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This dissertation presents an investigation of the impact of Multidrug Resistance-associated Protein 2/ATP-binding cassette superfamily C member 2 (Mrp2/Abcc2) and 3 (Mrp3/Abcc3) on the pharmacokinetics (PKs) of methotrexate (MTX) using gene knockout murine models. MTX is a substrate for numerous human ATP-binding cassette (ABC) efflux transporters, yet the impact of these transporters on the pharmacokinetics of MTX over a large dose range has not been examined. To investigate the effects of two transporters, Abcc2 (Mrp2) and Abcc3 (Mrp3), involved in MTX hepatobiliary disposition in vivo, MTX plasma, urine and feces concentrations were analyzed after 10, 50, and 200 mg/kg intravenous (IV) doses to groups of wild type (WT), Abcc2-/- and Abcc3-/- mice. The absence of Abcc2 caused a decrease in total clearance of MTX relative to WT mice at all dose levels yet was accompanied by compensatory increases in renal excretion and metabolism to 7-hydroxymethotrexate (7OH-MTX). In Abcc3-/- mice total clearance was elevated at the two lower dose levels that was attributed to stimulation of biliary excretion and confirmed by elevated fecal excretion; however at the high 200 mg/kg dose clearance was severely retarded and could be attributed to hepatotoxicity as conversion to 7OH-MTX was diminished. We also sought to characterize the effects of Abcc2 and Abcc3, on the PKs of MTX after oral dosing. Plasma, urine, and fecal concentrations of MTX were measured after 10, 50, and 200 mg/kg oral doses to cohorts of WT, Abcc2-/- and Abcc3-/- mice mouse strains. The absence of Abcc2 caused an approximate 2-fold increase in system exposure and a slight increase in oral bioavailability of MTX relative to WT mice at all dose levels. These elevations were accompanied by compensatory increases in conversion to 7OH-MTX, and based on AUC7OH-MTX/AUCMTX (area under the curve ratio of metabolite and parent drug) that ranged from 3% to 9% in WT mice increased to a range of 16% to 26% in Abcc2-/- mice. Renal excretion of unchanged MTX was unaltered in the Abcc2-/- strain; fraction urinary excretion (fr) ranged from about 4% to 11% in WT mice, whereas in Abcc2-/- mice fr ranged from about 7% to 23%. Abcc3-/- mice exhibited more than a 2-fold decrease in Cmax and significant reductions in AUCMTX when compared to WT mice at all dose levels. There were no compensatory increases in either metabolism or in renal and biliary excretion, which suggests future studies for investigating a potential unknown mechanism. Regardless of the mouse strain, increases in the MTX dose were not accompanied by proportional increases in AUCMTX. The PKs of MTX in different mouse strains was successfully modeled by a nonlinear semi-mechanistic 3-compartmental conditional model incorporating key efflux transporters. The model employed population-based analysis and conditional transport terms to well capture the nonlinear properties of MTX systemic disposition for a wide dose range of 10 - 200 mg/kg in WT and knockout strains. The model correlates the mechanistic nature of the nonlinear phenomenon with the key efflux transporters effects on MTX PKs and provides insight for preclinical therapeutic study design. Overall, the information obtained in this investigation underscores the significance of efflux transporters, Abcc2 and Abcc3, for they significantly influence the pharmacokinetics of MTX and their impact can be reflected by a nonlinear semi-mechanistic 3-compartmental conditional model. The studies also provide implication in the preclinical therapeutic study design and insights on the source of inter-patient variability as well as on the combination drug regimens to maximize drug activity yet without toxicity. / Pharmaceutical Sciences

Oxidative stress from high-dose ionizing radiation can contribute to accumulating cellular damage, affecting various fitness related traits. However, studies on low-dose ionizing radiation (LDIR) have shown hormetic effects on growth, longevity, and immunity. Comprehensive lifetime studies assessing LDIR effects and studies investigating LDIR immune stimulation in insects are limited. We utilized 137Cs gamma radiation with a dose rate of 0.25 Gy/min. We examined the impacts of early-life exposure (doses: 0, 0.2, 0.5, 1, 2, 4, 7, and 10 Gy) on life history and immunity in Acheta domesticus. Moderate doses (above 4 Gy) increased mean longevity but decreased growth rate, adult body mass and innate immunity. We also performed a time course study in male A. domesticus to assess the acute effects of radiation (doses: 0, 0.2, 0.5, 0.75, 1, 5, and 15 Gy) on innate immunity and redox status. LDIR (below 1 Gy) generally achieved immune stimulation and improved the encapsulation response but effects were time dependent. Benefits could extend to improved immune responses and protection against infection. Our results provide evidence of immune stimulation with LDIR in insects but with potential trade- offs with life history traits when assessing early-life exposure. With increasing concern of radiation exposure in the environment, more comprehensive studies utilizing a multi- discipline approach will help to elucidate the full mechanism of hormesis. / Thesis / Master of Science (MSc) / High-dose ionizing radiation can have inhibitory effects on cellular systems while low doses can have lasting stimulatory effects. The latter phenomenon, known as hormesis, can act on growth, longevity, and immunity. We investigated the effects of early life gamma radiation exposure on life history traits and measures of innate immunity in the cricket (Acheta domesticus). We observed trade-offs between survival, growth, and immunity. We also tested late life radiation exposure to assess potential hormetic effects on innate immunity and redox status. Our results show immune stimulation with low doses but effects are complex and dependent on dose, type of immunity measured, and time of assessment.

Radioimmunotherapy consists in the use of beta radioactive labeled monoclonal antibodies as selective carriers of radiation to tumors. Internal spatially distributed sources created at the disease sites would deliver high radiation doses to tumors while the normal tissues would not be exposed to the intense radiation as in conventional forms of cancer treatments. A rapid and accurate estimation of the spatial dose distribution from nonuniform sources is essential for the optimization of this form of cancer therapy. The method used for such calculations is based on the knowledge of dose distributions around a unit source, quantities referred to as dose kernels. Thus far, the Monte Carlo technique is the most accurate way of the dose kernel determinations. However, for routine dosimetry simpler and less time consuming methods of adequate accuracy may appear more preferable. The "scaling factor" method is used to determine the depth dose distribution in a medium based on data about the dose distribution in an arbitrary reference medium (e.g. air, water). The transformation of the dose distribution curves from the reference medium to the desired new medium is done using a constant, known as scaling factor or relative dose attenuation, and a closely related renormalization factor imposed by the energy conservation. This work investigates the accuracy of the scaling factor method using a statistical approach (generalized chi-squared test), focusing on a particular case of potential practical interest, the scaling factor water to bone. The work also investigates a procedure for extending the applicability of the scaling factor method to dosimetry in dissimilar media, as a first step, a planar interface. / Thesis / Master of Science (MS)

In the fields of water safety, food safety, and public communications, the overarching goal is to improve public health. Thus, this dissertation focuses on risk assessment and applying novel methods for exposure assessments and dose responses to contaminants in drinking water and foods. Factors that greatly impact contaminant exposures and human dose response include: population susceptibility (i.e., healthy adults or children), different routes of exposures (i.e., ingestion or inhalation), carrier matrices (i.e., water or food), and intricacies of chemical and biological mixtures. Chemical spills, such as the 2014 crude MCHM spill in Charleston, WV, revealed the complexities of both minor and major components in the chemical mixture. Slight shifts in geometric structures (isomers) can affect the fate and transport properties of the chemical mixture and as a result, the level of human exposure and dose response to each component in the chemical mixture. Odorous properties of both minor and major components can affect human inhalation exposure, especially during showering, and can be as detrimental as the ingestion route exposure and are different for healthy adults versus for children. Food contaminants, such as Shiga toxin producing Escherichia coli (STEC) in beef products, can be mitigated through a quantitative microbial risk assessment (QMRA) framework that follows a farm-to-fork model. Methods to ensure greatest microbial reduction include: employed intervention strategies at slaughter plants (i.e., water washing of beef carcass), improved cooking times and temperature methods at the consumer and retail level, and assessed minimum effective dose response modeling for different population susceptibilities. Current public communication tools, including the Drinking Water Taste-and-Odor Wheel or Consumer Confidence Reports (better known as water quality reports), should be redeveloped to uphold water safety. Furthermore, public health campaigns that uses social media strategies and informative websites can better educate the public on food contaminants. Ultimately, the objective is to prevent human illnesses due to water contaminants and foodborne pathogens and to bridge the communication gap between the consumers and the experts concerned with water and food safety. / Ph. D. / In the fields of water safety, food safety, and public communications, the overarching goal is to improve public health. Thus, this dissertation focuses on risk assessment and applying novel methods for exposure assessments and dose responses to contaminants in drinking water and foods. Factors that greatly impact contaminant exposures and human dose response include: population susceptibility (i.e., healthy adults or children), different routes of exposures (i.e., ingestion or inhalation), carrier matrices (i.e., water or food), and intricacies of chemical and biological mixtures. Chemical spills, such as the 2014 crude MCHM spill in Charleston, WV, revealed the complexities of both minor and major components in the chemical mixture. Slight shifts in geometric structures (isomers) can affect the fate and transport properties of the chemical mixture and as a result, the level of human exposure and dose response to each component in the chemical mixture. Odorous properties of both minor and major components can affect human inhalation exposure, especially during showering, and can be as detrimental as the ingestion route exposure and are different for healthy adults versus for children. Food contaminants, such as Shiga toxin producing Escherichia coli (STEC) in beef products, can be mitigated through a quantitative microbial risk assessment (QMRA) framework that follows a farm-to-fork model. Methods to ensure greatest microbial reduction include: employed intervention strategies at slaughter plants (i.e., water washing of beef carcass), improved cooking times and temperature methods at the consumer and retail level, and assessed minimum effective dose response modeling for different population susceptibilities. Current public communication tools, including the Drinking Water Taste-and-Odor Wheel or Consumer Confidence Reports (better known as water quality reports), should be redeveloped to uphold water safety. Furthermore, public health campaigns that uses social media strategies and informative websites can better educate the public on food contaminants. Ultimately, the objective is to prevent human illnesses due to water contaminants and foodborne pathogens and to bridge the communication gap between the consumers and the experts concerned with water and food safety.

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Yes / We investigated the potential for digital tomosynthesis (DT) to reduce pediatric x-ray dose while maintaining image quality. We utilized the DT feature (VolumeRadTM) on the GE DefiniumTM 8000 flat panel system installed in the Winnipeg Children’s Hospital. Facial bones, cervical spine, thoracic spine, and knee of children aged 5, 10, and 15 years were represented by acrylic phantoms for DT dose measurements. Effective dose was estimated for DT and for corresponding digital radiography (DR) and computed tomography (CT) patient image sets. Anthropomorphic phantoms of selected body parts were imaged by DR, DT, and CT. Pediatric radiologists rated visualization of selected anatomic features in these images. Dose and image quality comparisons between DR, DT, and CT determined the usefulness of tomosynthesis for pediatric imaging. CT effective dose was highest; total DR effective dose was not always lowest – depending how many projections were in the DR image set. For the cervical spine, DT dose was close to and occasionally lower than DR dose. Expert radiologists rated visibility of the central facial complex in a skull phantom as better than DR and comparable to CT. Digital tomosynthesis has a significantly lower dose than CT. This study has demonstrated DT shows promise to replace CT for some facial bones and spinal diagnoses. Other clinical applications will be evaluated in the future. / Medical Physics Division at CancerCare Manitoba and GE Healthcare (Waukesha, WI).