Glucans are (1→3)-β-D-glucose polymers that are found in the cell wall of fungi, bacteria and plants. Glucans are known to stimulate humoral and cell-mediated immunity in humans and animals. In addition to the potent immune stimulatory effects of (1→3)-β-D-glucans, there are a number of toxicological effects associated with exposure to the water-insoluble, microparticulate form of the polymer. Recent investigations have suggested a potential role for (1→3)-β-D-glucans in inhalational toxicity. Specifically, (1→3)-β-D-glucans have been implicated in the symptomatology associated with 'sick building' syndrome. The mechanisms by which (1→3)-β- D-glucans mediate immune stimulation and, perhaps, toxicity are currently under investigation. It is now established that (1→3)-β-D-glucans are recognized by macrophages and, perhaps, neutrophils and natural killer cells via a (1→3)-β-D-glucan specific receptor. Following receptor binding, glucan modulates macrophage cytokine expression. Here we review the chemistry, immunobiology and toxicity of (1→3)-β-D-glucans and how it may relate to effects caused by inhalation.

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This thesis concerned with iodine status, sources in human body, and measurements especially here in Canada, where iodine status for the Canadian population is not well known. With the recent re-emergence of iodine deficiency among individuals in other industrial countries, understanding the main sources of iodine to the Canadian population is necessary to ensure fortification strategies are justified and effective. Uncertinaty has arisen to the importance of iodized salt recently, along with medical warnings to reduce salt consumbtion. This conflicts give rise to improve scientific research and hone thier methods with new applications. The research question here is that: Can we benefit from the existence of long-lived radioiodine-129 in the environment and explore its potential as a tracer? To answer this question, the study was divided into an introductory chapter contains a review about the topic, then three research chapters. The second chapter was devoted to study the possibility of extracting 129I from human urine. As for third chapter of the thesis, it was about refining a method that already established, and use it to extract 129I from breastmilk using combustion, then determine the radiological dose of 129I in infants’ thyroid. While the fourth chapter was devoted to investigate the main sources of 127I and 129I in the Canadian diet based on daily food consumption and modelling the urinary iodine concentration for adults and infants through the novel application of a well-established compartment model implemented in AMBER. The path of this thesis was crowned with a set of results, which are detailed in the end of each chapter as follow: 1- The advantage of accelerator mass spectrometry (AMS) helps to measure 129I in human urine for the first time. The result for 25 participants from Ottawa ranged from 3.3 x 106 atoms/L to 884 x 106 atoms/L with a median of 108.7 x 106 atoms/L, and the 129I/127I ratio ranged from 7.38 x 10-12 to 3.97 x 10-10 with a mean of 1.3 x 10-10. 2- The concentration of 127I and 129I in Ottawa urine samples were significantly correlated and generally similar to the 129I concentrations and 129I/127I ratios from environmental samples collected around Ottawa. 3- This correlation suggests that 129I could be a potential nutritional tracer of dietary iodine. 4- In chapter 3, the 129I in breastmilk ranged from 1.26x108 atoms/L to 6.64x108 atoms/L with a median of 2.10 x108 atoms/L, and the 129I/127I ratio ranged from 1.27x10-10 to 9.9x10-10 with a median of 2.13x10-10. 5- A correlation was also observed between 127I and 129I concentrations in breastmilk. 6- The isotopic ratios in breastmilk were similar to Canadian cow’s’ milk, indicating that the milk of both cows and humans is a reflection of the 129I concentration of their local environment and the food ingested. 7- Result from chapter 3 confirms that humans are exposed to the 129I from birth through their mother breastmilk, giving them an average dose of 1.10 x10-4 Bq/year and thyroid dose rate equal to 5.92 x10-10 Sv/year. 8- In fourth chapter, the daily milk consumption was measured for 78 mother-infants’ pairs, and ranged from 275 -1202 g/day, with a mean of 731 g/day. This value agrees well with global infant milk intake which estimated at 730g/day. 9- The daily iodine intake from breastmilk ranged from 11.2 µg/day to 476.2 µg/day with a median of 127.9 µg/day. 10- The urinary iodine concentrations were estimated without urine collection using iodine biokinetic model, giving a median urinary iodine concentration (n=78) at 304.7 µg/L. The result was compared to those measured by Health Canada (median= 398.7 µg/L), showing a moderate correlation (r= 0.496). 11- A further comparison of the results was made based on gender shows that the difference between UIC in male and female infants measured by Health Canada and those estimated by AMBER is non-significant. 12- Through AMBER software, the influence of seven common diets on UICs was assessed to determine which foods play an important role in ensuring iodine adequacy. We observed that the main source of iodine in a vegan diet is grain products providing up to 70%, while in remaining diets the main source of iodine was dairy products (50-69%) when they are consumed. 13- The contribution of iodized salt to all Canadian diets was ranked second, after dairy, unless the diet is vegan or ovo-vegetarian, where dairy is not consumed, iodized salt was ranked first. 14- Among 23 scenarios for seven different diets, the urinary iodine-129 concentrations ranged from 1.4 x10-7 to 3.3 x10-7 µg/L with a median of 3.1 x10-7 µg/L, and the isotopic 129I/127I ratio ranged from 1.1 x10-9 to 1.2 x10-8 with a median of 2.8 x10-9. 15- In contrast to stable iodine, the highest isotopic ratio was observed in vegan diet, while the lowest was observed in ketogenic diet. This suggests that grain products are the main contributor of 129I to humans. 16- Despite being the primary contributors of stable iodine (127I), salt and dairy show a lower contribution of 129I. Based on this we can qualitatively predict the source of iodine 127 using isotopic ratio 129I/127I. For example, in cases where the isotopic ratio was between 10-8 and 10-9, therefore, the main sources of iodine in this person may be from grains products, vegetables, and fruits; and in cases where the isotopic ratio was between 10-10 and 10-11, therefore, the main sources of iodine in this person may be from dairy products and some contribution from salt. This study has shown the capability of 129I to be used in biomedical fields. In this thesis 129I used as a nutritional tracer where it helps to detect the sources of stable iodine in human body based on isotopic ratio. The extraction method invented in Chapter 2 can be used to evaluate 129I exposure directly in the human body for those who live nearby nuclear fuel reprocessing plants. An additional application for this method can be in assessing 129I in human to investigate 131I uptake in the event of a nuclear emergency using 129I in urine as a proxy. Moreover, the extraction technique used Chapter 3, can be extended to other biological samples such as thyroid or brain. Furthermore, Chapter 4 shows that with the right estimation of daily iodine intake and urine volume, a biokinetic model of iodine, built in the AMBER software, can predict urinary iodine concentration with a high degree of accuracy without collecting urine samples.

Irrigation with saline waters is an agricultural practicethat is becoming increasingly common as competition for freshwater increases. In this thesis the mechanisms behind salinityand drought stress has been studied using data from fieldexperiments in combination with a modelling tool, theCoupModel. Measurements from field experiments on salinity,boron toxicity and drought stressed tomatoes grown during twoclimatically different seasons in the Arava desert, Israel,showed a linear relationship between relative growth andevapotranspiration, for all treatments and seasons. Data fromthe spring was used to concurrently simulate growth andtranspiration, hence accounting for feedback mechanisms betweenthe plant and the environment. Salinity stress was modelled asan osmotic effect (reduction of water uptake at high soilsalinities, W approach) or a toxicity effect (direct reductionof photosynthesis with soil salinity, G approach). Goodagreement between simulated growth and transpiration wasachieved with both salinity stress approaches, with twoexceptions. When growth and transpiration were simulated withthe W approach at different salinity levels, transpiration wasunderestimated at high stress. The G approach resulted in anunderestimation of growth at high water stress under moderatesalinity. A direct decrease of photosynthesis leads to adecreasing water-use efficiency with salinity while water-useefficiency remains constant with salinity when the salinitystress is modelled as a reduction in water uptake. Measurementsshowed decreasing water-use efficiency for the salinitygradient, explaining why the W approach was not applicable. Itwas not possible to detect any considerable differences betweenthree different approaches for water uptake tested in thestudy. <b>Keywords:</b>Water-use efficiency; osmotic effect; iontoxicity; semi-arid. / NR 20140805

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The maximum daily dose of vitamin D currently recommended is 2000 IU. Ergocalciferol (D2) 50,000 IU orally weekly for 8-12 weeks is often used to treat vitamin D deficient patients (25(OH) vitamin D <20 ng/mL). The lack of vitamin D toxicity after massive doses of ergocalciferol has yet to be reported in the literature. We report a case of a 56-year-old woman who received supratherapeutic doses of ergocalciferol (150,000 IU orally daily) for 28 years without toxicity. We discuss the possible mechanisms which may account for a lack of toxicity despite intake of massive daily doses of ergocalciferol in this patient.

Boron is an essential nutrient for plants and the potential exists for efficient removal of this element by wetland treatment systems due to accumulation by plants. To evaluate the efficacy of using Spirodella polyrrhiza to treat boron-contaminated wastewater or to be a suitable species for removing other nutrients from boron-containing wastewater the toxicity of this micronutrient was determined using standard methods. Frond production is apparently a more sensitive endpoint than either growth rate or the presence of abnormal fronds. Frond production in S. polyrrhiza was significantly reduced at 3.55 mg B/l. Significant reductions in growth rate and the percentage of abnormal (chlorotic, necrotic, and dead) fronds were observed at 18.9 and 22.4 mg B/l, respectively. The EC50 for frond production, frond growth rate, and abnormal fronds were 14.3, 11.7, and 17.7 mg B/l, respectively. S. polyrrhiza did not remove significant amounts of boron from the treatment solutions under the conditions and concentrations existing in this study. The inability of S. polyrrhiza to remove even small amounts of boron from the test solutions indicates this species is not suitable for treating boron-containing wastewater, even those with low boron concentrations.

Purpose: In vivo screening of phage-displayed random peptide libraries (RPLs) has been used to identify peptide ligands to targets found on endothelial cells of blood vessels supplying specific tissues such as brain, kidney, and tumor tissue. Peptides that bind specifically to blood vessels supplying tumor tissue have been conjugated to cytotoxic agents and used to successfully eradicate tumors in a mouse model. With the ultimate goal of developing similar methods for treating human cancer, we describe an in vivo RPL screening process that, unlike previous in vivo experiments, does not harm the animal being screened. Methods: RPLs were administered to FVB, BalbC, and tumor-bearing MRL/MpJ-fasLPR mice in a variety of dosing formats. Tumor nodules were excised 10 min following infusion and phage were amplified from the specimens. Phage were reinjected into the same animal within 48 h. This process was repeated twice for a total of three in vivo screens of mouse tumor tissue within the same animal. Mice were observed for systemic side effects, histopathologic damage, and presence of phage in organs. Peptide sequences were determined from several third-pan phage clones. Results: Overall there was minimal toxicity from administration of single or repeat doses of RPLs. Amino acid consensus sequences were identified and some of the sequences were similar to those of peptide ligands that bind matrix metalloproteinases. Conclusions: Serial administration of an RPL is well tolerated and serial panning in individual mice leading to consensus sequence motifs is possible. Based on these preclinical data the Food and Drug Administration has approved the implementation of human clinical trials with this technique.

Dehydropyrrolizidine alkaloids (DHPAs) are a large group of globally important plant-derived pro-toxins that can contaminate or are naturally present in animal feed and the human food supply as well as herbal supplements. Their bioactive metabolites are potentially hepatotoxic, pneumotoxic, genotoxic and carcinogenic. Due to the difficulty in obtaining sufficient quantities of purified DHPAs, toxicity studies have largely relied on single intraperitoneal injections in rodent models, and carcinogenicity studies have been limited to a small handful of the hundreds of isolated DHPAs. To assess the relative toxicity of structurally diverse DHPAs in a more biologically relevant manner, male California White chicks were dosed orally with 0.01, 0.04, 0.13, or 0.26 mmol of seven different DHPAs and three DHPA N-oxides kg-1 bodyweight for 7 days. DHPAs were grouped in relation to their toxicity based on clinical, serum biochemical, and histopathological evaluations as well as tissue adduct accumulation rates. Using the same model, a reduced extract from comfrey, a commonly used DHPA containing herb, was compared to its two major constituent DHPAs, intermedine and lycopsamine. Based on the same parameters, the comfrey extract was more toxic than pure lycopsamine or intermedine. Addressing the need for a more sensitive carcinogenicity model, male heterozygous p53 knockout mice were treated with riddelliine 5, 15 or 45 mg kg–1 bodyweight day-1 by oral gavage for 14 days, or given a long-term treatment of riddelliine 1 mg kg-1 bodyweight day–1 in pelleted feed for 12 months. Exposure to riddelliine increased the odds of tumor development in a dose-responsive manner (odds ratio 2.05 and Wald 95% confidence limits between 1.2 and 3.4). The most common neoplasm was hepatic hemangiosarcoma, which is consistent with previously published lifetime rodent studies. The results of this research demonstrate that the California White chick model is sensitive for comparison of DHPA toxicity, and data obtained from this research can be used to validate previous DHPA toxicity research. It also demonstrates that comfrey toxicity may have been previously underestimated. The heterozygous p53 knockout mouse model is beneficial for further investigation of comparative carcinogenesis of structurally and toxicologically different DHPAs and their N-oxides.

Aflatoxin B1 (AFB1), a secondary metabolite of Aspergillus flavus and Aspergillus parasiticus, is known for its potent carcinogenicity and immunosuppressive effects. It is also known that AFB1 toxicity appears in different degrees in different animal species and strains. The present study was performed to reveal the involvement of the hypothalamus-pituitary-adrenal gland (HPA) axis in the immunosuppressive effects of AFB1 on C57B/6 mice. Splenic lymphocy1es were assayed to investigate their phenotyping using flow cy1ometry, proliferative response against mitogen and allogenic lymphocy1es, cy1oly1ic cell activity, and IL-2 production. In addition, antibody-mediated immunocompetence was checked using sheep red blood cell (SRBC)-challenged animals by plaque-forming cell (PFC) assay and enzyme-linked immunosorbent assay (ELISA). Corticotropin releasing factor (CRF) in brain hypothalamus and cerebral cortex, plasma adrenocorticotropic hormone (ACTH), and corticosterone were determined by radioimmunoassay (RIA). Hypothalamic catecholamine and its metabolites were assayed by high-performance liquid chromatography (HPLC). The adrenalectomized animals and their respective control animals were used to evaluate corticosterone involvement in AFB1 immunosuppressive effects. A relatively higher dose was applied in the present study, compared to the previous studies that used different strains of mice. Immunosuppressive effects were observed in blastogenic response, IL-2 production, and primary antibody production of splenic cells. The amount of circulating anti-SRBC antibody was also affected. Decreases were observed in the helper-T cell and B cell percentage in phenotyping splenic lymphocyte. No significant changes were observed in natural killer cell activity, mixed lymphocyte response, brain biogenic amine concentrations, concentration of CRF in the hypothalamus, and those of ACTH and corticosterone in plasma. However, the expected effect of adrenalectomy to compensate for the immunosuppression of AFB1 was not observed. The results indicate that the HPA axis does not appear to have a major role in AFB1-induced immunotoxicity.