Current protection of the marine environment from radiation is based largely on measuring, estimating and modelling accumulation and impact(s) of radionuclides in a few marine species. Using a relevant marine organism, this thesis focusses on investigating some poorly described phenomena that could cause deviations from predicted measurements. Paper I investigated the biological transformation of tritium (radioactive hydrogen) into an organic compound. The resulting organically bound tritium (OBT) showed increased accumulation in mussels, unique incorporation into a key biological molecule (DNA), extended persistence in tissues, and greater toxicity than the inorganic form. Paper II demonstrated significant disparity in OBT accumulation between functionally similar microalgae species and that OBT in algae is readily transferred to a consumer. Highly radioactive particles are a complex issue in radioecology due to their concentrated dose geometry, potentially inducing very different impacts in organisms, compared to external irradiation. Paper III developed a method to introduce radioactive particles that would facilitate their recovery, improve dose-calculation, and aid the measurement of toxicological endpoints. It also showed that such particles can be incorporated into mussel tissues, causing significant effects. In Paper IV, hypoxia – another major ecological hazard in the marine environment – was expected to reduce radiosensitivity. The minimal observable effect from radiation prevented identification of such an interaction, and indicates drawbacks in the (otherwise sensitive) endpoints used. It appears that stressors like hypoxia may be more of a health hazard to marine organisms than environmental levels of ionising radiation. By understanding such causes of variation in accumulation and impact, it is possible to improve risk assessment, providing more justification for regulations chosen and minimising conservatism in setting environmental standards. / <p>At the time of doctoral defense, the following papers were not published and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.</p>

The present thesis is focused on the development and application of dose response models for radiation therapy. Radiobiological models of tissue response to radiation are an integral part of the radiotherapeutic process and a powerful tool to optimize tumor control and minimize damage to healthy tissues for use in clinical trials. Ideally, the models could work as a historical control arm of a clinical trial eliminating the need to randomize patents to suboptimal therapies. In the thesis overview part, some of the basic properties of the dose response relation are reviewed and the most common radiobiological dose-response models are compared with regard to their ability to describe experimental dose response data for rat spinal cord using the maximum likelihood method. For vascular damage the relative seriality model was clearly superior to the other models, whereas for white matter necrosis all models were quite good except possibly the inverse tumor and critical element models. The radiation sensitivity, seriality and steepness of the dose-response relation of the spinal cord is found to vary considerably along its length. The cervical region is more radiation sensitive, more parallel, expressing much steeper dose-response relation and more volume dependent probability of inducing radiation myelitis than the thoracic part. The higher number of functional subunits (FSUs) consistent with a higher amount of white matter close to the brain may be responsible for these phenomena. With strongly heterogeneous dose delivery and due to the random location of FSUs, the effective size of the FSU and the mean dose deposited in it are of key importance and the radiation sensitivity distribution of the FSU may be an even better descriptor for the response of the organ. An individual optimization of a radiation treatment has the potential to increase the therapeutic window and improve cure for a subgroup of patients.

Xylitol, classified as a natural sugar substitute, has for about 35 years been known as an agent that may act against caries. The mechanism of action; how it inhibits mutans streptococci (MS) and the clinical dose-response relationship are not however fully investigated. The general aim of the investigations was to evaluate the effect of xylitol on oral ecology in children and adolescents. A series of experimental and controlled clinical trials were performed in which samples of saliva and plaque was collected and analysed with respect to xylitol content, pH, microbial composition and lactic acid production. In paper I, significantly reduced proportions of xylitol-sensitive MS in saliva were demonstrated after 18 weeks of regular use of two dose regimens of xylitol-containing tablets (1.7g and 3.4g xylitol/day) but the acidogenicity in dental plaque was not affected. In paper II, the effect on interdental plaque-pH of two different single dose intakes (2.0g and 6.0g) of xylitol was evaluated. The higher xylitol dose counteracted the pH-drop significantly (p&lt;0.05) when the chewing was followed by a sucrose rinse while the lower dose did not differ from the control. In paper III, the xylitol concentrations in saliva after use of different common xylitol-containing products (0.1g-1.3g) were investigated. Statistically significant elevations of salivary xylitol levels were demonstrated for all products during the first 8-16 min when compared with baseline (p&lt;0.05) but the individual variation was considerable. In samples of supragingival dental plaque, a high dose rinse (6.0g) increased the xylitol concentrations for a longer period (&gt;30 min) than a low dose rinse (2.0g). In paper IV, it was demonstrated that 6.0g of xylitol in chewing gums, every day in 4 weeks, gave significantly less visible plaque and a significantly reduced sucrose-induced lactic acid formation (p&lt;0.05) in saliva. Furthermore, the proportion of MS decreased significantly (p&lt;0.05) compared to baseline. In paper V, the salivary uptake of [14C]-xylitol was compared with a specific assay determining xylitol-sensitive MS and a fair positive correlation (p&lt;0.05) between the two assays was found. In a controlled trial, the proportions of MS and the salivary xylitol uptake decreased significantly (p&lt;0.05) in the xylitol gum test group after 4 weeks compared to baseline which was in contrast to the control gum group. No serious adverse effects were reported in any of the investigations. The main conclusions from this thesis were: a) various xylitol-containing products increased the xylitol levels in saliva and plaque, b) 6.0g of xylitol could counteract the interdental pH-drop after sugar consumption and reduce lactic acid formation in saliva c) a daily dose of 6.0g xylitol reduced the amount of visible plaque and altered the salivary microbial composition, d) a transient shift of MS strains in saliva was demonstrated during periods of regular intake of xylitol products but no long-term impact was found after its termination. The relatively high amount of xylitol needed for a beneficial effect on the oral ecology calls for a further development of effective and safe routes for administration.

The objective of this study was to determine if the presence of two ALS inhibiting herbicide residues in three Saskatchewan soils would result in an additive, synergistic, or antagonistic interaction. This was determined through field trials where herbicides were applied sequentially over the course of two years and through dose-response modelling. The herbicides examined in these experiments were imazamethabenz, flucarbazone-sodium, sulfosulfuron, and florasulam, each in combination with imazamox/imazethapyr. The phytotoxicity and persistence of the herbicides in soil was assessed using an Oriental mustard root inhibition bioassay. The determination of herbicide interaction was made through the comparison of the experimentally observed values to theoretically expected values derived from a mathematical equation.<p>The dose response curves created by placing incremental concentrations of these herbicides in soil were compared using the I50 parameter, which is the concentration resulting in a 50% reduction in root length. It appeared that soil organic matter followed by soil pH had the greatest effect in reducing herbicide residue phytotoxicity in the tested soils. Based on the bioassay analysis of sequentially applied ALS inhibiting herbicides, it is proposed that the phytotoxic effect of herbicide residues in soil result in additive injury effects rather than synergistic or antagonistic interactions.

The objective of this study was to determine if the presence of two ALS inhibiting herbicide residues in three Saskatchewan soils would result in an additive, synergistic, or antagonistic interaction. This was determined through field trials where herbicides were applied sequentially over the course of two years and through dose-response modelling. The herbicides examined in these experiments were imazamethabenz, flucarbazone-sodium, sulfosulfuron, and florasulam, each in combination with imazamox/imazethapyr. The phytotoxicity and persistence of the herbicides in soil was assessed using an Oriental mustard root inhibition bioassay. The determination of herbicide interaction was made through the comparison of the experimentally observed values to theoretically expected values derived from a mathematical equation.<p>The dose response curves created by placing incremental concentrations of these herbicides in soil were compared using the I50 parameter, which is the concentration resulting in a 50% reduction in root length. It appeared that soil organic matter followed by soil pH had the greatest effect in reducing herbicide residue phytotoxicity in the tested soils. Based on the bioassay analysis of sequentially applied ALS inhibiting herbicides, it is proposed that the phytotoxic effect of herbicide residues in soil result in additive injury effects rather than synergistic or antagonistic interactions.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 109-119.

During a risk assessment undertaken in a factory dealing with fiber reinforced plastic products in the northwestern part of Peninsular Malaysia, styrene was identified as the most potential hazard in the factory. It was therefore chosen to focus the rest of the risk assessment on this chemical. The purpose of this risk assessment was to find out which negative health effects styrene could have on the factory workers, especially on the laminators who are dealing daily with styrene at a close range during lamination through hand lay-up. This was investigated theoretically through a literature research and practically through measurements of styrene in the air in the factory. The styrene doses were measured on two occasions at several distances away from the potential sources. These measurements were high compared with dose-response relationships found in the literature and various national occupational exposure limit values with regards to styrene. The calculated risk quotient (RQ) was also greater than one and it is therefore likely that styrene has negative health effects on the workers in the factory. The various negative health effects identified in the literature were then included in a risk matrix were they were ranked according to the probability that they would have a negative effect on the factory workers. Hearing- and colourvision effects were ranked as very likely, effects on the central nervous system and the respiratory system as well as livertoxicity were classified as likely and genotoxicity was ranked as a possible negative health effect. In the future it would be interesting to talk to the current laminators and do health check-ups to see if they are suffering from any of the suggested negative health effects. It would also be interesting to follow them on a longterm basis to see if their health is changing and if this can be linked to the styrene handling in the factory. / Vid en riskbedömning i en fabrik i nordvästra Malaysia identifierades styren som den största hälsofaran för fabriksarbetarna, framförallt laminerarna eftersom de ofta hanterar styren på nära håll. Det valdes därför att fokusera den resterande riskbedömningen just på styren och dess möjliga negativa hälsoeffekter. Syftet med studien var att ta reda på om styren kan ha en negativ effekt på fabriksarbetarnas hälsa. Detta undersöktes teoretiskt genom en litteraturstudie och praktiskt genom mätningar av styrenhalten i fabriken. Vid två tillfällen mättes styrenhalten i fabriken. De uppmätta halterna jämfördes sedan med de dos-responssamband som funnits vid litteraturstudien, samt med olika nationella hygieniska gränsvärden för styren. De uppmätta värdena visade sig vara höga jämfört med de funna i litteraturen. Det bidrog tillsammans med den beräknade riskkvoten som visade sig vara större än ett, till slutsatsen att styren har en negativ effekt på fabriksarbetarnas hälsa. De möjliga negativa hälsoeffekter som identifierats i litteraturen rangordnas med hjälp av en riskmatris enligt sannolikheten att de skulle utgjöra en risk för arbetarna i fabriken. Effekter på hörseln och färgseendet ansågs vara mycket sannolikt, effekter på centrala nervsystemet (CNS) och levern samt irritation av andningssystemet ansågs sannolika och att styren skulle vara genotoxiskt ansågs möjligt. Övriga hälsoeffekter ansågs osannolika eller mycket osannolika. I framtida studier skulle det vara intressant att diskutera med de nuvarande laminerarna och undersöka dem medicinskt för att se om de har påverkats utav några av de förväntade hälsoeffekterna. Det vore också intressant att följa dessa arbetare under en längre tid för att se om deras hälsa ändras på något sätt som skulle kunna kopplas till styrenhanteringen i fabriken.

An important objective in statistical risk assessment is estimation of minimum exposure levels, called Benchmark Doses (BMDs) that induce a pre-specified Benchmark Response (BMR) in a target population. Established inferential approaches for BMD analysis typically involve one-sided, frequentist confidence limits, leading in practice to what are called Benchmark Dose Lower Limits (BMDLs). Appeal to hierarchical Bayesian modeling and credible limits for building BMDLs is far less developed, however. Indeed, for the few existing forms of Bayesian BMDs, informative prior information is seldom incorporated. Here, a new method is developed by using reparameterized quantal-response models that explicitly describe the BMD as a target parameter. This potentially improves the BMD/BMDL estimation by combining elicited prior belief with the observed data in the Bayesian hierarchy. Besides this, the large variety of candidate quantal-response models available for applying these methods, however, lead to questions of model adequacy and uncertainty. Facing this issue, the Bayesian estimation technique here is further enhanced by applying Bayesian model averaging to produce point estimates and (lower) credible bounds. Implementation is facilitated via a Monte Carlo-based adaptive Metropolis (AM) algorithm to approximate the posterior distribution. Performance of the method is evaluated via a simulation study. An example from carcinogenicity testing illustrates the calculations.

Background: Physical inactivity has been consistently associated with numerous negative health outcomes that track from childhood into adulthood, making physical activity a special concern in the pediatric population. Dose-response studies are particularly useful when trying to understand the minimal and optimal amounts of physical activity needed to reduce the risk of negative health outcomes. Unfortunately, previous work within youth has relied on self-reported measures of physical activity, and this research does not provide a clear picture of the true relation between physical activity and health. Objectives: Manuscript 1. Describe the dose-response relation between dyslipidemia and moderate-to-vigorous physical activity (MVPA) in youth. Manuscript 2. Quantify the difference between self-reported and objectively measured MVPA in youth. Taken together, the overall objective of this thesis was to examine the dose-response relation between objectively measured MVPA and dyslipidemia in youth and determine how this may affect current Canadian physical activity guidelines. Methods: Both manuscripts used data from the U.S. National Health and Nutrition Examination Survey. Fractional polynomial regression modeling was used to fit the dose-response curves between MVPA and lipid/lipoprotein measurements. Regression analysis as well as a Bland-Altman plot was used to explain the discrepancy between self-reported and objective measures of MVPA. All analyses were completed using SAS statistical software. Results: Manuscript 1. Risks for high-risk HDL-cholesterol and triglyceride values decreased in a curvilinear manner with increasing minutes of MVPA. The greatest reduction in risk occurred within the first 30 min/d of MVPA. The relation between level of MVPA and LDL-cholesterol was unclear. Manuscript 2. The average youth over-reported their MVPA by ~30 min/d. The over-reporting was not mediated by basic demographic factors; however, the difference in reporting was systematic in nature such that inactive youth over-reported to the greatest extent. Conclusions: Manuscript 1. Youth need to accumulate 30 min/d of MVPA to greatly reduce their risk for dyslipidemia. Manuscript 2. Youth tend to over-report their daily MVPA by approximately 30 min/d. Combined, the results from this thesis suggest that physical activity recommendations for cardiovascular health in youth should suggest a minimum of 30 min/d of MVPA and preferred level of 60 min/d. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2009-09-07 08:48:03.896

Background: Cancer and diabetes are the second and twelfth leading global causes of death, respectively. Cancer incidence is increased in diabetics compared to non-diabetics. Common pathobiological pathways are shared by the two diseases: hyperglycaemia, hyperinsulinaemia, chronic inflammation and altered concentrations of endogenous hormones. These pathways can all directly or indirectly be linked to chronic hyperglycaemia. Lifestyle factors also affect cancer, diabetes and hyperglycaemia. Hypothesis: Chronic hyperglycaemia is the common biological pathway linking cancer, diabetes and lifestyle factors. Chronic hyperglycaemia can be assessed by monitoring glycated haemoglobin (HbA1c) levels. Aim: The first aim is to investigate whether the link between diabetes and increased cancer risk can be explained by increasing HbA1c levels. Secondly, glycaemic and overall models of lifestyle factors should be developed and compared to determine the relative influence of lifestyle factors on blood glucose level and, subsequently, cancer risk. This could clarify whether improved glycaemic control via lifestyle factors is sufficient to significantly reduce cancer risk. Method: Dose-response meta-analyses on cancer risk and HbA1c levels were performed and the results communicated via a research article. Statistical glycaemic and overall models were developed from published studies on colorectal cancer (CRC), lifestyle factors and HbA1c, via meta-analysis. Log-linear and restricted cubic spline models were considered for studies relating CRC risk to lifestyle factors or HbA1c. Linear models were considered for studies relating HbA1c to lifestyle factors. Only statistically significant models were compared. Results: Increased cancer risk with increasing HbA1c levels was present for a number of cancers, with some cancer types also showing increased risk in the pre-diabetic and normal HbA1c ranges. Comparison of the glycaemic and overall models revealed that HbA1c significantly affected cancer risk and was significantly affected by lifestyle factors. However, the overall effects of lifestyle factors were much stronger than their glycaemic effects (between 9% and 25% difference in risk between overall effects and glycaemic effects at the exposure levels analysed). Glycaemic and overall models for cigarette smoking and chronic stress revealed increased cancer risk with increasing exposure, but decreased cancer risk for increased dietary fibre intake. The glycaemic model for alcohol consumption displayed decreased cancer risk, while the overall model revealed increased cancer risk, emphasising the strong effect of carcinogenic substances in alcohol. Conclusions: Risk for a number of cancers increased with HbA1c levels in diabetic and non-diabetic persons. Cancer prevention by improved blood glucose control seems plausible. The overall effects of lifestyle factors on cancer risk are much stronger than their glycaemic effects. Lifestyle factors alone do not provide enough reduction in blood glucose levels. Other therapeutic strategies for reducing blood glucose levels, such as pharmacotherapeutics or fasting, should be investigated. The possible harmful effects of reducing blood glucose levels, such as neuroglycopaenia, should be considered before implementation of therapeutic strategies. Although there seems to be a strong association between HbA1c and cancer risk, this does not imply causality. The possibility of residual confounding cannot be ignored, even though the most adjusted estimates were used to develop the models, where possible. / MIng (Electrical and Electronic Engineering), North-West University, Potchefstroom Campus, 2014