Theses and Dissertations

Permanent URI for this collection

https://hdl.handle.net/10217/100420

Browse

Now showing 1 - 20 of 252

Embargo
Assessment and intervention strategies for agricultural inhalation exposures in occupational and community environments
(Colorado State University. Libraries, 2024) Erlandson, Grant, author; Schaeffer, Joshua, advisor; Magzamen, Sheryl, committee member; Abdo, Zaid, committee member; Martenies, Sheena, committee member
Agriculture represents an industry vital to the U.S. economy, supplying the public with nutritious food and providing millions of workers with employment. Also characterized as one of the most hazardous industries for workers, agricultural environments contain a variety of inhalation hazards capable of impacting the health of workers and adjacent community residents. Agricultural inhalation hazards include airborne organic and inorganic dusts; livestock associated gases, pesticides, bacteria, viruses, and antibiotics. This study will focus on (1) bioaerosol exposures in dairy operations and (2) inorganic dust pesticide exposures from agricultural applications. In dairy environments, workers are regularly exposed to high levels of organic dust (bioaerosols) and their inflammatory constituents (e.g., endotoxin, muramic acid, and β-glucans). Dairy bioaerosol exposure is associated with increased prevalence of respiratory disease (e.g., asthma, rhinitis, and chronic obstructive pulmonary disease) in dairy workers. While bioaerosol exposure in dairy environments has been well characterized in previous research, efforts to identify hygienic interventions that control exposure remain unsuccessful. In crop production agriculture, it is well documented that workers are exposed to high levels of pesticides associated with adverse health outcomes (e.g., respiratory and neurologic diseases). Further, in agricultural adjacent community environments, where lower chronic pesticide exposures are found, there is mounting evidence linking adverse health effects (e.g., adult and iii childhood cancers, neurologic and respiratory diseases, and birth outcomes) in residents to exposure from agricultural pesticide applications. However, weak and sometimes inconsistent associations previously reported highlight the limitations of current community exposure assessment techniques used for pesticides. For specific Aim 1, we pilot tested a novel low-cost nasal rinse intervention to modulate airway inflammation in ten bioaerosol exposed dairy workers. Dairy workers were randomly split into treatment (n = 5) and control (n = 5) groups and administered saline nasal rinses before and after their shift for five consecutive days. Treatment group participants received pre-shift hypertonic saline rinses while the control group received normotonic saline rinses. Both received normotonic rinses post-shift. Pro and anti-inflammatory cytokines were measured from recovered saline rinses. Linear mixed model results indicated treatment group participants experienced significantly higher concentrations of anti- (IL-10) and pro-inflammatory cytokines (IL-6 and IL-8) than the control group (p < 0.02, p <0.04, and p < 0.01 respectively). This study demonstrates the capacity of hypertonic saline nasal rinses to successfully upregulate anti-inflammatory cytokine production. However, conflicting upregulation of pro-inflammatory markers cloud interpretations of efficacy. For Aim 2, we further evaluated the immunomodulatory effects of hypertonic saline rinses vs. normotonic saline rinses longitudinally (2-5 shifts) in 45 bioaerosol exposed dairy workers. However, in this aim, treatment group participants received hypertonic rinses pre- and post-shift and 16S sequencing was added to analyses to capture potential washout effects on microbial diversity. No significant differences were observed between group or day for any of the measured markers or microbiome diversity metrics. Yet, non-significant increases in anti-inflammatory IL-10 concentrations across the study period were observed independent of iv treatment group suggesting the rinse itself may be more impactful than tonicity. This study provided mixed but encouraging results that justify further research on nasal rinses as an intervention in bioaerosol exposed dairy workers. For Aim 3, we evaluated the agreement between three exposure assessment techniques used to estimate residential organophosphate (OP) exposure in agricultural adjacent communities located in the Central Valley of California. OP exposure was estimated from household dust samples, California Pesticide Use Report (CPUR) pesticide use modeling, and urinary DAP metabolites across two sampling campaigns. Simple correlation tests revealed moderate correlations (ρs = 0.46) between household dust and use model exposure estimates. Estimates from urinary DAP metabolites exhibited low to no correlation with the other two estimates. Linear mixed model results also indicated no association between urinary DAP metabolites and household dust or use model estimates. This study illustrates a lack of agreement between community pesticide exposure assessment techniques regularly used in research and motivates the development of more robust assessment techniques.
Embargo
Pathogens, pulmonary function, and the nasal microbiome of dairy workers
(Colorado State University. Libraries, 2024) Seidel, James, author; Schaeffer, Joshua, advisor; Magzamen, Sheryl, committee member; Abdo, Zaid, committee member; Valley, Morgan, committee member
Dairy workers are exposed to bioaerosols that are diverse in both size (0-100 µm in aerodynamic diameter) and inflammatory constituents (e.g. endotoxins, muramic acid, and β-glucans). Bioaerosol exposure at dairies is associated with a higher prevalence of chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, respiratory pneumonitis, and asthma-like reductions in pulmonary function. More recently, opportunistic pathogens present at dairies such as the novel influenza D virus (IDV), influenza A (IAV), and livestock-associated Methicillin-resistant Staphylococcus aureus (MRSA) have also been a focus of research, as these pathogens can infect workers and pose a public health risk through community spread. Intrinsic factors such as genetics and childhood exposures likely play a major role in exposure response and respiratory disease pathology, but little research has been focused on the nasal microbiome's role in pathogen exposure and cross-shift changes of pulmonary function. From a longitudinal (2-5 working shifts) cohort of dairy workers in the High Plains Region of the US, this research analyzed pathogens found in the nares of dairy workers via pre- and post-shift nasal lavages. The same nasal lavages underwent targeted 16S rRNA gene sequencing to quantify the bacterial communities that comprise the nasal microbiome. Spirometry was also performed on dairy workers pre- and post-shift to measure cross-shift changes in pulmonary function. Overall, 32.1% (n=237) of nasal lavages tested positive for Methicillin-susceptible Staphylococcus aureus (MSSA), 11.4% tested positive for MRSA, 17.3% for IDV, 2.5% for IAV, and 1.3% for influenzas C virus (ICV). Only 1 of the original 31 participants never tested positive for a pathogen during their workweek. Differences in nasal microbiome characteristics emerged based on pathogen positivity, and differential abundance analysis revealed significant differences in genera based on the positivity of both bacterial and viral pathogens. The dairy workers in this study also experienced decreases in cross-shift pulmonary function. The average decrease in forced expiratory volume in one second (FEV1) over 108 working shift was -74.4 ml, and the average decrease of forced vital capacity (FVC) was -92.5 ml. Significant differences in microbiome characteristics did emerge based on post-shift and cross-shift spirometry performances, and taxonomic differences were noted in participants performing poorly on cross-shift FVC. The nasal microbiomes of workers also underwent community state typing, and participants in CST3 showed the most resilience to cross-shift changes in lung function. This research also investigated the efficacy of a hypertonic saline nasal lavage in improving cross-shift changes in pulmonary function. From a cohort of 44 dairy workers, 22 workers received pre- and post-shift hypertonic saline nasal lavages with an osmotic concentration of 400 milliosmole (mOsm). The 22 participants in the control group received pre- and post-shift normotonic saline (308 mOsm) nasal lavages. Based on constructed mixed linear models, the treatment improved cross-shift outcomes of the forced expiratory flow at 25-75% of the vital capacity (FEF25-75%), but had little effect on FEV1 and FVC. The use of a pre- and post-shift lavage of any osmolarity, however, appeared to reduce the burden of cross-shift pulmonary function decline often experienced by dairy workers. For the first time, this research showed that both viral and bacterial pathogens are present in the nares of US dairy workers. This work also identified the nasal microbiome characteristics that may play a role in pathogen exposure and cross-shift lung function outcomes. The use of a saline nasal lavage as an intervention was also explored, and the intervention appeared to improve cross-shift pulmonary function outcomes.
Open Access
Characterizing stooped posture of agricultural tasks
(Colorado State University. Libraries, 2024) Sanders, Denali, author; Rosecrance, John, advisor; Brazile, Bill, committee member; Hobbs-Murphy, Kayna, committee member
Agricultural field workers worldwide are often required to work in stooped postures during their working tasks. Stooped postures constitute a significant risk factor for the development of musculoskeletal disorders, specifically low back pathologies that cause pain. Chronic low back pain is a devastating disorder that can lead to depression, decreased mobility, lower quality of life, absenteeism from work, and decreased work productivity. Unfortunately, few studies have quantified stooped postures among agricultural workers, which makes it difficult to develop targeted work design improvements. The present study aimed to characterize stooped postures among workers engaged in several common agricultural tasks. Agricultural workers (N=43) were recruited from multiple Colorado farms and represented eight distinct work tasks. Participants wore a biomodule that contained a tri-axial accelerometer (Zephyr BioHarness) on their chests to record and log trunk postures in degrees for approximately two hours during specific work tasks. Data recorded on the sensor module were downloaded and analyzed in a customized RStudio program by participant and task to determine task cycle time, percentage of time spent in three posture categories (<0° to 30°, >30° to <60°, ≥60°), and mean trunk flexion. Stooped posture was defined as a trunk flexion equal to or greater than 60 degrees. The data indicated differences in task cycle time, percentage of time spent in posture categories, and mean trunk flexion across agricultural tasks. The results of the current study provide quantitative data that can help inform the development of targeted interventions aimed at reducing stooped postures in agricultural workers. Additionally, the methods developed in the present study may assist the Colorado Department of Agriculture and farm owners with evaluating the policies established in the Colorado Senate Bill (SB 21-087), which limits stooped postures during agricultural tasks that involve thinning and weeding during crop production.
Open Access
Effects of pH, temperature and competing ions on the adsorption of radiocesium on Prussian blue coated detonation nanodiamonds from aqueous solutions
(Colorado State University. Libraries, 2024) Zaiger, Megan, author; Sudowe, Ralf, advisor; Johnson, Thomas, committee member; Lindsay, James, committee member
The accident at the Fukushima Nuclear Powerplant, in 2011, resulted in the generation of radioactive contaminated water which is currently being stored on site. The Tokyo Electric Power Company (TEPCO), who owns the powerplant has begun treating and releasing the water into the ocean after most of the radioactivity has been removed by the Advanced Liquid Processing System (ALPS). Current techniques for preconcentration of radioisotopes, particularly radiocesium, from ocean waters are very labor and time intensive and often take months. Therefore, efficient, rapid, and reliable methods are needed for the determination of radiocesium in ocean water which represents a critical gap that this work seeks to address. A new technique using Prussian Blue (PB) coated detonation nanodiamonds (DND) to adsorb radiocesium from water samples is being investigated by the research group. The new technique takes hours to preconcentrate the radiocesium instead of months. The current study focuses on the effects of varying pH, temperature, competing ions, and stable cesium (Cs) on adsorption behavior of radiocesium. The results of the study show that high pH will result in a minimal decrease in Cs adsorption, while adsorption increases as pH increases, with the lowest adsorption of 95%. Temperature changes resulted in minimal decreases in Cs adsorption with the lowest adsorption of 98% measured at 4°C. Presence of potassium chloride (KCl), sodium chloride (NaCl), and lithium chloride (LiCl) at concentrations up to 1.0 M had no effect on the uptake of radiocesium showing adsorption of above 97% for all elements. However, adsorption decreased significantly in the presence of rubidium chloride (RbCl) as interferent concentration increased, with the lowest adsorption of 68% recorded for 1.0 M RbCl. The addition of stable Cs to low amounts of Cs-137 (1 Bq) saw high uncertainties and low adsorption reflecting the difficulty to obtain consistent results at very low concentrations. The study has shown promise for the use of DND in environmental settings with a continued need to be able to detect low levels of Cs-137.
Embargo
Community noise exposure from oil and gas drilling operations
(Colorado State University. Libraries, 2024) Stepherson, Phillip, author; Brazile, William, advisor; VanDyke, Michael, advisor; Gutilla, Margaret, committee member
Due to an increase in oil and gas (O&G) extraction activity near residential areas in Colorado, many community members may be at a higher risk of harmful noise exposure. The Colorado Energy and Carbon Management Commission (ECMC) has identified multiple sources of high-volume sound associated with O&G site preparation, drilling, and fracking including engines, mud circulation systems, rig top drives, and ancillary equipment. Acute and chronic exposure to elevated levels of environmental noise has been found to cause adverse health effects such as sleep disturbance, annoyance, cognitive performance decline, heart disease, and self-reported impact to overall wellbeing. While there is existing literature quantifying the extent and consequences of community noise exposure from other environmental sources (e.g., air traffic, road traffic, and railway transportation) there are limited published studies on noise exposure from proximity to O&G extraction sites. Researchers suggest, however, that oil and gas extraction operations may be producing harmful levels of noise. It also appears that the noise produced includes substantial low-frequency noise which can make it difficult to control. In addition, low frequency noise exposure may exacerbate the health effects associated with general noise exposure. To assess community noise exposure, a comprehensive environmental noise survey was performed at a new O&G extraction site in Northern Colorado during the drilling phase of operations. The research team collected noise emission data 24 hours per day over two months that included 1-second measurements of sound-pressure level, 1/3 octave bands, and triggered audio recordings. Based on the noise-monitoring results, it was determined that the noise levels from the drilling activities exceeded ECMC published noise exposure limits and noise thresholds related to adverse health effects. Distance was found to be a crucial factor in establishing compliance and reducing exposure, especially for low frequency noise. Increasing the O&G operations setback from community residences to 2,000 feet, as compared to the previous setback distance of 350 feet, was estimated to reduce noise levels by 15dB, which, while a substantial improvement, was not entirely sufficient to eliminate the risk of health effects or establish compliance with low frequency noise limits. High noise levels were found to occur on days that the rig's hoisting mechanism and/or drill were likely in use.
Open Access
Neutron fluence in a Howitzer drum and construction of a water moderated neutron irradiator
(Colorado State University. Libraries, 2024) Diaz Ruiz, Anilu S., author; Sudowe, Ralf, advisor; Johnson, Thomas, committee member; Fisher, Gwen, committee member
The Department of Environmental and Radiological Health Sciences at Colorado State University is utilizing a variety of irradiators to study the effects of ionizing on materials and tissue. Two of these are neutron irradiators based on 1 Ci and 5 Ci plutonium/beryllium (PuBe) sources, respectively. Neutron activation analysis is utilized to measure the neutron fluence at various positions in a Neutron Howitzer containing the 5 Ci source and a water tank containing the 1 Ci source. By determining the neutron flux in both systems, neutron irradiation at different intensities will become available for future research at Colorado State University. Additionally, both the drum and tank will be excellent teaching tools as they demonstrate neutron moderation, neutron shielding, material activation, and fluence measuring. Manufactured by the Nuclear-Chicago Corporation, the Model NH-3 Neutron Howitzer Drum is constructed in such a fashion that the PuBe neutron source can be moved in and out of irradiation position. In the irradiation position, two samples may be exposed to neutrons from the source by placing them in one of two horizontal ports in the drum. Both drum and ports are shielded with paraffin, which allows moderation of the neutron flux to thermal energies. In the experimental study, multiple metal foils were activated in the drum by irradiating them up to the point of measurable activity. Using a High Purity Germanium (HPGe) detector, the activity of the foils is quantified. The results of the measurements were used to calculate the neutron fluence using known neutron capture cross-sections. The calculated neutron fluence was then compared to the neutron fluence determined through a computational model of the drum using the Monte-Carlo N-Particle transport code (MCNP). Using the principles and methods practiced on the Howitzer drum, a water moderated neutron tank was constructed as a secondary neutron irradiator. The compared experimental and modeled neutron fluence spectrum in the drum were used to derive an effective model for total neutron fluence with respect to spacing from the inner end of the sample channel (x) of y = 69759e-0.17x and thermal neutron fluence of y = 12035e-0.176x.
Open Access
Association between exposure to cadmium and lead during gestation and adverse birth outcomes in the household air pollution intervention network (HAPIN) trial
(Colorado State University. Libraries, 2024) Alhassan, Mohamed Adnan, author; Peel, Jennifer, advisor; Clark, Maggie, committee member; Keller, Kayleigh, committee member; Neophytou, Andreas, committee member
Low- and middle-income countries (LMICs) are particularly vulnerable to the adverse effects of metal exposure. These countries' rapid industrialization coupled with population growth, result in substantial environmental exposures, which many governments have limited capacity to formally regulate. Even when regulations exist, many governments have a limited capacity to enforce those regulations. Additionally, LMICs bear a disproportionate burden of adverse birth outcomes, including low birth weight and preterm birth, which carry long-term health implications such as increased risk of chronic diseases, developmental delays, and mortality. Several studies have examined the association between metals and adverse birth outcomes such as low birth weight and preterm births. Specifically, despite the low number of studies, cadmium has been consistently linked to lower birth weights, smaller sizes for gestational age, and reduced head circumference. However, the association between lead exposure and birth outcomes shows inconsistent results. This inconsistency in findings, along with the low number of studies overall, especially in LMICs, regarding lead has prompted further investigation in our current study. Here we utilized data from the Household Air Pollution Intervention Network (HAPIN) trial, a randomized controlled trial conducted in rural areas of Guatemala, Peru, Rwanda, and India. The HAPIN trial evaluated the impact of replacing biomass stoves with liquefied petroleum gas stoves on various health outcomes, including infant birth weight among 3200 participants. The participants in the current analysis included pregnant women with a live singleton birth with exposure and birth data (n=2396). Maternal exposure to cadmium and lead were evaluated by analyzing dried blood spots using inductively coupled mass spectrometry. Blood spots were collected at baseline (9 - <20 weeks gestational age) and 32-36 weeks gestational age; we also evaluated the average of these two measurements. Birth weight was measured using a digital infant scale, with low birth weight defined as <2500 grams, and gestational age at birth was determined using screening data and ultrasonography, with preterm birth defined as <37 weeks. We utilized linear regression for birth weight and gestational age, logistic regression for dichotomous low birth weight, and Cox proportional hazards model for preterm birth. The models accounted for infant sex, maternal age, nulliparity, body mass index, maternal hemoglobin, mother's dietary diversity, food insecurity, tobacco smoking in the household, and study arm. We assessed effect modification by study location, sex, and study arm by including an interaction term. In sensitivity analyses, we included study location, household assets, maternal education in the models; replaced values below the limits of detection (LOD) with LOD/√2, and evaluated metal concentrations standardized by potassium levels. We also excluded maternal hemoglobin from the main model. The mean birth weight was 3,020 (standard deviation [SD]=445.5) grams, and 10.3% of all births were classified as low birth weight. The mean gestational age was 39.5 weeks (SD=1.7 weeks), and 5.2% of the births were preterm. The median lead concentration across the time points was 1.4 μg/dL (IQR: 0.9 – 2.2 μg/dL), and the median cadmium concentration was 1.0 ng/mL (IQR: 0.7 – 1.4 ng/mL), values comparable to those found in other studies. Overall, the results did not indicate a consistent or strong association between lead or cadmium and adverse birth outcomes. Baseline cadmium levels showed a modest increase in the odds ratio for low birth weight (OR per IQR increase: 1.2, 95% CI: 0.97 to 1.47). Sensitivity analyses closely aligned with the main findings. All the results for effect modification did not indicate differences in the strata. The study found a suggestive, but inconsistent evidence between exposure to cadmium and low birth weight. This study has some limitations. There is potential for non-differential measurement error due to the hematocrit effect, which alters the estimated spot volume based on participants' hematocrit levels. A sensitivity analysis using potassium standardized metal concentrations partially addressed this, but individual hematocrit variability can still bias the observed association towards the null, with a moderate magnitude. The probability of the bias is moderate. The chromatographic effect, which can cause variations in concentration due to the interaction between blood and the analyte with the filter paper, was also partially addressed using internal standards, blanks, calibration samples, quality controls, and reference materials. This potential bias is of low probability and magnitude, biasing the observed association toward the null. Confounding bias was considered a concern due to incomplete adjustment for covariates like seasonal variation, which can affect metal exposure and birth outcomes. Sensitivity analyses supported the main model findings, suggesting a low probability and magnitude of confounding bias, which could bias the observed association towards or away from the null. Despite residual confounding concerns linked to socio-economic indicators like assets and diet diversity, the sensitivity analyses did not deviate from the main model findings, indicating a small probability and magnitude of the bias, which would bias the observed association in either direction. The study had several strengths including a large sample size compared to previous studies, especially those in LMICs and it was conducted in three distinct rural LMIC settings, which, to the best of our knowledge, had not been done before. This study's strength lies in its large sample size of 2,152 participants with complete data, enhancing its statistical robustness and addressing the common issue of small sample sizes and missing data in prior LMIC research. Additionally, its unique examination across three distinct rural LMIC settings provides valuable insights into the regional variations affecting the outcomes studied. Future steps include using whole blood samples instead of dried blood spots (DBS) and measuring exposure at multiple time points, particularly at birth via the umbilical cord, could yield more accurate concentrations. It is also recommended that subsequent studies employ better socio-economic indicators to reduce residual confounding effects. Expanding the geographical scope of the study to include a broader range of urban areas within the HAPIN countries would improve the generalizability of the findings. Additionally, future research should consider analyzing the effects of metal mixtures to better replicate real-world environmental conditions and interactions. The results are generally consistent with existing limited data indicating no evidence of an association between lead and adverse birth outcomes and a potential association between higher cadmium exposure during pregnancy with increased risk of low birth weight.
Open Access
Developing a method to sample potential resuspension of radioactive contaminants near the former Rocky Flats Technical Plant
(Colorado State University. Libraries, 2024) Alcantar, Richard V., author; Sudowe, Ralf, advisor; Johnson, Tom, committee member; Volckens, John, committee member
From 1952 until 1989, the Rocky Flats Technical Plant processed plutonium for use as triggers in nuclear weapons. Throughout the facility's nearly 37 years in operation, several events led to radioactive contamination in areas within and surrounding the site. Since then, multiple cleanup projects have occurred, remediating contamination to acceptable levels. However, an increase in the number, size, and severity of Colorado wildfires in recent years has raised public concern for the potential resuspension of radioactive surface contamination to the now-populous areas surrounding Rocky Flats. Air sampling during specific conditions such as high winds, naturally occurring wildfires, and controlled burns would provide valuable data to determine if resuspension of radioactive contamination may be of concern. Sampling under such circumstances, however, is restricted by situation, permission, and weather. Whereas traditional aerosol sampling collects "total dust" samples to amass particles in the air with equal efficiency, without regard to particle size fraction, the use of a cascade impactor to separate aerosols by size can be utilized to relate how deep varied-sized particles might penetrate the human respiratory tract after inhalation. This would not only indicate the presence of radionuclides but also the deposition location within the human body, an important factor in determining the best dose estimate for the person. This study will compare the efficacy of a 3D-printed cascade impactor in separating particle size fractions to the capability of a commercial Andersen cascade impactor. Methods used in this thesis included radiological analysis with a Mirion LB4200 gas proportional counter. Significant imperfections of a printed prototype indicate that a stage-to-stage comparison between a commercial and a 3D-printed cascade impactor cannot be justified. Additionally, it is unlikely that current technology is capable of printing the exact same impactor with each subsequent print. The determination of a similar decay curve between stages of both impactors in some instances as well as similar trends in activity fraction by filter, however, indicate that a functional 3D-printed cascade impactor is feasible. Individually, each printed cascade impactor would require proper characterization to determine the particle size fraction that each stage captures. The evidence outlined in this study suggests that a functional cascade impactor can be fabricated by 3D printing. Still, additional studies would be necessary to characterize particle size distribution properly.
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
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.
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.
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.