Theses and Dissertations

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Open Access
Occupational noise exposure and hearing assessment of hydraulic fracturing workers: quiet versus conventional fleets
(Colorado State University. Libraries, 2024) Blevens, Melissa S., author; Brazile, William, advisor; Tsai, Candace Su-Jung, committee member; Van Dyke, Michael, committee member; Autenrieth, Daniel, committee member; Lipsey, Tiffany, committee member
Oil and gas extraction companies are exempt from implementing hearing conservation programs for their workers according to the Occupational Safety and Health Administration's (OSHA) noise standard. The occupational noise exposure and hearing status of these workers has not been published in scientific literature before the present study, presumably due to this exemption. In this study, area and personal noise exposures and worker hearing acuity were measured at both conventional and quiet hydraulic fracturing fleets, allowing a comparison between the fleets. Quiet fleets refer to the use of engineering controls to decrease noise levels of the pumps while conventional fleets do not employ these measures. In both fleets, the authors conducted personal noise dosimetry, equipment noise measurements, and pure tone audiometry pre- and post-work shift to determine if there were temporary threshold shifts (TTS) in hearing. Based on the personal noise dosimetry results, 42/50 (84%) of the quiet fleet and 34/34 (100%) of the conventional fleet workers sampled were at or over 100% noise dose according to the American Conference of Governmental Industrial Hygienists' (ACGIH) noise Threshold Limit Value (TLV). Based on the OSHA Permissible Exposure Limit (PEL) noise criteria, 9/50 (18%) of the quiet fleet workers and 15/34 (44.1%) of the conventional fleet workers were at or over 100% noise dose. Workers in both fleets experienced TTS, but no significant difference was observed between the types of fleets in relation to TTS. Most equipment of both fleets exceeded 85 decibels, but the pumps of the quiet fleet were ~14 dB lower than those of the conventional fleet. Although the quiet fleet noise controls reduced personal noise exposure, a portion of the quiet fleet workers sampled still faced noise levels that could increase the risk of hearing loss. The researchers suggest the initiation of a hearing conservation program despite OSHA exemption to safeguard worker health and recommend workers involved in certain job tasks employ dual hearing protection based on the exposure monitoring results.
Embargo
Quantitative health impact assessments as a tool for exploring public health dimensions of environmental exposures
(Colorado State University. Libraries, 2024) Dean, Daniel, author; Rojas-Rueda, David, advisor; Anderson, G. Brooke, advisor; Peel, Jennifer, committee member; Hurrell, James, committee member
Public health is influenced by a population's built and natural environment in both negative (e.g., natural disasters or ongoing stress from heat) and positive (for instance, heat-moderating effects of vegetation) ways, as well as interactively with behavioral and social dynamics. One framing of policy priorities and urban resilience is a "triad" consisting of exposure reduction (limiting the extent to which community members are exposed to environmental hazards—including "ambient" ones like stressful temperatures), vulnerability reduction (mitigating the impacts of sustained hazards), and hazard reduction (actively reducing the frequency or intensity of hazards) (Hoegh-Guldberg et al. 2018). Because any such measures carry tradeoffs in financial and other resources, it is important that policymakers and other stakeholders weigh comparative benefits of potential environmental hazards or interventions with consistent, quantifiable metrics. In this body of work, we applied quantitative health impact assessments, an epidemiology framework that provides a valuable tool here, allowing researchers to project health outcome changes for a population of interest given predicted changes in a relevant exposure and using epidemiological evidence, including exposure-response functions (exposure-response functions), which link exposure and health outcomes. In this body of work, we use HIAs to explore three different resilience-relevant systems spanning a range of intervention types, environmental systems, and spatiotemporal scales: Project 1: Health Impacts of Future Tropical Cyclones in the Eastern United States: While tropical cyclones are among the most damaging natural disasters faced by the United States, the temporal and spatial rarity of these events impedes traditional frequency-based estimates for public health and related risk projections, leading to potential oversights in risk characterization. In addition, mortality associated with tropical cyclones may not be readily apparent between delayed onset and indirect causes (e.g. stress, disrupted medical care, infections), meaning that immediate mortality counts often underestimate full attributable mortality. In this project, we performed a pilot quantitative health impact assessment designed to address aspects of these limitations. First, we tested extending the historical tropical storm dataset using a pool of 10,000 simulated, or "synthetic" tropical cyclone seasons from the widely used and open-source STORM algorithm, trained from and intended to represent the "gold standard" of historical International Best Tracks Archive for Climate Stewardship (IBTrACS) data. To the extent that STORM represents real-world conditions, this vastly expanded 'sample population provided information on potential tropical cyclone exposure risk than would be possible from historical data alone. For the second challenge of accounting for delayed and indirect attributable mortality, we combined the synthetic data with a recently-developed exposure-response function: an integrated Bayesian causal-predictive model trained on Medicare Claims data (simplified to Americans aged 65 and older), featuring an integrated model approach to combine a whole-population causal inference model for central trends with county-specific predictive models for give county-specific estimates. This model also tracked up to 21 days of "lag time" in health outcomes after a TC exposure to capture delayed mortality. This combination of methodologies promises a comprehensive, county level picture of tropical cyclone-associated all-cause mortality risk among older adults. This approach provided insights including regions of the country at the greatest risk for tropical cyclone-related exposures among older adults. However, as our study represented a new application of the STORM algorithm (in particular, our emphasis focusing on post-landfall behavior of tropical cyclones), we also assessed the level of agreement between STORM and the historical dataset, finding some discrepancies including lower overall frequency, and considerably 'smoother' spatial distribution in exposures; some discrepancies were in line with previously noted limitations. This project used recent innovations in atmospheric science and epidemiology modeling to explore the utility of a quantitative health impact assessment framework for present-day risk and could inform policy and planning decisions in terms of tropical cyclone preparedness and response measures. Project 2: Health impacts of Urban Tree Canopy policy scenarios in Denver and Phoenix: We explored potential health impacts (in terms of all-cause mortality, stroke, and dementia) of standing policy goals in Denver, Colorado and Phoenix, Arizona, for increasing the urban tree canopy coverage in these relatively arid cities. We projected health benefits (in terms of reduced attributable all-cause mortality, stroke, and dementia incidence) at a census block group level using several existing exposure-response functions based on the widely used Normalized Difference Vegetation Index (NDVI). Because the cities expressed policy goals in terms of percentage urban tree canopy, we generated predictive models to "translate" between this metric used in policy goals and the NDVI metric. We modeled the public health impacts of proposed real-world policies for near-future policy interventions in the form of increasing urban tree canopy, using current populations, and modeling an "overnight" change in exposure, with policy scenario benefits modeled for populations in year 2020, rather than demographic projections for the 2030 (Phoenix) and 2050 (Denver) dates in the policy goal timelines. We also considered socioeconomic dimensions by using the census-based Social Vulnerability Index to trace the equity of current UTC and NDVI exposures, as well as of potential benefits. We determined that each city could, by reaching its standing policy goals, could avert hundreds of all-cause mortality cases, with even a partial attainment scenario (halfway between current and desired UTC levels) having appreciable benefits, with roughly half the captured mortality prevention; with respect to equity of UTC access, more-vulnerable communities in the cities saw lower access to current canopy cover, and consequently greater potential per-capita benefits under successful intervention scenarios. Project 3: Health Impacts of Future Temperature Extremes Under a Solar Climate Intervention Scenario. In this project, we explored potential all-cause mortality implications of a proposed climate intervention effort intended to counteract anthropogenic warming, modeling the years 2050-2060 under alternate climate scenarios. Specifically, we projected temperature-associated mortality under a stratospheric aerosol injection (SAI) intervention scenario, as well as a corresponding scenario of "middle-of-the-road" climate change. We used a study population of 65-and-older Americans in eight major US cities (Seattle, Chicago, New York, Philadelphia, Los Angeles, Phoenix, Houston, and Miami) spanning a range of local climates. We built our analysis on widely used models and the shared socioeconomic pathway platform, allowing our two scenarios to be compatible, differing only in the SAI intervention itself. We focused on two age groups (65-75, and 75+) to reflect elevated heat- and cold-associated mortality risks among this population, finding broadly similar trends between age groups. We explored city-specific exposure-response functions for the temperature-mortality association, using a widely used modeling, comparing the anticipated number of cold- and heat-related deaths under each scenario, and highlighted tradeoffs for either policy scenario, finding considerable heterogeneity in trends between these cities. To make our analysis more specific to the mid-21st century, we incorporated existing estimates for population growth and mortality rate changes based on the same climate modeling scenarios as the SAU exposure scenarios. We observed dramatic variability in minimum mortality temperatures and temperature-attributable mortality between cities and found that SAI was not associated with decisive reductions in all-cause mortality among either age group. While SAI did effectively reduce heat-attributable mortality, lower cold-attributable mortality under the warmer, non-SAI scenario counterbalanced this effect, yielding a weak net impact in central tendencies. This observation could help inform planning and resilience efforts as far as types of temperature-related stress under each scenario, as well as provide insights for larger cost-benefit analyses for the overall proposition of SAI. Together, these projects demonstrated how quantitative health impact assessments can help form a methodological foundation for exploring epidemiology and resilience-relevant systems. The variety of projects covered demonstrated the utility of this methodology in a variety of spatial scales, ranging from census block groups (comparable to neighborhoods) in Project 2 to county-level characterizations of tropical cyclone-associated risk for much of the eastern United States in Project 1. We also explored a range of time periods, ranging from Project 1's focus on characterizing tropical cyclone risk representative of the past several decades (as represented by the STORM resampling algorithm), through our attempts to explicitly model mid-21st century populations and temperature-related mortality trends using both climate and demographic projections. The modularity of the quantitative health impact assessment framework enabled our projects to leverage of existing research and datasets for low-cost, comparatively rapid assessments, as well as to lay infrastructure for future research and introduce several specific innovations in their respective designs.
Embargo
Infectious disease, age, and environmental contaminants as neurotoxicants that modulate glia and contribute to neurodegenerative pathology
(Colorado State University. Libraries, 2024) Latham, Amanda Shellee, author; Moreno, Julie A., advisor; Basaraba, Randall J., advisor; Tjalkens, Ronald B., committee member; Santangelo, Kelly S., committee member; Elf, Jessica, committee member
Neurodegenerative disease cases are expected to double over the next twenty years. These diseases, which include Alzheimer's Disease (AD) and Parkinson's Disease (PD), are incurable with a largely unknown etiology. It is acknowledged within the field that age is the greatest risk factor for neurodegenerative disease, and that genetics and environmental factors, such as neurotoxicants and infectious agents, likely play a role. Despite this knowledge, it is not entirely understood why select individuals are pushed into a state of disease, while others progress into a state of normal brain aging. This is further complicated by the shared neuropathology between brain aging and neurodegenerative disease, which includes blood-brain barrier (BBB) modulation, gliosis, misfolded protein accumulation, and loss of function or degradation of neurons. To address these gaps in our understanding, the studies herein provide valuable insight as to how infectious disease, specifically through infection with Mycobacterium tuberculosis, contributes to the progression of neuropathology, evaluates an alternative model of brain aging that better recapitulates human disease, and provides mechanistic understanding of the neuroprotective and neurotoxic roles of glia in disease. Altogether, these data elucidate the etiology and mechanisms that drive neurodegenerative disease, as well as possible therapeutic avenues that may bring us one step closer to a cure.
Open Access
Effects of major inorganic constituents of asphalt on the rapid determination of plutonium
(Colorado State University. Libraries, 2024) Chunko, Raissa, author; Sudowe, Ralf, advisor; Brandl, Alexander, committee member; Quackenbush, Sandra, committee member
In case of a nuclear incident, standard radioanalytical techniques must be available to analyze radionuclides in unusual matrices. Radiochemical analysis of samples in standard matrices of soil, water, and air are very well established; however, much less research has been conducted on the effect of unusual matrices such as steel, concrete, glass, and asphalt. In the event of a detonation of an improvised nuclear device (IND) in an urban environment, the standard separation techniques used for plutonium separations from asphalt samples originating from roadways and roofing shingles must rigorously be tested to provide useful insight on the characteristics of the special nuclear material. Batch studies were used to determine the changes in uptake of plutonium on extraction chromatography resins in the presence of trace metal components found in asphalt including aluminum, iron, and manganese at possible ranges found in asphalt samples. In these studies, selected cations with a +3-oxidation state had some interesting effects on the uptake of plutonium on the extraction chromatography resins. Aluminum increased the sorption of plutonium only on DGA and TRU resins especially at rising concentrations. Iron very unexpectedly increased the sorption of plutonium on all resins particularly at high concentrations. Additionally, metals found in the +3 oxidation state were shown to interfere with the recovery of plutonium from column studies conducted due to the synergistic effects. From this data, the contaminates found in asphalt with a +3-oxidation state may either compete with plutonium or give rise to a "salting out" effect that increases the sorption on the extraction chromatography resins and will need to be considered during the development of a rapid separation technique for plutonium from asphalt samples.
Open Access
Characterizing mold VOCs in residential structures impacted by flood
(Colorado State University. Libraries, 2024) Murphy, Molly, author; Schaeffer, Joshua, advisor; Magzamen, Sheryl, committee member; Carter, Ellison, committee member
Mold growth is a health concern for people re-entering their homes after a flooding event. Mold exposure can be hazardous, especially for people with asthma. Mold produces volatile organic compounds (VOCs) as it grows, and those VOCs can be used to detect the presence of mold. While VOC profiles of mold have been constructed in laboratory settings, there has been little work with samples directly from the field. VOC samples were taken from the homes of 55 Houston residents. 33 homes had been flooded, and 22 had not. The VOCs were analyzed using GCMS and identified using a NIST library of mass spectra. The VOCs found in flooded homes were compared to VOCs found in unflooded homes. There was a difference in VOCs identified, and the concentration of those VOCs, in flooded versus non-flooded homes, and some of those VOCs have been previously associated with mold growth. However, the origin of those VOCs is still not clear. Further work should include associating the VOCs found with the maximum water levels in the flooded homes, and with health data collected from the participants.
Open Access
Monte Carlo determination of detection efficiency for portal monitoring
(Colorado State University. Libraries, 2024) Blair, Noah Jeffrey, author; Brandl, Alexander, advisor; Sudowe, Ralf, committee member; Jeckel, Kimberly, committee member
At ports of entry into the country, at high security events such as political or athletic gatherings of crowds, and at high risk locations, portal monitors are used to detect the presence of ionizing radiation and ensure radiological/nuclear materials do not fall out of regulatory control or are utilized with malicious intent. This work uses computer models to determine the probability of photon radiation being detected in polyvinyl toluene, a plastic scintillator material, for a range of source energies, truck positions relative to the detector, and cargo materials. These results are used to develop models for operators of portal monitors to predict the activity of a radioactive source given the measured count rate and integrated count measurements. A linear model of the detection eﬀiciency produces an analytic expression of the measured count rate given the emission spectrum of a source which allows for calculation of net counts between two points on the truck's trajectory and the time derivative of the count rate. The time derivative of the count rate has a similar characteristic behavior along the truck's trajectory and has the potential to be an indicator of weak radiological sources. A MARS model allows for accurate prediction of the net count rate for truck positions and source energies not directly modeled. These models best predict detection eﬀiciency for higher energy photons and are primarily useful for the prediction of detection of fission and activation products.
Open Access
Colorado EnviroScreen as a predictor of mortality: an ecological analysis of 2019 county-level data
(Colorado State University. Libraries, 2024) Pusker, Stephanie, author; Rojas-Rueda, David, advisor; Clark, Maggie, advisor; Gutilla, Molly, committee member
Background In today's rapidly evolving landscape of environmental awareness in public health, Colorado stands at the forefront of innovation with its Environmental Justice (EJ) mapping and health screening tool, Colorado EnviroScreen (Colorado EnviroScreen, 2022). This tool, developed by Colorado Department of Public Health and Environment (CDPHE), empowers governmental agencies, research institutions, and the broader public to quantify and understand the interplay between environmental factors and community health by calculating an "EnviroScreen Score" (Colorado EnviroScreen, 2022). The higher the EnviroScreen score, the more likely the area will be affected by environmental health injustices at the census block group, census tract, and/or county levels (Colorado EnviroScreen, 2022). The purpose of this study is to bridge a gap in the current research landscape by exploring the association between aggregate county-level data derived from an EJ mapping tool and all-cause mortality rates. Specifically, we aim to investigate the relationship between the CO EnviroScreen score and the component scores – Demographics, Sensitive Populations, Climate Vulnerability, Environmental Effects, and Environmental Exposures – and all-cause mortality rates at the county level in Colorado in 2019. By conducting this ecological analysis, we seek to provide valuable insights into the potential impact of environmental justice factors on public health outcomes, thereby contributing to a more comprehensive understanding of the interaction between environmental conditions and mortality rates within communities. Methods An ecological study was conducted at the county-level spatial scale using a generalized linear model to assess the association between three EnviroScreen component score percentiles (Demographics, Environmental Exposures, and Climate Vulnerability) and age-standardized all-cause mortality at the county level. These three score percentiles were selected due to correlation with other scores, as well as the indicators included in some of the component scores being more comprehensive than others. County-level covariates included in the model were insufficient sleep, alcohol overindulgence, physical inactivity, and smoking. In addition to the full model, secondary models were created, including Demographics, Environmental Exposures, and Climate Vulnerability as independent predictors. Furthermore, the total EnviroScreen score percentile, which includes all component scores, was used in the analysis. Results In the fully adjusted model, a 10% increase in the EnviroScreen Environmental Exposures component score was associated with a 3% increase in all-cause mortality rate at the county level in Colorado in 2019 (95% CI: 1.00, 1.05). In the crude model, a 10% increase in EnviroScreen score was associated with a 5% increase in all-cause mortality rate at the county level in Colorado in 2019 (95% CI: 1.03, 1.07). Neither Demographics nor Climate Vulnerability component scores percentile were associated with an increase or decrease in all-cause mortality rates. Discussion This study suggests that there is a potential association between a higher EnviroScreen component score and an increase in age-standardized, all-cause mortality at the county level in Colorado. This is the first study to estimate the association between aggregate environmental and health-related scores from CO EnviroScreen with mortality. This study supports the notion of cumulative impacts as a tool to monitor possible health disparities and environmental injustice.
Open Access
Tumor microenvironment in spontaneously occuring tumors and in vitro evaluation of hypoxia associated mutagenesis
(Colorado State University. Libraries, 2008) Trncic, Nadira, author; LaRue, Susan M., advisor
The importance of the tumor oxygenation status in tumor progression and tumor response to radiation and other forms of treatment has been investigated in many experimental and clinical studies. Oxygen status can impact cell killing associated with radiation treatment and, interestingly radiation can also impact subsequent oxygen levels. Part I of my dissertation is concerned with this phenomenon of reoxygenation. A multiparameter study was conducted in naturally occurring canine tumors to evaluate physiological changes in the tumor microenvironment following a 3 Gy fraction of radiation. Pre-treatment values of partial pressure of oxygen, interstitial fluid pressure, microvascular perfusion, level of apoptosis, and microvessel density were compared to the 24 hours post-radiation measurements in the same location. I analyzed changes in all parameters and evaluated the relationship between parameters and pO2. In disagreement with my working hypothesis, I only found inverse correlation between changes in oxygen level and changes in IFP. In Part II, I used the CHO AL mutation assay to investigate the role of hypoxia alone in the induction of mutagenesis. After exposing cells to different hypoxic conditions I found that only severe hypoxia can cause mutations in human-hamster hybrid cells (AL). Level of oxygen that induced mutations was less than 0.63 mm Hg. Both the complement-mediated AL mutation assay and the flow cytometry mutation assay were done. Mutant cells were sorted from the mutant peak, and the clonal populations of cells were analyzed with the AL flow cytometry assay to determine if cells were really mutated (negative for CD59) and not just downregulated in hypoxia. Quantitative analysis of mutations that were performed did not detect any changes in the CD59 gene. Tumor reoxygenation, as shown here, may not be associated with improved tumor perfusion, but rather with other factors such as decreased oxygen consumption. These studies proved that severe hypoxia can cause mutations and possibly tumor genetic instability, and that those levels of oxygenation can be found in spontaneous tumors in dogs, which are a great tumor model for translating findings to human cancers.
Open Access
Analyses and exposure assessment of bacterial endotoxin in agricultural environments
(Colorado State University. Libraries, 2008) Saito, Rena, author; Reynolds, Stephen J., advisor
Endotoxins, or lipopolysaccharides (LPS), found in organic dust are a component of the cell membrane of Gram-negative bacteria that play an important role in respiratory disease. However, accurate endotoxin measurements are difficult in agricultural environments since agricultural dusts contain a complex mixture of biological and chemical agents. This dissertation research was designed to improve the understanding of the variability in endotoxin measurements in agricultural environments. The first study determined patterns of 3-OHFA distribution in dusts from dairy farms, cattle feedlots, grain elevators, and farms, and evaluated correlations between the GC/EI-MS and the rFC bioassay results. Patterns of 3-OHFA distribution varied by dust type; livestock dusts contained approximately two times higher concentrations of 3-OHFAs than grain dusts. Pearson correlations and multiple regressions showed higher correlations between GC/EI-MS and rFC results for livestock dusts than for grain dusts. Odd-chain length 3-OHFAs were found to correlate with rFC responses, as well as with even-chain length 3-OHFAs. The second study evaluated traditional LAL and novel rFC assay responses to endotoxins in chicken, dairy, horse, swine, and turkey dusts, and investigated potential interference with assays using GC/EI-MS. Strong positive correlations existed between LAL and rFC results, but responses to assays varied by dust type. LAL overestimated/rFC underestimated endotoxin exposures in chicken and horse dusts, and LAL underestimated/rFC overestimated endotoxin concentrations in dairy, swine, and turkey dusts. The variability in assay responses might be explained by differences in bacterial composition and other dust components; the rFC assay may react positively with Actinobacteria. The third study characterized agricultural tasks and evaluated determinants of personal dust and endotoxin exposures in dairy farms, cattle feedlots, grain elevators, and farms. Dust and endotoxin exposures differed by agricultural environment and by task and combinations of tasks varied by environment. Regression analysis indicated that hours at running legs in grain elevators was the major determinant of dust. Hours at running legs in grain elevator and hours at feeding livestock in cattle feedlots were two major determinants in endotoxin measurements. This dissertation addressed the need for understanding differences in agricultural environments for endotoxin exposure assessment.
Open Access
Epidemiologic studies of hard tick-associated illness in the United States
(Colorado State University. Libraries, 2009) Murphree, Rendi, author; Bachand, Annette M., advisor
This dissertation describes three epidemiologic studies of hard tick-associated illness in the United States. The first is the prospective health assessment of Fort Campbell, Kentucky patrons bitten by ticks during 2004-2006. The study was designed to determine the frequency, clinical characteristics, and etiology of Amblyomma americanum-associated illness and to identify associated risk factors. Amblyomma americanum is an aggressive human biting tick associated with a Lyme disease-like illness of unknown etiology. Study findings suggested that a variety of symptoms were temporally associated with tick bite but data provided no clear evidence that symptoms were caused by an infectious process. Removing ticks by hand or being bitten on a limb may have been risk factors for illness. The second examines 248,074 cases of Lyme disease reported to the Centers for Disease Control during 1992-2006 using descriptive and inferential statistics. In the United States, Lyme disease is caused by Borrelia burgdorferi sensu stricto, a spirochete transmitted to humans by infected Ixodes scapularis and I. pacificus ticks. During the 15-year study period, the number of cases reported annually increased 101% and the majority of cases occurred in northeastern and north-central states. An increasing trend in the number of counties reporting at least one case annually was observed in Minnesota, Rhode Island, and Wisconsin. A disproportionate increasing trend in reported cases was observed in children and young males compared with other demographic groups. The third study is a pilot ecologic analysis of human social or economic factors affecting, or resulting from, Lyme disease emergence. The objectives were to identify space-time clusters of increased Lyme disease risk and determine if risk could be partially explained using existing data on environment, socioeconomics, and healthcare. As expected, Ixodes tick distribution was a significant predictor of counties with increased risk. Measures of socioeconomic status surfaced as predictors of ecologic risk, and it appeared that persons of high SES lived where ticks were reported in northeastern states and persons of low SES lived where ticks were reported in the north-central states.
Open Access
Characterizing in vitro propagation and radiation response of murine mammary stem cells
(Colorado State University. Libraries, 2009) Magers, Tonya Sirisalee, author; Ullrich, Robert L., advisor
Stem cells in breast tissue may be sensitive to known carcinogens (i.e. ionizing radiation), which impact their susceptibility to transformation. The involvement of mammary stem cells in tumorigenesis could explain the heterogeneity and molecular complexity of breast cancer. However, the involvement and the underlying mechanisms of such targets have yet to be fully elucidated. This study was designed to investigate mammary stem cells as plausible targets of radiation-induced damage in radiation-induced mammary carcinogenesis. We utilized an in vitro system (mammospheres) that was developed for the detection of mammary stem cells. We expanded the applicability of this in vitro assay through the development of a methodology and novel size criteria to address specific radiation biology endpoints. We applied the methodology and size criteria to analyze the effects of ionizing radiation (IR) on the survival of mammary stem cells derived from mice carrying one mutated copy of Atm. Our results demonstrated that mammary stem cells derived from Atm-ΔSRI heterozygous mice (Atm(+/ΔSRI)) do not exhibit increased radiation sensitivity compared to their wildtype littermates (Atm(+/+)). In fact, mammary stem cells derived from Atm-ΔSRI heterozygous mice exhibited increased radioresistance. To our knowledge, this is the first study to examine the radiation response of mammary stem cells as mammospheres using Atm heterozygous mice carrying a known missense mutation found in human A-T. These studies demonstrated the proof of principle for this model development and the utility of this methodology. Our improved methodology has expanded the feasibility and the applicability of this model to examine numerous functional in vitro endpoints. We believe the methodology described here will facilitate investigating the radiation response of mammary stem cells and their progeny, and key components involved in early events of the carcinogenic process in murine model systems.
Open Access
Physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling of 3,3',4,4',5-pentachlorobiphenyl (PCB126)
(Colorado State University. Libraries, 2008) Lohitnavy, Manupat, author; Yang, Raymond H. S., advisor; Reisfeld, Brad, advisor
3,3',4',4',5-Pentachlorobiphenyl (PCB126) is a persistent environment carcinogen. Despite its high lipophilicity, PCB126 was primarily recovered from liver. In addition, PCB126 could achieve its steady state in the liver in a relatively short period of time. Using a three-dimensional quantitative structure-activity relationship (3D-QSAR) model, PCB126 was predicted to be a Mrp2 substrate with a relatively high binding affinity (Km) value. With this newly emerging knowledge, we incorporated a Mrp2-mediated excretion process into our physiologically-based pharmacokinetic (PBPK) model of PCB126. Our model could describe numerous tissue concentration-time courses in different dosing conditions. Our PBPK model revealed an important role of Mrp2 in PCB126 disposition. In addition, to establish a correlation between PCB126 pharmacokinetics and its pharmacodynamic (PD) endpoint (i.e. hepatocarcinogenic effect), we used a chosen internal dose surrogate [i.e. area under the curve of PCB126 in liver (AUCLiver)] to predict the PD effect of PCB126. With this PBPK/PD model, correlation between the AUCLiver and our liver glutathione- S-transferase placental form positive (GSTP+) foci development data was demonstrated. We also conducted a pharmacokinetic interaction study between PCB126 and methotrexate (MTX), a known Mrp2 substrate, by exposing rats with multiple oral doses of PCB126 followed by an oral single dose of MTX. Liver samples were collected and analyzed for hepatic MTX and PCB126 concentration levels. Using a PBPK modeling technique incorporating with competitive inhibition processes between the two chemicals at the level of hepatic Mrp2, liver concentration-time courses of both chemicals were successfully simulated. To further investigate PD effects of PCB126 within liver GSTP + foci, we conducted an experiment by exposing rats with PCB126 using our modified liver foci bioassay up to 6 months. Liver foci positive or negative for GSTP+, transforming growth factor-α+ (TGFα+) and transforming growth factor-β Type 2 receptor (TGFβ2Rc-) were investigated. In rats treated with PCB126, time-dependent changes in all of three biomarkers were observed. Interestingly, when the GSTP+ foci were categorized into four phenotypic groups according to their TGFα and TGFβ2Rc expression, GSTP+ foci with TGFα expression and absence of TGFβ2Rc expression had significantly higher hepatocyte division rates than those of GSTP+ foci without TGFα expression and with TGFβ2Rc expression.
Open Access
Comparison of occupational and environmental exposures at Colorado dairies
(Colorado State University. Libraries, 2008) Lester, Bradley Raymond, author; Reynolds, Stephen J., advisor
Occupational contaminant levels and environmental emissions were compared at two Colorado dairies. Along with meteorological conditions, analytes measured included odor, hydrogen sulfide, ammonia, total and inhalable particulate and endotoxin, and bioaerosols including fungi, mesophilic bacteria, and gram-negative bacteria. Meteorologic conditions varied widely in temperature (range: -12.5 - 4 1.1°C), relative humidity (range: 0.6 - 92.3%) and wind speeds during sampling (range: 0.48 - 8.66 m/s). Geometric mean bioaerosol concentrations for the Anderson sampler and SKC Biosampler include: mesophilic bacteria, 1282 and 383 CFU/m3, gram-negative bacteria, 667 and 265 CFU/m 3, and fungi, 781 and 252 CFU/m3. The Anderson sampler collected significantly (p<0.001) higher bioaerosol concentrations for all three categories. Peak ammonia levels at the study and control dairies ranged from 2.0 - 142 and 2.0 - 23 ppm. Peak ammonia was significantly (p<0.05) higher at the study dairy. Mean hydrogen sulfide levels at the study and control dairies ranged from 4.0 - 394 and 4.0 - 890 ppb. Peak hydrogen sulfide levels at the study and control dairies ranged from 37 - 17,000 and 210 - 5,200 ppb. Mean peak hydrogen sulfide was significantly (p<0.05) higher at the control dairy. Odor measures ranged from 0-15 D/T at both dairies. Inhalable particulate at study and control dairy lagoons ranged from < LOD - 2.3 mg/m3. Inhalable endotoxin at study and control dairy lagoons ranged from 2.1 - 487.2 EU/m3. Total particulate at study and control dairy lagoons ranged from < LOD to 2.4 mg/m3. Total endotoxin at study and control lagoons ranged from 2.5 - 6587 EU/m3. Inhalable particulate for tasks at both dairies ranged from 0.06 - 8.0 mg/m3. Total particulate for tasks at both dairies ranged from 0.03 - 6.9 mg/m 3. Inhalable endotoxin for tasks at both dairies ranged from 2.0 - 11096 EU/m3. Total endotoxin for tasks at both dairies ranged from 5.9 - 6758 EU/m3. Supported by NIOSH Grant 5U500H008085.
Open Access
Depressive symptoms, drinking patterns and farm-work injury among Colorado farm residents
(Colorado State University. Libraries, 2008) Leff, Marilyn Grace Petersen, author; Stallones, Lorann, advisor
Introduction. Farm-work injury is a major occupational health problem. The purposes of this study were to (1) describe farm residents who are heavy drinkers with high depressive symptoms and (2) assess the association between farm-work injury and depressive symptoms, farm-work injury and drinking pattern, and farm-work injury and the interaction of these two in cross-sectional and prospective analysis. Methods. A population-based sample of farm residents within Colorado was followed for three years. Information on socio-demographic and health related variables were gathered including farm-work injuries, depressive symptoms, and alcohol use. Multinomial logistic regression was used to describe differences and similarities between farm residents with high depressive symptoms and heavy drinking, high depressive symptoms only, and heavy drinking only compared to those without either. Poisson regression with repeated measures was conducted to estimate the effect of depressive symptoms and alcohol use and the interaction between the two variables on farm-work injury. Results. An association between smoking and co-occurring heavy drinking and high depressive symptoms was found (OR 3.69, 95% CI 1.0, 13.1) that was not seen among those with heavy drinking only or high depressive symptoms only. Time spent in farm work was also associated with depressive symptoms and with co-occurring heavy alcohol use. In both the cross-sectional and prospective regression analyses, no association was found between drinking pattern and injury for men or for women. After adjusting for age and smoking status, high depressive symptoms was associated with farm-work injuries among women (OR 3.6, 95% CI 1.8-6.9) in the cross-sectional analysis but not in the prospective analysis. No association between farm-work injuries and depressive symptoms was found for men. No interaction between drinking pattern and depressive symptoms in relation to injuries was seen in either men or women. Discussion/Conclusions. The association between smoking and co-occurrence of heavy drinking and high depressive symptoms may provide useful information for smoking cessation efforts. Depressive symptoms were more likely a result of farm-work injury in women rather than a cause. Future studies are needed to understand the impact of farm-work injuries in the context of differences in the roles of men and women farmers.
Open Access
Understanding the association between the Abbreviated Injury Scale score for the head region and outcomes following traumatic brain injury, Colorado 1998-2000
(Colorado State University. Libraries, 2007) Gujral, Indira Beatrice, author; Stallones, Lorann, advisor
Annually, an estimated 1.4 million Americans are affected by traumatic brain injury (TBI). It is the leading cause of morbidity and mortality among trauma individuals. While advances in medicine have helped to decrease mortality from TBI, less is known about the long-term outcomes following TBI. The goal of this research was to further ourunderstanding of long-term outcomes following TBI by identifying associations betweenone anatomical coding system and one-year outcomes following TBI. The Abbreviated Injury Severity Score is an anatomical scoring system used by injury researchers throughout the United States and the world to characterize individual injury. One attribute of this measure is the ability to independently characterize injury severity for one body region, for this study, specifically, the head region. Although the Abbreviated Injury Severity Score for the Head region (HAIS) is ananatomic measure of TBI severity, no study has assessed the inter- and intra-rater agreement of HAIS between trauma registrars at hospitals and trained state coders. Further, no studies have specifically assessed the association between HAIS and longterm outcomes following TBI using population-based data. The objectives of this study were to utilize data from two Colorado population-based studies containing HAIS scores to investigate the reliability of HAIS and its ability to predict long-term physical and cognitive outcomes after traumatic brain injury. The purposes of this study were: 1) to describe the intra-rater reliability of HAIS scores by having a trained coder employed by the Colorado Department of Public Health and Environment recode HAIS scores for traumatic brain injured cases from the Colorado Traumatic Brain Injury Surveillance system for the years 1999-2000; 2) to describe the inter-rater reliability of HAIS scores by comparing HAIS scores from cases in the Colorado Traumatic Brain Injury Surveillance system for 2000 to HAIS scores from trauma registrars at hospitals throughout Colorado; and, 3) to use HAIS scores to evaluate functional outcomes of traumatic brain injured individuals in Colorado who were enrolled between 1998 and 1999 in the Colorado Traumatic Brain Injury Registry and Follow-up System. Cases were defined using the International Classification of Diseases, 9th Revision, Clinical Modification diagnostic codes for TBI (800 - 801.9, 803 - 804.9, or 850 854.1, and 959.01) and included Colorado residents who were either admitted to hospitals or died prior to reaching the hospital from a TBI. To assess inter- and intra-rater agreement, data was selected from the Colorado Traumatic Brain Injury Surveillance system for years 1999 - 2000. A sample of 250 cases was randomly selected to assess intra-rater agreement. Approximately 624 cases were selected to assess inter-rater agreement. Weighted and non-weighted kappa statistics were used to assess inter- and intra-rater agreement, respectively. Landis and Koch (1977) cut points were used to interpret agreement findings. To identify long-term outcomes following TBI, 1,802 cases were used from the Colorado Traumatic Brain Injury Registry and Follow-up System (CTBIRFS), 1998 - 1999. Outcomes selected for this study were based on the conceptual model of function and disability developed by the World Health Organization. Logistic regression models were used to determine the association between TBI severity categories (HAIS) and one-year activity and societal participation outcomes. Logistic regression was used to determine the association between HAIS and cognitive outcomes one-year following TBI. All statistical analyses were conducted using SAS 9.1©. Results of this study found intra-rater agreement of HAIS to be “almost perfect” while inter-rater agreement between the trained state coder and the hospital trauma registrars was “substantial.” This finding was surprising given that individuals performing the coding often have varying levels of education and training, experience,and use and knowledge of database systems. Factors that potentially affect agreement thatwere not tested include injury factors such as impact forces, multi-system trauma, pharmaceutical drug usage, and use of personal protective equipment, such as helmets. Future studies should be conducted to identify the role of these factors when coding HAIS. In order to accurately assess function and disability following TBI, the severity of the TBI must be taken into account. Using HAIS categories mild, moderate, and severe TBI, individuals with moderate TBI (5.04 [95% confidence interval (1.67, 15.6)]) and severe TBI (4.08 [95% confidence interval (1.29, 12.7)]), were five times as likely to report needing help with Activities of Daily Living throughout the study period as compared to those with mild TBI, after adjusting for identified potential confounders. Similarly, subjects with moderate and severe TBI were more than 60% as likely to report needing help with Instrumental Activities of Daily Living throughout the study period as compared to those with mild TBI. The odds ratios for moderate and severe TBI were 1.90 [95% confidence interval (1.01, 3.57)] and 1.62 [95% confidence interval (0.81, 3.26)], respectively. Adjusting for identified potential confounders, subjects with moderate and severe TBI were more than 50% as likely to report diminished societal participation throughout the study period as compared to those with mild TBI. The odds ratios for moderate and severe TBI were 1.72 [95% confidence interval (1.18, 2.51)] and 1.58 [95% confidence interval (1.01, 2.47)], respectively. However, moderate and severe TBI were not associated with cognitive dysfunction. The results of this study indicate that HAIS is a good predictor of function and disability at the individual and societal levels, as measured by the activities and participation domains. The study failed to find an association between HAIS and cognitive disability. The results of this study support the need for individuals with a moderate and severe TBI (HAIS score greater than three) to participate in some form of rehabilitation to increase function and reduce disability following TBI. The objective of this study was to use data from the CTBIRFS and the CO TBI Surveillance system to expand upon the literature regarding outcomes following TBI. Specifically, the purpose of this study was to increase understanding of the Abbreviated Injury Scale for the head (HAIS) - an anatomical scoring system that potentially could be a predictor for long-term outcomes following TBI. As medicine advances and more individuals survive TBI, demands on rehabilitation resources will rise. The results of this study indicate that HAIS is a reliable scoring system that is associated with one-year outcomes following TBI. Using HAIS to assess severity of TBI will allow clinicians to identify and target rehabilitative efforts for TBI individuals and help individuals receive the rehabilitation services they need. Future research is needed to expand upon these findings to identify barriers to rehabilitation, such as cost and access to care, and to assess the role of rehabilitation on quality of life following TBI.
Open Access
Analysis of agriculture injuries using workers' compensation data
(Colorado State University. Libraries, 2008) Douphrate, David Irvin, author; Rosecrance, John C., advisor
Background. In the United States, agriculture is among the most hazardous of industries. The lack of information regarding agriculture injuries has been recognized as an obstacle to effective injury prevention efforts. Methods. Three separate but related studies analyzed workers' compensation data to elucidate injury and claimant characteristics associated with agriculture injuries. Specific emphasis was placed on tractor-related and livestock-handling injuries. Results. Results indicated high injury rates among workers employed by dairy farms, cattle/livestock raisers, and cattle dealers. Large proportions of injuries were associated with tractor mounting and dismounting, milking, cattle pinning/sorting, and horseback riding activities. Tractor-related and livestock-handling work injuries are a significant problem, more costly, and result in more time off work than other agriculture injuries. Conclusions. Injury prevention efforts should be directed at livestock-handler education, dairy parlor and livestock-handling facility design, and tractor design characteristics related to tractor mounting and dismounting.
Open Access
Characterization of atrazine induced protein adducts
(Colorado State University. Libraries, 2007) Dooley, Gregory, author; Tessari, John D., advisor
Atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) (ATRA) is the most commonly applied herbicide in the U.S. and is frequently detected in drinking water at significant levels. ATRA metabolism yields diaminochlorotriazine (DACT), an electrophilic molecule that can react with nucleophilic protein residues forming a covalent adduct. We first demonstrated this interaction with hemoglobin from rats exposed to 30-300 mg/kg ATRA. Mass spectrometry (MS) analysis of hemoglobin tryptic digests indicated a 110 Da adduct on Cys-125 of the β-subunit. Based on in vitro incubations of 90 ug/ml DACT and hemoglobin yielding the identical adduct observed with in vivo ATRA exposures, adduct formation was by a nucleophilic substitution reaction between DACT and Cys-125. Albumin was then investigated since it contains an exposed Cys-34 that could be targeted by DACT. Again using MS, a 110 Da adduct was located on Cys-34 of albumin from rats exposed to 20-200 mg/kg ATRA and rat and human albumin exposed in vitro to 90 ug/ml DACT. Immunochemical detection using a DACT adduct antibody also detected the adduct in albumin samples from rats given 5-200 mg/kg ATRA and rat and human albumin exposed in vitro to DACT. No adducts were detected in control animals or in the in vitro controls with this method. These data support a novel immunochemical detection system that could provide a rapid screening methodology for the detection of ATRA in exposed human populations. Finally, we used the DACT antibody to located modified proteins in the pituitaries of ATRA exposed rats and DACT exposed LβT2 rat pituitary cells. Since ATRA exposure suppresses the luteinizing Hormone (LH) surge, protein adducts in the pituitary may be involved in this mechanism of action. 2DE followed by Western blotting showed numerous spots (>30) that were not present in control from both exposed rats and LβT2 cells. Using MS analysis of matched protein spots, 8 unique proteins in the rats and 19 unique proteins in LβT2 cells were identified. Each of these proteins contained solvent exposed cysteine residues, making them targets for DACT. Future research will be necessary to elucidate the functional role of these adduct and their involvement in ATRA/DACT induced LH suppression.
Open Access
Menstrual cycle characteristics in women exposed to atrazine in drinking water
(Colorado State University. Libraries, 2009) Cragin, Lori Ann, author; Reif, John, advisor
Introduction. Atrazine is the most commonly used herbicide in the United States and a wide-spread groundwater contaminant. Concern regarding potential health effects of human exposure to atrazine is based on its well recognized designation as an endocrine disruptor. Studies have shown that menstrual cycle characteristics are markers for reproductive conditions. The specific hypothesis tested in this research was: Exposure to atrazine in municipal drinking water is associated with menstrual cycle abnormalities which, in turn, are modulated through a diminution of the pre-ovulatory luteinizing hormone surge. In addition, the following secondary hypothesis was tested: There is agreement between retrospective menstrual cycle questionnaire data and data obtained prospectively from menstrual cycle diaries. This study was the first to examine the effects of drinking water exposure to atrazine on menstrual function in humans and the first to examine the underlying mechanism of this association.
Open Access
Indoor air pollution from cookstove smoke and adverse health effects among Honduran women
(Colorado State University. Libraries, 2007) Clark, Maggie L., author; Peel, Jennifer, advisor
Elevated indoor air pollution exposures associated with the burning of biomass fuels in developing countries are well established. Several studies have demonstrated the value of estimating exposures by evaluating stove type, personal cooking practices, and household parameters. Adverse health endpoints have been associated with cookstove exposures, although little research has been performed on cardiovascular health endpoints in these settings. We conducted a cross-sectional survey among 79 non-smoking Honduran women. Thirty-eight women cooked with traditional stoves and 41 with improved stoves with chimneys. For a subgroup of these women (N=54-58), carbon monoxide and particulate matter (PM2.5) levels were assessed via eight-hour indoor monitoring, as well as eight-hour personal PM2.5 monitoring. Stove quality was assessed using a four-level subjective scale representing the potential for indoor emissions. The stove scale and ventilation factors predicted more than 50% of the variation in personal and indoor PM2.5 and 85% of the variation in indoor carbon monoxide. In addition to the stove scale, other factors predicting exposure measurements were the age of the stove, the total area of the kitchen windows, the number of kitchen walls, the primary material of the kitchen walls, the volume of the kitchen, and the number of walls with eave spaces. Forced expiratory volume in one second and peak expiratory flow, as well as respiratory symptoms and demographic characteristics were assessed. Finger-stick blood samples were collected and dried on filter paper in order to assess a biomarker of inflammation, C-reactive protein (CRP). Women exposed to cookstove exposures reported symptoms of cough, phlegm, wheeze, headache, and shortness of breath more frequently than those not exposed. Associations consistent with a null association were observed between cookstove exposures and lung function and CRP. Results of the exposure assessment could provide a cost-effective alternative to air quality monitoring. The ease and convenience of collecting, storing, and transporting finger-stick blood samples, could prove to be a useful tool for larger community-based investigations, especially in developing countries.
Open Access
An epidemiologic evaluation of risk factors associated with asthma severity and phenotypes
(Colorado State University. Libraries, 2008) Busacker, Ashley A., author; Keefe, Thomas J., advisor
Asthma is an inflammatory disorder of the airways characterized by airway hyperresponsiveness, periodic episodes of bronchoconstriction and airway obstruction. Severe asthma accounts for a minority of asthma, but utilizes a disproportionate amount of asthma-associated healthcare costs. Further studies are needed to identify risk factors associated with severe asthma, a very heterogeneous disease. Asthma-particularly severe asthma-consists of several different phenotypes. Limited epidemiologic studies have been conducted to identify risk factors specific to severe asthma. Factors associated with proposed asthma phenotypes have not been evaluated in a multivariate manner. This study investigated the risk factors associated with severe asthma, with specific phenotypes of asthma, and the association between a potential biomarker, C-reactive protein (CRP), and aspirin intolerant asthma. The project utilized data that were collected from National Institutes of Health funded studies and data collected from an electronic chart review. Data from questionnaires, histological, radiological and physiological studies were used to determine univariate associations between these factors and asthma severity and then to determine associations between the factors and different asthma phenotypes. Multiple logistic regression analysis was used to evaluate the differences between severe and non-severe asthma, early and late onset asthma, asthma subjects who did or did not exhibit air trapping, and aspirin intolerant and tolerant asthma with particular attention to CRP levels. This investigation found important clinical differences between severe and non-severe asthma that should be further evaluated as risk factors that may give insight into severe-asthma mechanisms to be targeted in asthma treatment. The analysis of asthma phenotypes also yielded important findings. Specifically, early onset asthmatics appear to be a relatively homogeneous group with strong genetic influences and presence of allergic responses, whereas late onset disease is more heterogeneous. The analysis of the air trapping phenotype demonstrated that quantitative CT-determined air trapping in asthmatic subjects identifies a group of individuals with a increased odds of intensive health care utilization. Additionally, several independent risk factors for the presence of this phenotype were identified, perhaps most interestingly history of pneumonia, neutrophilic inflammation, and atopy. Lastly, this study provides evidence that CRP may be elevated in aspirin intolerant subjects and that CRP deserves further study as a potential biomarker for the aspirin intolerant phenotype of asthma.