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.

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.

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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

This thesis concerns optimal designs and estimation approaches for a class of nonlinear dose response models, namely multi-response Emax models. These models describe the relationship between the dose of a drug and two or more efficacy and/or safety variables. In order to obtain precise parameter estimates it is important to choose efficient estimation approaches and to use optimal designs to control the level of the doses administered to the patients in the study. We provide some optimal designs that are efficient for estimating the parameters, a subset of the parameters, and a function of the parameters in multi-response Emax models. The function of interest is an estimate of the best dose to administer to a group of patients. More specifically the dose that maximizes the Clinical Utility Index (CUI) which assesses the net benefit of a drug taking both effects and side-effects into account. The designs derived in this thesis are locally optimal, that is they depend upon the true parameter values. An important part of this thesis is to study how sensitive the optimal designs are to misspecification of prior parameter values. For multi-response Emax models it is possible to derive maximum likelihood (ML) estimates separately for the parameters in each dose response relation. However, ML estimation can also be carried out simultaneously for all response profiles by making use of dependencies between the profiles (system estimation). In this thesis we compare the performance of these two approaches by using a simulation study where a bivariate Emax model is fitted and by fitting a four dimensional Emax model to real dose response data. The results are that system estimation can substantially increase the precision of parameter estimates, especially when the correlation between response profiles is strong or when the study has not been designed in an efficient way. / <p>At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 1: Manuscript; Paper 2: Manuscript; Paper 3: Manuscript; Paper 4: Manuscript.</p>

First-in-man (FIM) Phase I clinical trials are part of the critical path in the development of a new compound entity (NCE). Since FIM clinical trials are the first time that an NCE is dosed in human subjects, the designs used in these trials are unique and geared toward patient safety. We develop a method for obtaining the desired response using an adaptive non-linear approach. This method is applicable for studies in which MTD, NOEL,NOAEL, PK, PD effects or other such endpoints are evaluated to determine the desired dose. The method has application whenever a measurable PD marker is an indicator of potential efficacy and could be particularly useful for dose finding studies. The advantages in the adaptive non-linear methodology is that the actual range of dose response and lowest non-effective dose levels are more quickly and accurately determined using fewer subjects than typically needed for a conventional early phase clinical trial. Using the nonlinear logistic model, we demonstrate, with simulations, that the DOSEFIND approach has better asymptotic relative efficiency than a fixed-dose approach. Further, we demonstrate that, on average, this method is consistent in reproducing .the target dose, that it has very little bias. This is an indicator of reproducibility of the method, showing that the long-run average error is quite small. Additionally, DOSEFIND is more cost effective because the sample size needed to obtain the desired target dose is much smaller than that needed in the fixed dose approach.

Micro-irradiation systems are used to analyse the effect of ionizing radiation at the cellular and tissue level, targeting individual cells within a population with a controlled low dose. Cell survival experiments using micro-irradiation systems are limited by factors including: 1) the radiation attenuation and optical properties of the chosen cell dish substrate, 2) the registration of the cell dish before and after irradiation or between multiple imaging modalities and 3) the analysis of the cell or colony growth after irradiation. In this thesis, a set of tools have been developed to improve micro-irradiation experiments and to increase the accuracy of information provided by the cell survival data. The first contribution, the substrate cell dish evaluation, provides a set of characteristics defining the substrates used for micro-irradiation experiments based on minimal energy loss and optical clarity using unstained cell imaging. The second contribution was the development of a novel and low cost fiducial marking device for micro-irradiation experiments using an 808 nm laser and providing marks suitable for imaging with multiple modalities. The minimum focused spot diameter was calculated as 22.9 urn and the device was used to create fiducial marks with diameters ranging from 20 urn to 130 urn. The third contribution, the development of a cell counting methodology for use with a lens-free imaging device, has been shown to accurately count thousands of cells suitable for immediate analysis. Approximately 1000 cell colonies, containing 17 729 cells on 11 cell dishes were used for testing and training for automatic cell counting. Validation of the cell counting method showed that 76% and 89% of the cell colonies were counted within a ± 20% and ± 30% error of the ground truth, respectively. Further development of the fiducial marking device, by modifying the choice of laser and making it suitable for multiple types of cell dish substrates, would increase the applications of the device. Development of the cell counting methodology for different cells line, and for cells grown on multiple types of substrates, would make the system suitable for analysis of a wide variety of cell survival studies. The cell counting methodology, applied to the CyMap lens-free imaging device, has the potential to be an extremely useful and cost effective tool for cell survival studies.

O interesse em efeitos sinérgicos ou antagônicos através de experiências com associações cresceu imensamente nas últimas décadas. Com o objetivo de estudar a associação de dois herbicidas inibidores da ALS (sulfometuron-methyl e chlorimuron-ethyl) em Digitaria insularis, empregou-se dos métodos estatísticos fornecidos por meio das curvas dose-resposta e isobologramas. O conceito de curvas dose-resposta tem sido amplamente utilizado para avaliar os resultados das experiências com herbicidas. No entanto, a abordagem estatística em torno das curvas deve ser cuidadosa; cosiderar as curvas dose-resposta semelhantes quando elas não são pode influenciar muito na comparação entre as moléculas e afetar o cálculo da potência relativa. A potência relativa ajuda a entender qual é a relação de potência entre as moléculas, esse conhecimento é fundamental para os estudos com os herbicidas em associação. Sabendo-se disso foram conduzidos experimentos do tipo dose-resposta em dois tipos de substratos utilizando Digitaria insularis como planta daninha indicadora. Os experimentos foram conduzidos em casa de vegetação do Centro de Pesquisa e Desenvolvimento da DuPont em Paulínia (SP). Para cada molécula foram aplicadas, em pré-emergência, oito doses com quatro repetições cada e quatro plantas testemunha nos diferentes substratos. O substrato A é somente substrato comercial (marca Tropstrato HT&reg;) puro; E o substrato B é uma mistura de solo arenoso, peneirado e livre de contaminação mais substrato comercial na proporção 3:1 v/v. Neste caso ficou evidente a maior capacidade do sulfometuronmethyl em reduzir a biomassa da espécie, as curvas dose-resposta foram descritas pelo modelo log-logístico com os valores de ED50 e as declividades de cada curva variando livremente, pois as hipóteses testadas nos diferentes substratos de curvas paralelas foram rejeitadas. O valor calculado da potência relativa para o nível de resposta de 50% entre os herbicidas CLASSIC&reg; (chlorimuron-ethyl) e CURAVIAL&reg; (sulfometuron-methyl) nas condições desse estudo foi de 8,596 e 44,047 nos Substrato A e B respectivamente. A partir dessa informação foram utilizadas as mesmas condições do experimento anterior para o experimento com as isoboles dos herbicidas em associação, cinco curvas dose-resposta, foram propostas, duas curvas para os produtos isolados e três curvas para as associações em diferentes proporções [(25% : 75%); (50% : 50%); (75% : 25%)] chlorimuron-ethyl / sulfometuron-methyl, totalizando 144 parcelas. Vários modelos isoboles foram testados, o modelo de Concentração Aditiva foi significativamente descartado, mas foi levado em consideração para testar teoricamente o grau de sinergia ou antagonismo que modelos mais complexos podiam fornecer. O modelo de isobole proposto por Hewlett e Plackett (1959) teve ajuste significativo e parâmetro de interação menor que um (&lambda;=0,33). O modelo que mais se ajustou aos dados foi o proposto por Vølund e os resultados também mostraram que nessas condições a associação de sulfometuron-methyl com chlorimuron-ethyl foi antagônica; as isoboles são potentes ferramentas para capturar e descrever associações de herbicidas. Entretanto a literatura mostra que associar duas moléculas e testar em um sistema biológico complexo sofrendo variações das diferentes condições ambientais possíveis pode gerar respostas variáveis, portanto esses resultados devem ser repetidos em outras condições para validar as conclusões ou então serem executados em condições controladas de laboratório e usar organismos vivos de menor complexidade como bioindicador. / The interest in synergistic or antagonistic effects through experiences with associations has immensely grown in recent decades. In order to study the association of two ALS inhibitor herbicides (sulfometuron-methyl and chlorimuronethyl) in Digitaria insularis, the statistical methods provided by the dose-response curves and isobolograms were used. The concept of dose-response curves has been widely used to evaluate the results of herbicide experiments. However, the statistical approach around curves must be careful; considering the dose-response curves when they are not can greatly influence the comparison between molecules and affect the calculation of relative potency. Relative potency helps to understand what the power ratio is between molecules, this knowledge is fundamental for studies with herbicides in association. Knowing this, dose-response experiments were conducted on two types of substrates using Digitaria insularis as an indicator weed. The experiments were conducted in a greenhouse of the DuPont Research and Development Center in Paulínia (SP). For each molecule were applied, in pre-emergence, eight doses with four replicates each and four control plants on different substrates. Substrate A is pure commercial substrate (brand Tropstrato HT&reg;); and substrate B is a mixture of sandy soil, sifted and contamination-free plus commercial substrate in the ratio 3:1 v/v. In this case it was evident the greater capacity of the sulfometuron-methyl to reduce the biomass of the species, the dose-response curves were described by the log-logistic model with the values of ED50 and the slopes of each curve varying freely, since the hypotheses tested in the different substrates of parallel curves were rejected. The calculated value of relative potency for the 50% response level between CLASSIC&reg; (chlorimuron-ethyl) and CURAVIAL&reg; (sulfometuron-methyl) herbicides under the conditions of this study was 8.596 and 44.047 on Substrate A and B respectively. From this information the same conditions of the previous experiment for the isoboles of the herbicides in association were used, five doseresponse curves were proposed, two curves for the isolated products and three curves for the associations in different ratios [25% : 75%); (50% : 50%); (75% : 25%)] chlorimuron-ethyl / sulfometuron-methyl, totaling 144 plots. Isoboles models were tested, the Concentration Additive model was significantly discarded, but was taken into account to theoretically test the degree of synergy or antagonism that more complex models could provide. The isobole model proposed by Hewlett and Plackett (1959) had a significant adjustment and interaction parameter smaller than 1 (&lambda; = 0.33). The model that best fit the data was the one proposed by Vølund and the results also showed that under these conditions the association of sulfometuronmethyl with chlorimuron-ethyl was antagonistic; isoboles are potent tools for capturing and describing herbicide associations. So these results must be repeated in other conditions to validate the conclusions or to be executed in controlled laboratory conditions and to use living organisms of lesser complexity as a bioindicator.