Radiation from Computed Tomography (CT) is now the major contributor to population radiation dose. Despite controversy around the dose-effect relationship of radiation from CT, the linear non-threshold (LNT) theory is endorsed by many authorities, and constitutes the basis of cancer risk estimates. The purpose of this study was (1) a literature review of radiobiological theories, and methods of dose saving stategies in CT; (2) to highlight the importance of dose saving in CT, and to demonstrate how dose can be saved in a radiology department: Following a 40% reduction in reference X-ray tube current for a CT of the urinary tract, the effecitve dose and estimated lifetime attributable risk of incident cancer due to this CT in a group (n=103) were reduced by 37% and 38% in an age and sex-matched group respectively. The literature review showed that the public health implications of CT radiation exposure remain uncertain. / Health Studies / M.A. (Public Health)

A literature review of metal mixture interaction analyses identified that there was not a consistent method to determine the impact of metal mixtures on an aquatic organism. The review also revealed that a majority of the research on mixtures made use of water concentrations only. Therefore research was conducted to determine the relationship between exposure, bioaccumulation and chronic effects of the four elements As, Co, Cr and Mn individually. Mechanistically based saturation models of bioaccumulation and toxicity were determined for the benthic invertebrate Hyalella azteca, from which lethal water concentrations and body concentrations were also determined. These models were then combined with those previously done for the metals Cd, Cu, Ni, Pb, Tl and Zn to model the impact of 10 metal mixtures on bioaccumulation in short term (1-week) exposures and on bioaccumulation and toxicity in chronic (4-week) exposures at “equi-toxic” concentrations. Interactions between the metals were identified in which; Cd, Co and Ni bioaccumulations were significantly inhibited, Tl and Zn bioaccumulations were marginally inhibited, there was no impact on Cr, Cu or Mn bioaccumulation, and both As and Pb bioaccumulation were enhanced by some mixtures of metals. It was determined that strict competitive inhibition may be a plausible mechanism of interaction affecting Co, Cd and Ni bioaccumulation but not for any of the other metals. However, it is possible that other interactions such as non-competitive or anti-competitive inhibition may have been responsible. A metal effects addition model (MEAM) was developed for Hyalella azteca based on both the bioaccumulation (body concentrations) to effects and the exposure (water concentration) to effects relationships developed from the single metal only studies The MEAM was used to predict the impact of metal mixture exposures on mortality. Toxicity was under-estimated when based on measured water or body concentrations, however, its best prediction was based on body concentrations. The MEAM, when based on measured body concentrations, takes bioavailability into account, which is important since the chemical characteristics of water can greatly alter the bioavailability and therefore toxicity of metals. The MEAM was compared to the traditional Concentration Addition Model (CAM), which calculates toxic units based on water concentrations and LC50s or body concentrations and LBC50s. The CAM overestimated toxicity, but had its best prediction when based on water concentrations. Over all, the best fit to observed mortality was the prediction by the MEAM, based on body concentrations. The measurement of bioaccumulated metals and the use of the MEAM could be important in field site assessments since it takes into account changes in bioavailability due to different site water chemistries whereas the traditional CAM based on water concentration does not.

A literature review of metal mixture interaction analyses identified that there was not a consistent method to determine the impact of metal mixtures on an aquatic organism. The review also revealed that a majority of the research on mixtures made use of water concentrations only. Therefore research was conducted to determine the relationship between exposure, bioaccumulation and chronic effects of the four elements As, Co, Cr and Mn individually. Mechanistically based saturation models of bioaccumulation and toxicity were determined for the benthic invertebrate Hyalella azteca, from which lethal water concentrations and body concentrations were also determined. These models were then combined with those previously done for the metals Cd, Cu, Ni, Pb, Tl and Zn to model the impact of 10 metal mixtures on bioaccumulation in short term (1-week) exposures and on bioaccumulation and toxicity in chronic (4-week) exposures at “equi-toxic” concentrations. Interactions between the metals were identified in which; Cd, Co and Ni bioaccumulations were significantly inhibited, Tl and Zn bioaccumulations were marginally inhibited, there was no impact on Cr, Cu or Mn bioaccumulation, and both As and Pb bioaccumulation were enhanced by some mixtures of metals. It was determined that strict competitive inhibition may be a plausible mechanism of interaction affecting Co, Cd and Ni bioaccumulation but not for any of the other metals. However, it is possible that other interactions such as non-competitive or anti-competitive inhibition may have been responsible. A metal effects addition model (MEAM) was developed for Hyalella azteca based on both the bioaccumulation (body concentrations) to effects and the exposure (water concentration) to effects relationships developed from the single metal only studies The MEAM was used to predict the impact of metal mixture exposures on mortality. Toxicity was under-estimated when based on measured water or body concentrations, however, its best prediction was based on body concentrations. The MEAM, when based on measured body concentrations, takes bioavailability into account, which is important since the chemical characteristics of water can greatly alter the bioavailability and therefore toxicity of metals. The MEAM was compared to the traditional Concentration Addition Model (CAM), which calculates toxic units based on water concentrations and LC50s or body concentrations and LBC50s. The CAM overestimated toxicity, but had its best prediction when based on water concentrations. Over all, the best fit to observed mortality was the prediction by the MEAM, based on body concentrations. The measurement of bioaccumulated metals and the use of the MEAM could be important in field site assessments since it takes into account changes in bioavailability due to different site water chemistries whereas the traditional CAM based on water concentration does not.

Activation of mammalian stress responsive pathways by plant secondary metabolites may contribute to the protection against certain chronic diseases afforded by fruit and vegetable consumption. This work focuses on the identification of plant compounds that activate the stress-responsive enzyme quinone reductase (QR) by stabilizing the transcription factor NF-E2 related factor-2 (Nrf2). Screening methanolic extracts of plants from Western Canada for QR induction in a mouse hepatoma cell line (Hepa-1c1c7) led to the identification of twenty-one extracts capable of doubling the activity of QR. Bioassay-guided fractionation of six extracts led to the identification of novel classes of compounds with QR-inducing activity including fatty-acid derived polyacetylenes, phthalides, and cannabinoids. Studies using low molecular weight thiols and the recombinantly expressed protein Keap1, the principal negative regulator of Nrf2, supported a mechanism of QR activation involving covalent modification of Keap1 cysteines for the polyacetylenes and phthalides. Analysis of transcriptional changes in response to treatment with a panel of QR-inducing compounds provided strong support for Nrf2 activation by the polyacetylene (3S,8S)-falcarindiol and the isothiocyanate (R)-sulforaphane and weaker support for the compounds (3R,8S)-falcarindiol, 6-isovaleryl-umbelliferone (6-IVU) and (Z)-ligustilide. Additionally, transcript level analyses supported a role for the aryl-hydrocarbon receptor in QR-activation by (3R,8S)-falcarindiol, (Z)-ligustilide, (R)-sulforaphane, 6-IVU and cannabidiol and suggested that treatment with polyacetylenes with a (3R)-configuration, (Z)-ligustilide and 6-IVU causes substantial changes in the expression of genes associated with lipid homeostasis and energy metabolism. As a whole, this work provides evidence that compounds that activate QR (and Nrf2) are widely distributed in the Canadian flora. However, of these QR activators, few are active at concentrations that are expected to be achieved through dietary consumption. Nevertheless, the most exceptional compounds isolated in this work, the compounds (3S,8S)-falcarindiol and epoxyfalcarindiol are highly potent and appear to be or are expected to be specific for activating Nrf2 and thus warrant attention with respect to dietary implications and as drug candidate leads.

Radiation from Computed Tomography (CT) is now the major contributor to population radiation dose. Despite controversy around the dose-effect relationship of radiation from CT, the linear non-threshold (LNT) theory is endorsed by many authorities, and constitutes the basis of cancer risk estimates. The purpose of this study was (1) a literature review of radiobiological theories, and methods of dose saving stategies in CT; (2) to highlight the importance of dose saving in CT, and to demonstrate how dose can be saved in a radiology department: Following a 40% reduction in reference X-ray tube current for a CT of the urinary tract, the effecitve dose and estimated lifetime attributable risk of incident cancer due to this CT in a group (n=103) were reduced by 37% and 38% in an age and sex-matched group respectively. The literature review showed that the public health implications of CT radiation exposure remain uncertain. / Health Studies / M.A. (Public Health)

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD+) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD+ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPRmt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD+ and through increasing levels of the pro-longevity ketone body beta-hydroxybutyrate (BHB). In a previous study from my lab, NR increased C. elegans lifespan to a much larger extent when administered starting at the L1 larval stage as compared to when started at the L4 larval stage. Conversely, a high dose of BHB greatly increased lifespan when administered starting at the L4 stage. But this same dose decreased lifespan when it was first administered at the L1 stage. I further found that NR greatly extended lifespan when only administered during larval development and that the combination of both individual pro-longevity NR and BHB treatments significantly decreased lifespan. These chemical epistasis experiments suggest that NR and BHB function in parallel pathways to extend C. elegans lifespan through a common downstream target with hormesis playing a role. Therefore, human subjects who supplement with both NAD+ precursors and ketone esters should be aware of possible negative interactions when high doses of both are administered.