Ultraviolet and Visible Light Exposure Among Indoor Agricultural Workers

Thesis (Master's)--University of Washington, 2016-06

Validation of a food-frequency questionnaire assessment of carotenoid and vitamin E intake using weighed food records and plasma biomarkers: The method of triads model

Background: Reliability or validity studies are important for the evaluation of measurement error in dietary assessment methods. An approach to validation known as the method of triads uses triangulation techniques to calculate the validity coefficient of a food-frequency questionnaire (FFQ). Objective: To assess the validity of an FFQ estimates of carotenoid and vitamin E intake against serum biomarker measurements and weighed food records (WFRs), by applying the method of triads. Design: The study population was a sub-sample of adult participants in a randomised controlled trial of beta-carotene and sunscreen in the prevention of skin cancer. Dietary intake was assessed by a self-administered FFQ and a WFR. Nonfasting blood samples were collected and plasma analysed for five carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene) and vitamin E. Correlation coefficients were calculated between each of the dietary methods and the validity coefficient was calculated using the method of triads. The 95% confidence intervals for the validity coefficients were estimated using bootstrap sampling. Results: The validity coefficients of the FFQ were highest for alpha-carotene (0.85) and lycopene (0.62), followed by beta- carotene (0.55) and total carotenoids (0.55), while the lowest validity coefficient was for lutein (0.19). The method of triads could not be used for b- cryptoxanthin and vitamin E, as one of the three underlying correlations was negative. Conclusions: Results were similar to other studies of validity using biomarkers and the method of triads. For many dietary factors, the upper limit of the validity coefficients was less than 0.5 and therefore only strong relationships between dietary exposure and disease will be detected.

Assessment of P availability in heavily fertilized soils using the diffusive gradient in thin films (DGT) technique

Phosphorus-availability tests typically provide an indication of quantity of P available (Colwell bicarbonate-extractable P), or of the intensity of supply (0.01 M CaCl2-extractable P). The soil's capacity to buffer P is more difficult to assess, and is generally estimated using a P-adsorption curve. The diffusive gradient in thin films (DGT) approach may provide a simpler means of assessing a soil's ability to maintain soil solution P. Optimal extraction conditions were found to be 24 h exposure of DGT samplers to saturated soil. The DGT approach was evaluated on a range of 24 soils, some of which had high Colwell- (>100 mu g g(-1)) and Bray 1- (>30 mu g g(-1)) extractable P content, but showed a tomato (Lycopersicon esculentum Mill.) yield response to the addition of P fertilizer. The DGT approach provided an excellent separation of soils on which tomato showed a yield response, from those where fertilizer P did not increase dry-matter yield. Phosphorus accumulation was strongly correlated with soil solution P concentration and anion exchange resin-extractable P, but showed poor correlation with Colwell- or Bray 1-extractable P. The DGT P accumulation rate of 3.62 x 10(-7) to 4.79 x 10(-5) mol s(-1) m(-3) for the soils tested was comparable to the uptake rate of roots of tomato plants that were adequately supplied with P (2.25 x 10(-5) mol s(-1) m(-3)).

Science-policy in environmental and health risk assessment: if we cannot do without, can we do better?

How can empirical evidence of adverse effects from exposure to noxious agents, which is often incomplete and uncertain, be used most appropriately to protect human health? We examine several important questions on the best uses of empirical evidence in regulatory risk management decision-making raised by the US Environmental Protection Agency (EPA)'s science-policy concerning uncertainty and variability in human health risk assessment. In our view, the US EPA (and other agencies that have adopted similar views of risk management) can often improve decision-making by decreasing reliance on default values and assumptions, particularly when causation is uncertain. This can be achieved by more fully exploiting decision-theoretic methods and criteria that explicitly account for uncertain, possibly conflicting scientific beliefs and that can be fully studied by advocates and adversaries of a policy choice, in administrative decision-making involving risk assessment. The substitution of decision-theoretic frameworks for default assumption-driven policies also allows stakeholder attitudes toward risk to be incorporated into policy debates, so that the public and risk managers can more explicitly identify the roles of risk-aversion or other attitudes toward risk and uncertainty in policy recommendations. Decision theory provides a sound scientific way explicitly to account for new knowledge and its effects on eventual policy choices. Although these improvements can complicate regulatory analyses, simplifying default assumptions can create substantial costs to society and can prematurely cut off consideration of new scientific insights (e.g., possible beneficial health effects from exposure to sufficiently low 'hormetic' doses of some agents). In many cases, the administrative burden of applying decision-analytic methods is likely to be more than offset by improved effectiveness of regulations in achieving desired goals. Because many foreign jurisdictions adopt US EPA reasoning and methods of risk analysis, it may be especially valuable to incorporate decision-theoretic principles that transcend local differences among jurisdictions.

Urinary excretion of cadmium among Torres Strait Islanders (Australia) at risk of elevated dietary exposure through traditional foods

This study explored urinary cadmium levels among Torres Strait Islanders in response to concerns about potential health impact of high levels of cadmium in some traditional seafood (dugong and turtle liver and kidney). Cadmium levels were measured by inductively coupled mass spectrometry in de-identified urine samples collected during general screening programs in 1996 in two communities with varying dugong and turtle catch statistics. Statistical analysis was performed to identify links between cadmium levels and demographic and background health information. Geometric mean cadmium level among the sample group was 0.83 mu g/g creatinine with 12% containing over 2 mu g/g creatinine. Cadmium level was most strongly associated with age (46% of variation), followed by sex (females > males, 7%) and current smoking status (smokers > non-smokers, 4.7%). Adjusting model conditions suggested further positive associations between cadmium level and diabetes (p = 0.05) and residence in the predicted higher exposure community (p = 0.07). Positive correlations between cadmium and body fat in bivariate analysis were eliminated by control for age and sex. This study found only suggestive differences in cadmium levels between two communities with predicted variation in exposure from traditional foods. However, the data indicate that factors linked with higher cadmium accumulation overlap with those of renal disease risk (i.e. older, females, smokers, diabetes) and suggest that levels may be sufficient to contribute to renal pathology. More direct assessment of exposure and health risks of cadmium to Torres Strait Islanders is needed given the disproportionate level of diet-related disease and the cultural importance of dugong and turtle. This study highlights the need to consider social and cultural variation in exposure and to de. ne "safe'' cadmium levels during diabetes given its rising global prevalence.

Investigation of aspects of reactive gliosis in human astrocytoma cell lines:application for toxicity assessment

The process of astrogliosis, or reactive gliosis, is a typical response of astrocytes to a wide range of physical and chemical injuries. The up-regulation of the astrocyte specific glial fibrillary acidic protein (GFAP) is a hallmark of reactive gliosis and is widely used as a marker to identify the response. In order to develop a reliable, sensitive and high throughput astrocyte toxicity assay that is more relevant to the human response than existing animal cell based models, the U251-MG, U373-MG and CCF-STTG 1 human astrocytoma cell lines were investigated for their ability to exhibit reactive-like changes following exposure to ethanol, chloroquine diphosphate, trimethyltin chloride and acrylamide. Cytotoxicity analysis showed that the astrocytic cells were generally more resistant to the cytotoxic effects of the agents than the SH-SY5Y neuroblastoma cells. Retinoic acid induced differentiation of the SH-SY5Y line was also seen to confer some degree of resistance to toxicant exposure, particularly in the case of ethanol. Using a cell based ELISA for GFAP together with concurrent assays for metabolic activity and cell number, each of the three cell lines responded to toxicant exposure by an increase in GFAP immunoreactivity (GFAP-IR), or by increased metabolic activity. Ethanol, chloroquine diphosphate, trimethyltin chloride and bacterial lipopolysaccharide all induced either GFAP or MTT increases depending upon the cell line, dose and exposure time. Preliminary investigations of additional aspects of astrocytic injury indicated that IL-6, but not TNF-α. or nitric oxide, is released following exposure to each of the compounds, with the exception of acrylamide. It is clear that these human astrocytoma cell lines are capable of responding to toxicant exposure in a manner typical of reactive gliosis and are therefore a valuable cellular model in the assessment of in vitro neurotoxicity.

Substances hazardous to health:the nature of the expertise associated with competent risk assessment

This research investigated expertise in hazardous substance risk assessment (HSRA). Competent pro-active risk assessment is needed to prevent occupational ill-health caused by hazardous substance exposure occurring in the future. In recent years there has been a strong demand for HSRA expertise and a shortage of expert practitioners. The discipline of Occupational Hygiene was identified as the key repository of knowledge and skills for HSRA and one objective of this research was to develop a method to elicit this expertise from experienced occupational hygienists. In the study of generic expertise, many methods of knowledge elicitation (KE) have been investigated, since this has been relevant to the development of 'expert systems' (thinking computers). Here, knowledge needed to be elicited from human experts, and this stage was often a bottleneck in system development, since experts could not explain the basis of their expertise. At an intermediate stage, information collected was used to structure a basic model of hazardous substance risk assessment activity (HSRA Model B) and this formed the basis of tape transcript analysis in the main study with derivation of a 'classification' and a 'performance matrix'. The study aimed to elicit the expertise of occupational hygienists and compare their performance with other health and safety professionals (occupational health physicians, occupational health nurses, health and safety practitioners and trainee health and safety inspectors), as evaluated using the matrix. As a group, the hygienists performed best in the exercise, and this group were particularly good at process elicitation and at recommending specific control measures, although the other groups also performed well in selected aspects of the matrix and the work provided useful findings and insights. From the research, two models of HSRA have been derived, an HSRA aid, together with a novel videotape KE technique and interesting research findings. The implications of this are discussed with respect to future training of HS professionals and wider application of the videotape KE method.

Assessment of different formulations of oral Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccine in rodent models for immunogenicity and protection against aerosol challenge with M-bovis

Bovine tuberculosis (bTB) caused by infection with Mycobacterium bovis is causing considerable economic loss to farmers and Government in the United Kingdom as its incidence is increasing. Efforts to control bTB in the UK are hampered by the infection in Eurasian badgers (Metes metes) that represent a wildlife reservoir and source of recurrent M. bovis exposure to cattle. Vaccination of badgers with the human TB vaccine, M. bovis Bacille Calmette-Guerin (BCG), in oral bait represents a possible disease control tool and holds the best prospect for reaching badger populations over a wide geographical area. Using mouse and guinea pig models, we evaluated the immunogenicity and protective efficacy, respectively, of candidate badger oral vaccines based on formulation of BCG in lipid matrix, alginate beads, or a novel microcapsular hybrid of both lipid and alginate. Two different oral doses of BCG were evaluated in each formulation for their protective efficacy in guinea pigs, while a single dose was evaluated in mice. In mice, significant immune responses (based on lymphocyte proliferation and expression of IFN-gamma) were only seen with the lipid matrix and the lipid in alginate microcapsular formulation, corresponding to the isolation of viable BCG from alimentary tract lymph nodes. In guinea pigs, only BCG formulated in lipid matrix conferred protection to the spleen and lungs following aerosol route challenge with M. bovis. Protection was seen with delivery doses in the range 10(6)-10(7) CFU, although this was more consistent in the spleen at the higher dose. No protection in terms of organ CFU was seen with BCG administered in alginate beads or in lipid in alginate microcapsules, although 10(7) in the latter formulation conferred protection in terms of increasing body weight after challenge and a smaller lung to body weight ratio at necropsy. These results highlight the potential for lipid, rather than alginate, -based vaccine formulations as suitable delivery vehicles for an oral BCG vaccine in badgers.

Assessment of the astrogliotic responses of three human astrocytoma cell lines to ethanol, trimethyltin chloride and acrylamide

The astrogliotic responses of the CCF-STTG1, U251-MG, and U373-MG human astrocytoma lines were determined after exposure to ethanol, trimethyltin chloride (TMTC), and acrylamide over 4, 16, and 24 h. Basal glial fibrillary acidic protein (GFAP) expression in the U-251MG and U373-MG cells was 10-fold greater than the CCF-STGG1 line. Ethanol treatment over 24 h, but not at 4 and 16 h, resulted in significant increases in GFAP in all three glioma lines at sub-cytotoxic levels; the GFAP responses in the CCF-STTG1 line were the most sensitive, as concentrations of 0.1 and 1 mM led to increases in GFAP expression compared with control of 56.8 ± 15.7 and 58.9 ± 11.5%, respectively (P < 0.05). Treatment with TMTC (1 μM) over 4 h showed elevated GFAP expression in the U251-MG cell line to 28.0 ± 15.7% above control levels (P < 0.01), but not in the other U373-MG or CCF-STTG1 cells. At 4 h, MTT turnover was markedly increased compared with control, particularly in the U373-MG line at concentrations as low as 1 μM (17.1 ± 2.3%; P < 0.01). TMTC exposure over 16 and 24 h resulted in reduction in GFAP expression in all three lines at concentrations; at 24 h incubation, the reduction was >50% (P < 0.01). There were no changes in GFAP expression or MTT turnover in response to acrylamide except at the highest concentration ranges of 10-100 mM. This study underlines the significance of period of exposure, as well as toxin concentration in astrocytoma cellular response to toxic pressure. © 2007 Elsevier Ireland Ltd. All rights reserved.

Development of risk based treatability and engineering measures for reducing exposure to lead contaminated media in the Miami inner city, Florida

A major consequence of contamination at the local level’s population as it relates to environmental health and environmental engineering is childhood lead poisoning. Environmental contamination is one of the pressing environmental concerns facing the world today. Current approaches often focus on large contaminated industrial size sites that are designated by regulatory agencies for site remediation. Prior to this study, there were no known published studies conducted at the local and smaller scale, such as neighborhoods, where often much of the contamination is present to remediate. An environmental health study of local lead-poisoning data in Liberty City, Little Haiti and eastern Little Havana in Miami-Dade County, Florida accounted for a disproportionately high number of the county’s reported childhood lead poisoning cases. An engineering system was developed and designed for a comprehensive risk management methodology that is distinctively applicable to the geographical and environmental conditions of Miami-Dade County, Florida. Furthermore, a scientific approach for interpreting environmental health concerns, while involving detailed environmental engineering control measures and methods for site remediation in contained media was developed for implementation. Test samples were obtained from residents and sites in those specific communities in Miami-Dade County, Florida (Gasana and Chamorro 2002). Currently lead does not have an Oral Assessment, Inhalation Assessment, and Oral Slope Factor; variables that are required to run a quantitative risk assessment. However, various institutional controls from federal agencies’ standards and regulation for contaminated lead in media yield adequate maximum concentration limits (MCLs). For this study an MCL of .0015 (mg/L) was used. A risk management approach concerning contaminated media involving lead demonstrates that the linkage of environmental health and environmental engineering can yield a feasible solution.

Assessment of the occurrence and potential risks of pharmaceuticals and their metabolites in fish and water using liquid chromatography mass spectrometry

A comprehensive method for the analysis of 11 target pharmaceuticals representing multiple therapeutic classes was developed for biological tissues (fish) and water. Water samples were extracted using solid phase extraction (SPE), while fish tissue homogenates were extracted using accelerated solvent extraction (ASE) followed by mixed-mode cation exchange SPE cleanup and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Among the 11 target pharmaceuticals analyzed, trimethoprim, caffeine, sulfamethoxazole, diphenhydramine, diltiazem, carbamazepine, erythromycin and fluoxetine were consistently detected in reclaimed water. On the other hand, caffeine, diphenhydramine and carbamazepine were consistently detected in fish and surface water samples. In order to understand the uptake and depuration of pharmaceuticals as well as bioconcentration factors (BCFs) under the worst-case conditions, mosquito fish were exposed to reclaimed water under static-renewal for 7 days, followed by a 14-day depuration phase in clean water. Characterization of the exposure media revealed the presence of 26 pharmaceuticals while 5 pharmaceuticals including caffeine, diphenhydramine, diltiazem, carbamazepine, and ibuprofen were present in the organisms as early as 5 h from the start of the exposure. Liquid chromatography ultra-high resolution Orbitrap mass spectrometry was explored as a tool to identify and quantify phase II pharmaceutical metabolites in reclaimed water. The resulting data confirmed the presence of acetyl-sulfamethoxazole and sulfamethoxazole glucuronide in reclaimed water. To my knowledge, this is the first known report of sulfamethoxazole glucuronide surviving intact through wastewater treatment plants and occurring in environmental water samples. Finally, five bioaccumulative pharmaceuticals including caffeine, carbamazepine, diltiazem, diphenhydramine and ibuprofen detected in reclaimed water were investigated regarding the acute and chronic risks to aquatic organisms. The results indicated a low potential risk of carbamazepine even under the worst case exposure scenario. Given the dilution factors that affect environmental releases, the risk of exposure to carbamazepine will be even more reduced.

Assessment of the occurrence and potential risks of antibiotics and their metabolites in South Florida waters using liquid chromatography tandem mass spectrometry

An automated on-line SPE-LC-MS/MS method was developed for the quantitation of multiple classes of antibiotics in environmental waters. High sensitivity in the low ng/L range was accomplished by using large volume injections with 10-mL of sample. Positive confirmation of analytes was achieved using two selected reaction monitoring (SRM) transitions per antibiotic and quantitation was performed using an internal standard approach. Samples were extracted using online solid phase extraction, then using column switching technique; extracted samples were immediately passed through liquid chromatography and analyzed by tandem mass spectrometry. The total run time per each sample was 20 min. The statistically calculated method detection limits for various environmental samples were between 1.2 and 63 ng/L. Furthermore, the method was validated in terms of precision, accuracy and linearity. ^ The developed analytical methodology was used to measure the occurrence of antibiotics in reclaimed waters (n=56), surface waters (n=53), ground waters (n=8) and drinking waters (n=54) collected from different parts of South Florida. In reclaimed waters, the most frequently detected antibiotics were nalidixic acid, erythromycin, clarithromycin, azithromycin trimethoprim, sulfamethoxazole and ofloxacin (19.3-604.9 ng/L). Detection of antibiotics in reclaimed waters indicates that they can't be completely removed by conventional wastewater treatment process. Furthermore, the average mass loads of antibiotics released into the local environment through reclaimed water were estimated as 0.248 Kg/day. Among the surface waters samples, Miami River (reaching up to 580 ng/L) and Black Creek canal (up to 124 ng/L) showed highest concentrations of antibiotics. No traces of antibiotics were found in ground waters. On the other hand, erythromycin (monitored as anhydro erythromycin) was detected in 82% of the drinking water samples (n.d-66 ng/L). The developed approach is suitable for both research and monitoring applications.^ Major metabolites of antibiotics in reclaimed wates were identified and quantified using high resolution benchtop Q-Exactive orbitrap mass spectrometer. A phase I metabolite of erythromycin was tentatively identified in full scan based on accurate mass measurement. Using extracted ion chromatogram (XIC), high resolution data-dependent MS/MS spectra and metabolic profiling software the metabolite was identified as desmethyl anhydro erythromycin with molecular formula C36H63NO12 and m/z 702.4423. The molar concentration of the metabolite to erythromycin was in the order of 13 %. To my knowledge, this is the first known report on this metabolite in reclaimed water. Another compound acetyl-sulfamethoxazole, a phase II metabolite of sulfamethoxazole was also identified in reclaimed water and mole fraction of the metabolite represent 36 %, of the cumulative sulfamethoxazole concentration. The results were illustrating the importance to include metabolites also in the routine analysis to obtain a mass balance for better understanding of the occurrence, fate and distribution of antibiotics in the environment. ^ Finally, all the antibiotics detected in reclaimed and surface waters were investigated to assess the potential risk to the aquatic organisms. The surface water antibiotic concentrations that represented the real time exposure conditions revealed that the macrolide antibiotics, erythromycin, clarithromycin and tylosin along with quinolone antibiotic, ciprofloxacin were suspected to induce high toxicity to aquatic biota. Preliminary results showing that, among the antibiotic groups tested, macrolides posed the highest ecological threat, and therefore, they may need to be further evaluated with, long-term exposure studies considering bioaccumulation factors and more number of species selected. Overall, the occurrence of antibiotics in aquatic environment is posing an ecological health concern.^

Multiplex PCR for Assessment of Tetracycline Resistance (tet) Genes in Antibiotic-Resistant Soil Bacteria and the Ecological Implications

Antibiotics are becoming increasingly prevalent in bacterial communities due to clinical and agricultural misuse and overuse in their environment. As exposure increases, so does the incidence of microbial resistance. Such is the case with bacterial resistance to tetracyclines, a phenotype often acquired through the horizontal gene transfer of tet genes between bacteria. The objective of this project was to analyze the bacterial diversity of tet resistance genes in soil from Miami-Dade County. Bacterial isolates were Gram-stained and the Kirby-Bauer antibiotic disk diffusion test was performed to determine each bacterium’s degree of resistance. The 16S rRNA gene from antibiotic-resistant isolates was amplified by PCR and sequenced to identify the isolates. All isolates’ tet genes were amplified by multiplex PCR, sequenced, and compared. Among eight isolates, three distinct species were positively identified based on their 16S rRNA sequences and four distinct tet genes were identified, though all tested susceptible to tetracycline via the Kirby-Bauer test. This project clarifies some aspects of the ecology of antibiotic resistance genes, their natural ecological function and the potential for the expansion of intrinsic multi-antibiotic resistance into new ecosystems and/or hosts.

Development of a Lab-on-a-Chip Device for Rapid Nanotoxicity Assessment In Vitro

Increasing useof nanomaterials in consumer products and biomedical applications creates the possibilities of intentional/unintentional exposure to humans and the environment. Beyond the physiological limit, the nanomaterialexposure to humans can induce toxicity. It is difficult to define toxicity of nanoparticles on humans as it varies by nanomaterialcomposition, size, surface properties and the target organ/cell line. Traditional tests for nanomaterialtoxicity assessment are mostly based on bulk-colorimetric assays. In many studies, nanomaterials have found to interfere with assay-dye to produce false results and usually require several hours or days to collect results. Therefore, there is a clear need for alternative tools that can provide accurate, rapid, and sensitive measure of initial nanomaterialscreening. Recent advancement in single cell studies has suggested discovering cell properties not found earlier in traditional bulk assays. A complex phenomenon, like nanotoxicity, may become clearer when studied at the single cell level, including with small colonies of cells. Advances in lab-on-a-chip techniques have played a significant role in drug discoveries and biosensor applications, however, rarely explored for nanomaterialtoxicity assessment. We presented such cell-integrated chip-based approach that provided quantitative and rapid response of cellhealth, through electrochemical measurements. Moreover, the novel design of the device presented in this study was capable of capturing and analyzing the cells at a single cell and small cell-population level. We examined the change in exocytosis (i.e. neurotransmitterrelease) properties of a single PC12 cell, when exposed to CuOand TiO2 nanoparticles. We found both nanomaterials to interfere with the cell exocytosis function. We also studied the whole-cell response of a single-cell and a small cell-population simultaneously in real-time for the first time. The presented study can be a reference to the future research in the direction of nanotoxicity assessment to develop miniature, simple, and cost-effective tool for fast, quantitative measurements at high throughput level. The designed lab-on-a-chip device and measurement techniques utilized in the present work can be applied for the assessment of othernanoparticles' toxicity, as well.

Advanced Techniques for Image Quality Assessment of Modern X-ray Computed Tomography Systems

X-ray computed tomography (CT) imaging constitutes one of the most widely used diagnostic tools in radiology today with nearly 85 million CT examinations performed in the U.S in 2011. CT imparts a relatively high amount of radiation dose to the patient compared to other x-ray imaging modalities and as a result of this fact, coupled with its popularity, CT is currently the single largest source of medical radiation exposure to the U.S. population. For this reason, there is a critical need to optimize CT examinations such that the dose is minimized while the quality of the CT images is not degraded. This optimization can be difficult to achieve due to the relationship between dose and image quality. All things being held equal, reducing the dose degrades image quality and can impact the diagnostic value of the CT examination.

A recent push from the medical and scientific community towards using lower doses has spawned new dose reduction technologies such as automatic exposure control (i.e., tube current modulation) and iterative reconstruction algorithms. In theory, these technologies could allow for scanning at reduced doses while maintaining the image quality of the exam at an acceptable level. Therefore, there is a scientific need to establish the dose reduction potential of these new technologies in an objective and rigorous manner. Establishing these dose reduction potentials requires precise and clinically relevant metrics of CT image quality, as well as practical and efficient methodologies to measure such metrics on real CT systems. The currently established methodologies for assessing CT image quality are not appropriate to assess modern CT scanners that have implemented those aforementioned dose reduction technologies.

Thus the purpose of this doctoral project was to develop, assess, and implement new phantoms, image quality metrics, analysis techniques, and modeling tools that are appropriate for image quality assessment of modern clinical CT systems. The project developed image quality assessment methods in the context of three distinct paradigms, (a) uniform phantoms, (b) textured phantoms, and (c) clinical images.

The work in this dissertation used the “task-based” definition of image quality. That is, image quality was broadly defined as the effectiveness by which an image can be used for its intended task. Under this definition, any assessment of image quality requires three components: (1) A well defined imaging task (e.g., detection of subtle lesions), (2) an “observer” to perform the task (e.g., a radiologists or a detection algorithm), and (3) a way to measure the observer’s performance in completing the task at hand (e.g., detection sensitivity/specificity).

First, this task-based image quality paradigm was implemented using a novel multi-sized phantom platform (with uniform background) developed specifically to assess modern CT systems (Mercury Phantom, v3.0, Duke University). A comprehensive evaluation was performed on a state-of-the-art CT system (SOMATOM Definition Force, Siemens Healthcare) in terms of noise, resolution, and detectability as a function of patient size, dose, tube energy (i.e., kVp), automatic exposure control, and reconstruction algorithm (i.e., Filtered Back-Projection– FPB vs Advanced Modeled Iterative Reconstruction– ADMIRE). A mathematical observer model (i.e., computer detection algorithm) was implemented and used as the basis of image quality comparisons. It was found that image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low-doses, large phantom sizes, and for low-contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose (increase in detectability index by up to 163% depending on iterative strength). The use of automatic exposure control resulted in more consistent image quality with changing phantom size.

Based on those results, the dose reduction potential of ADMIRE was further assessed specifically for the task of detecting small (<=6 mm) low-contrast (<=20 HU) lesions. A new low-contrast detectability phantom (with uniform background) was designed and fabricated using a multi-material 3D printer. The phantom was imaged at multiple dose levels and images were reconstructed with FBP and ADMIRE. Human perception experiments were performed to measure the detection accuracy from FBP and ADMIRE images. It was found that ADMIRE had equivalent performance to FBP at 56% less dose.

Using the same image data as the previous study, a number of different mathematical observer models were implemented to assess which models would result in image quality metrics that best correlated with human detection performance. The models included naïve simple metrics of image quality such as contrast-to-noise ratio (CNR) and more sophisticated observer models such as the non-prewhitening matched filter observer model family and the channelized Hotelling observer model family. It was found that non-prewhitening matched filter observers and the channelized Hotelling observers both correlated strongly with human performance. Conversely, CNR was found to not correlate strongly with human performance, especially when comparing different reconstruction algorithms.

The uniform background phantoms used in the previous studies provided a good first-order approximation of image quality. However, due to their simplicity and due to the complexity of iterative reconstruction algorithms, it is possible that such phantoms are not fully adequate to assess the clinical impact of iterative algorithms because patient images obviously do not have smooth uniform backgrounds. To test this hypothesis, two textured phantoms (classified as gross texture and fine texture) and a uniform phantom of similar size were built and imaged on a SOMATOM Flash scanner (Siemens Healthcare). Images were reconstructed using FBP and a Sinogram Affirmed Iterative Reconstruction (SAFIRE). Using an image subtraction technique, quantum noise was measured in all images of each phantom. It was found that in FBP, the noise was independent of the background (textured vs uniform). However, for SAFIRE, noise increased by up to 44% in the textured phantoms compared to the uniform phantom. As a result, the noise reduction from SAFIRE was found to be up to 66% in the uniform phantom but as low as 29% in the textured phantoms. Based on this result, it clear that further investigation was needed into to understand the impact that background texture has on image quality when iterative reconstruction algorithms are used.

To further investigate this phenomenon with more realistic textures, two anthropomorphic textured phantoms were designed to mimic lung vasculature and fatty soft tissue texture. The phantoms (along with a corresponding uniform phantom) were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Scans were repeated a total of 50 times in order to get ensemble statistics of the noise. A novel method of estimating the noise power spectrum (NPS) from irregularly shaped ROIs was developed. It was found that SAFIRE images had highly locally non-stationary noise patterns with pixels near edges having higher noise than pixels in more uniform regions. Compared to FBP, SAFIRE images had 60% less noise on average in uniform regions for edge pixels, noise was between 20% higher and 40% lower. The noise texture (i.e., NPS) was also highly dependent on the background texture for SAFIRE. Therefore, it was concluded that quantum noise properties in the uniform phantoms are not representative of those in patients for iterative reconstruction algorithms and texture should be considered when assessing image quality of iterative algorithms.

The move beyond just assessing noise properties in textured phantoms towards assessing detectability, a series of new phantoms were designed specifically to measure low-contrast detectability in the presence of background texture. The textures used were optimized to match the texture in the liver regions actual patient CT images using a genetic algorithm. The so called “Clustured Lumpy Background” texture synthesis framework was used to generate the modeled texture. Three textured phantoms and a corresponding uniform phantom were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Images were reconstructed with FBP and SAFIRE and analyzed using a multi-slice channelized Hotelling observer to measure detectability and the dose reduction potential of SAFIRE based on the uniform and textured phantoms. It was found that at the same dose, the improvement in detectability from SAFIRE (compared to FBP) was higher when measured in a uniform phantom compared to textured phantoms.

The final trajectory of this project aimed at developing methods to mathematically model lesions, as a means to help assess image quality directly from patient images. The mathematical modeling framework is first presented. The models describe a lesion’s morphology in terms of size, shape, contrast, and edge profile as an analytical equation. The models can be voxelized and inserted into patient images to create so-called “hybrid” images. These hybrid images can then be used to assess detectability or estimability with the advantage that the ground truth of the lesion morphology and location is known exactly. Based on this framework, a series of liver lesions, lung nodules, and kidney stones were modeled based on images of real lesions. The lesion models were virtually inserted into patient images to create a database of hybrid images to go along with the original database of real lesion images. ROI images from each database were assessed by radiologists in a blinded fashion to determine the realism of the hybrid images. It was found that the radiologists could not readily distinguish between real and virtual lesion images (area under the ROC curve was 0.55). This study provided evidence that the proposed mathematical lesion modeling framework could produce reasonably realistic lesion images.

Based on that result, two studies were conducted which demonstrated the utility of the lesion models. The first study used the modeling framework as a measurement tool to determine how dose and reconstruction algorithm affected the quantitative analysis of liver lesions, lung nodules, and renal stones in terms of their size, shape, attenuation, edge profile, and texture features. The same database of real lesion images used in the previous study was used for this study. That database contained images of the same patient at 2 dose levels (50% and 100%) along with 3 reconstruction algorithms from a GE 750HD CT system (GE Healthcare). The algorithms in question were FBP, Adaptive Statistical Iterative Reconstruction (ASiR), and Model-Based Iterative Reconstruction (MBIR). A total of 23 quantitative features were extracted from the lesions under each condition. It was found that both dose and reconstruction algorithm had a statistically significant effect on the feature measurements. In particular, radiation dose affected five, three, and four of the 23 features (related to lesion size, conspicuity, and pixel-value distribution) for liver lesions, lung nodules, and renal stones, respectively. MBIR significantly affected 9, 11, and 15 of the 23 features (including size, attenuation, and texture features) for liver lesions, lung nodules, and renal stones, respectively. Lesion texture was not significantly affected by radiation dose.

The second study demonstrating the utility of the lesion modeling framework focused on assessing detectability of very low-contrast liver lesions in abdominal imaging. Specifically, detectability was assessed as a function of dose and reconstruction algorithm. As part of a parallel clinical trial, images from 21 patients were collected at 6 dose levels per patient on a SOMATOM Flash scanner. Subtle liver lesion models (contrast = -15 HU) were inserted into the raw projection data from the patient scans. The projections were then reconstructed with FBP and SAFIRE (strength 5). Also, lesion-less images were reconstructed. Noise, contrast, CNR, and detectability index of an observer model (non-prewhitening matched filter) were assessed. It was found that SAFIRE reduced noise by 52%, reduced contrast by 12%, increased CNR by 87%. and increased detectability index by 65% compared to FBP. Further, a 2AFC human perception experiment was performed to assess the dose reduction potential of SAFIRE, which was found to be 22% compared to the standard of care dose.

In conclusion, this dissertation provides to the scientific community a series of new methodologies, phantoms, analysis techniques, and modeling tools that can be used to rigorously assess image quality from modern CT systems. Specifically, methods to properly evaluate iterative reconstruction have been developed and are expected to aid in the safe clinical implementation of dose reduction technologies.