopen, we will first submit this project for IRB review to determine if it is permissible to continue this project in the setting of COVID-19 exposures since participants have asthma.  If allowed to continue, we will attempt to re-recruit the 5 participants who completed the first exposure sessions and finish recruitment of remaining participants

Project 4: Above Base Project: Large Dataset Analyses to Determine Pollutant-induced Adverse Health Effects

An IRB protocol to linking medical datasets and wildfire exposure data in North Carolina was just approved (UNC Study #20-1196) and analysis will start over the summer. Due the extensive nature and novel tools to be used in these analyses, a new above base protocol (Project 10 – “Using EMR and other databases to determine health effects of woodsmoke”), which was newly funded 05/01/2020.

Project 5: Above Base Project: Autophagy as a Key Determinant of Cell Fate in Air Pollution Health Effects Among Healthy and Type 2 Diabetics

This project has been completed

Project 6: Above Base Project: Environmental Health Education

Opportunities for trainees to travel to meetings to further their education in Environmental Public Health

Requests for applications for this award will start in September, 2020 and complete applications need to be received by middle of October, 2020 to be eligible. Similarly, for spring meetings we will request applications in January 2021 and complete the review by February 2021. We anticipate 5-10 applications to make 2-3 awards.

Opportunities for trainees to interact with experts in Environmental Public Health

Due to the COVID-19 shutdown, the organizing committee has not been able to meet and decide on a potential candidate for the fall 2020. At the moment, seminar classes for the fall, including TOXC 722, are scheduled to occur virtually and not in person.

Enhance community-based research skills by supporting additional training opportunities

Since these applications are received and reviewed on a rolling basis, we cannot accurately predict the number of potential applications. However, we anticipate receiving several applications over the next 6 months.

Project 7: Above Base Project: Efficacy of Fish Oil or Olive Oil Supplementation on the Health Effects of Ozone Exposure in Healthy Young Subjects

This project is in progress and sputum samples continue to be processed in the Alexis lab for analysis of inflammatory endpoints. To date sputum samples from 40 subjects have been collected and processed. Differential cell counts have been performed on all samples to date. Supernatant samples are currently stored at -80 deg C for future fluid phase analysis. Elizabeth Cortiselli’s specific involvement however, with the Seahorse (extracellular flux/bioenergetics) analysis of the sputum samples has been discontinued and diverted to another project. 

Project 8:The influence of stress, neighborhoods and the built environment on environmental health

This project is ongoing and sample analyses will continue during the next reporting period.

Project 9:  Above Base Project: Effect of fuel and combustion conditions on pulmonary toxicity of smoke emissions

Based on the initial toxicity studies, experiments are ongoing further characterizing adverse biological effects induced by exposure to these different emission mixtures. Biological effects will be integrated with chemical characterizations to determine potential cause-and-effect relationships between emission components and toxicities. Furthermore, the experimental systems from this project are currently being expanded to develop additional exposure systems on the UNC campus and within the EPA.


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Journal Article 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
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  • Journal Article 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
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    83578501 (2015)
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  • Journal Article 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.
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    83578501 (2019)
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  • Journal Article 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
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  • Journal Article 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 83578501 (2016)
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article Bass V. San Antonio Oleic acid induces acute pulmonary injury and inflammation in vivo. Society of Toxicology, 2017;10(1):34
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  • Journal Article 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.
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article Snow SJ, Henriquez AR, Costa DL, Kodavanti UP. Neuroendocrine regulation of air pollution health effects:emerging insights. Toxicological Sciences 2018;164(1):9-20
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article Lyerly HK, Peden DB. Health and the Environment in North Carolina. North Carolina medical journal2018;79(5):302-5
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  • Journal Article Peden DB. The Unexpected Health Effects of Air Pollution. North Carolina medical journal2018;79(5):309-11
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  • Journal Article 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
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  • Journal Article 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
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Journal Article 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.
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  • Progress and Final Reports:

    Original Abstract
  • 2015 Progress Report
  • 2016 Progress Report
  • 2017 Progress Report
  • 2018 Progress Report