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Elevated arsenic concentrations in ground and surface water sources have been reported world-wide. Furthermore, arsenic exposure has been associated with several health disorders including type-2 diabetes. However, research in Argentina is limited and is typically confined to. a few provinces (e.g. Santiago del Estero; Cordoba and Buenos Aires). This research aimed to evaluate the relationship between arsenic exposure in water and levels in human hair, fingernail and toenail samples from four locations in Argentina, General Roca (Rio Negro), Los Menucos (Rio Negro), Eduardo Castex (La Pampa) and Copahue-Caviahue (Neuquen), Furthermore, it aimed to establish whether a link exists between type-2 diabetes and arsenic levels in human hair, fingernail, toenail, urine and blood (whole and serum) samples. The secondary aim of the research was to evaluate methods for the removal of arsenic from water, namely the use of solid phase material (iron oxide and hydroxide) and electrocoagulation. Ground, surface and tap water samples were collected from each of the four locations. This study found that the exposure of residents to total arsenic in water from each of the locations increased in the order: General Roca < Los Menucos < Eduardo Castex. Copahue-Caviahue is a unique location and was selected due to the potential exposure to arsenic from the volcanic r10 Agrio (upper r10 Agrio: 179 - 359 I-Ig/I AsT). However, the drinking water from glacial sources for the towns of Copahue and Caviahue contained arsenic levels « 0.2 - 0.98 I-Ig/I AsT) below that of General Roca « 0.2 to 7.6 I-Ig/I AsT). Hair, fingernail and toenail samples were also collected from each location, and arsenic levels were found to increase in the order: Copahue-Caviahue < General Roca < Los Menucos < Eduardo Castex. Furthermore, a positive relationship (Pearson Correlation) was found between arsenic exposure in water and levels in these samples. Residents from Eduardo Castex had the highest arsenic levels in hair « 0.03 - 4.24 mg/kg AsT), fingernail « 0.05 - 10.7 mg/kg AsT) and toenail (0.09 -13.8 mg/kg AsT) samples. This town was selected to establish a link between arsenic and type-2 diabetes. A Mann-Whitney U-Test found significantly lower arsenic levels in finger and toenail samples (p < 0.01), whereas significantly higher arsenic levels where found in urine and blood serum samples from type-2 diabetic individuals (p < 0.01). This study, has highlighted the requirement to evaluate the impact a health disorder, such as type-2 diabetes, has on the distribution of arsenic in the human body. The arsenic exposure studies highlighted the possible requirement for a low-cost arsenic removal method. Iron oxide/hydroxide and electrocoagulation were evaluated and high arsenic removal percentages were found in laboratory studies. Electrocoagulation was evaluated further in field-based tests in Argentina (Eduardo Castex, La Pampa; San Cristobel, Santa Fe) and high arsenic removal (96 to 97 %) was achieved after 2 hours. Overall, this research, for the first time, provides data on arsenic exposure in water and the relationship with levels in human samples from several regions of Argentina. Furthermore, this study has evaluated a wide range of biological sample types with regards to the potential link between arsenic and type-2 diabetes and has found no conclusive evidence that the arsenic levels represent cause and effect.

This thesis describes part of an on-going study of the metabolism of arsenosugars in sheep living on a diet of seaweed.  Two major analytical techniques have been combined in a three-pronged approach.  ICP-MS has served to quantify total arsenic in seaweed, urine and faeces and has enabled a mass balance to be drawn up indicating that around 86% of ingested arsenic (average 35 mg/d) is excreted in the urine, 13% in the faeces and less than 1% is accumulated in the animal. HPLC-ICP-MS has served to quantify both known and unknown metabolites at down to low ng/g levels in urine and in faeces, though they are often present in <span style='font-family:Symbol'>mg/g levels in the undiluted samples.  Seaweed fed to the sheep, <i>Laminaria digitata</i> and <i>L. hyperborea</i>, contained arsenic mainly (70%) as arsenosugars, a little (2%) as dimethylarsinic acid, DMA(V), and the remainder was inextractable.  The principal metabolite seen in the urine and in the faeces was DMA(V).  A major problem in these studies has been the low recovery of the chromatography, which has the consequence that the speciation must be considered thus far as incomplete.  The chromatographic recoveries, form urine samples alone, have ranged from 4 to 100%. Coupling of ICP-MS and electrospray MS (ES-MS) simultaneously to the outlet of the same HPLC column has permitted the identities of several new compounds to be established.  DMAA (dimethylarsinoyl acetic acid) has been found as an arsenosugar metabolite in urine for the first time.  The simultaneous coupling was crucial because DMAA co-elutes with methylarsonic acid (MA(V)) from the commonly used PRP-X100 strong anion-exchange column and without the use of a molecular detector it would have been misidentified. A new class of compounds has been identified in the urine samples by ES-MS, in which arsenic in its pentavalent state is bound to sulfur.  Dimethylarsinothioic acid (DMAS) has been positively identified by retention time and by molecular mass.  It turns out to have apparently the same retention time as a DMA(III) standard.

Arsenic is a universal environmental toxicant associated mostly with skin related diseases in people exposed to low doses over a long term. Low dose arsenic trioxide (ATO) with long exposure will lead to chronic exposure. Experiments were performed to provide new knowledge on the incompletely understood mechanisms of action of chronic low dose inorganic arsenic in keratinocytes. Cytotoxicity patterns of ATO on long-term cultures of HaCaT cells on collagen IV was studied over a time course of 14 days. DNA damage was also assessed. The percentages of viable cells after exposure were measured on Day 2, Day 5, Day 8, and Day 14. Statistical and visual analytics approaches were used for data analysis. In the result, a biphasic toxicity response was observed at a 5 μg/ml dose with cell viability peaking on Day 8 in both chronic and acute exposures. Furthermore, a low dose of 1 μg/ml ATO enhanced HaCaT keratinocyte proliferation but also caused DNA damage. Global gene expression study using microarray technique demonstrated differential expressions of genes in HaCaT cell exposed to 0.5 μg/ml dose of ATO up to 22 passages. Four of the up-regulated and 1 down-regulated genes were selected and confirmed with qRT-PCR technique. These include; Aldo-Keto Reductase family 1, member C3 (AKR1C3), Insulin Growth Factor-Like family member 1 (IGFL1), Interleukin 1 Receptor, type 2 (IL1R2) and Tumour Necrosis Factor [ligand] Super-Family, member 18 (TNFSF18), and down-regulated Regulator of G-protein Signalling 2 (RGS2). The decline in growth inhibiting gene (RGS2) and increase in AKR1C3 may be the contributory path to chronic inflammation leading to metaplasia. This pathway is proposed to be a mechanism leading to carcinogenesis in skin keratinocytes. The observed over expression of IGFL1 may be a means of triggering carcinogenesis in HaCaT keratinocytes. In conclusion, it was established that at very low doses, arsenic is genotoxic and induces aberrations in gene expression though it may appear to enhance cell proliferation. The expression of two genes encoding membrane proteins IL1R2 and TNFSF18 may serve as possible biomarkers of skin keratinocytes intoxication due to arsenic exposure. This research provides insights into previously unknown gene markers that may explain the mechanisms of arsenic-induced dermal disorders including skin cancer / Environmental Sciences / D. Phil. (Environmental science)

L'arsenic est un élément présent dans tous les compartiments de l'environnement, et les produits de la pêche représentent une source majeure d'exposition à l'arsenic par le biais de l'alimentation. Même s'il n'existe pas à ce jour de législation sur les teneurs en arsenic dans les aliments en France, les agences gouvernementales évaluent généralement les risques liés à la présence d'arsenic dans les produits de la pêche en se basant essentiellement sur la concentration totale de l'élément, sans tenir compte des différentes espèces présentes ni de leur bioaccessibilité. Par conséquent, le développement de méthodes d'analyse de spéciation revêt un intérêt particulier dans le cadre de l'évaluation des risques. La première partie de ce mémoire présente des informations générales sur les propriétés de l'arsenic, son occurrence dans les différents compartiments de l'environnement et sa toxicité, ainsi qu'une étude bibliographique des méthodes analytiques existantes pour étudier la spéciation de l'arsenic dans les matrices alimentaires, en particulier les produits de la pêche (extraction et séparation/détection). Les différentes approches pour l'évaluation de sa bioaccessibilité et de celle d'autres éléments traces métalliques d'intérêt sont également présentées. La deuxième partie de ces travaux porte sur la validation d'une méthode d'analyse de spéciation des principales espèces d'arsenic dans les produits la pêche (As(III), MA,DMA, As(V), AsB, TMAO, AsC) par couplage entre la chromatographie d'échange d'ions (IEC) et la spectrométrie de masse à plasma induit (ICP-MS) après extraction assistée par micro-ondes (MAE). L'évaluation des performances analytiques de la méthode, les contrôles qualités internes et externes mis en place et les différentes applications, en particulier les données d'occurrence des différentes espèces d'arsenic dans les produits de la pêche les plus consommés par la population française sont présentés et discutés. Dans la troisième partie, la bioaccessibilité maximale de l'arsenic et d'autres éléments d'intérêt est estimée à l'aide d'une méthode de lixiviation en ligne (impliquant la mesure en temps réel par ICP-MS de la fraction libérée par les différents fluides digestifs artificiels). La combinaison de ce procédé avec la méthode d'analyse de spéciation validée permet ainsi d'estimer la bioaccessibilité des différentes espèces d'arsenic. / Arsenic is an element present in all compartments of the environment, and seafood constitutes a major source of exposure to arsenic through human consumption. Although there is currently no legislation on arsenic in food in France, government agencies generally assess the safety of food items based solely on the total concentration of the element, without taking into account its different species or their bioaccessibility. Therefore, the development of speciation analysis methods is particularly relevant in the context of risk assessment. The first part of this thesis focuses on the properties of arsenic, its occurrence in the different compartments of the environment and its toxicity, and a literature review of existing analytical methods to study the speciation of arsenic in food matrices, especially seafood products (extraction and separation / detection). Different approaches for evaluating its bioaccessibility and that of other trace metals of interest are also presented.The second part of this work concerns the validation of a speciation analysis method for major arsenic species in seafood (As (III), MA, DMA, As (V), AsB, TMAO, AsC) by coupling ion exchange chromatography (IEC) with inductively coupled plasma mass spectrometry (ICP-MS) after microwave-assisted extraction (MAE). Evaluation of the analytical performance of the method, internal and external quality controls in place and applications of the method, particularly occurrence data of arsenic species in seafood most consumed by the French population are presented and discussed. In the third part, the maximum bioaccessibility of arsenic and other elements of interest is assessed using a continuous leaching method (involving the real-time measurement by ICP-MS of the fraction released by the different artificial digestive fluids). By coupling this leaching method with the above validated speciation analysis method, the bioaccessibility of different arsenic species is also assessed.

Arsenic is a universal environmental toxicant associated mostly with skin related diseases in people exposed to low doses over a long term. Low dose arsenic trioxide (ATO) with long exposure will lead to chronic exposure. Experiments were performed to provide new knowledge on the incompletely understood mechanisms of action of chronic low dose inorganic arsenic in keratinocytes. Cytotoxicity patterns of ATO on long-term cultures of HaCaT cells on collagen IV was studied over a time course of 14 days. DNA damage was also assessed. The percentages of viable cells after exposure were measured on Day 2, Day 5, Day 8, and Day 14. Statistical and visual analytics approaches were used for data analysis. In the result, a biphasic toxicity response was observed at a 5 μg/ml dose with cell viability peaking on Day 8 in both chronic and acute exposures. Furthermore, a low dose of 1 μg/ml ATO enhanced HaCaT keratinocyte proliferation but also caused DNA damage. Global gene expression study using microarray technique demonstrated differential expressions of genes in HaCaT cell exposed to 0.5 μg/ml dose of ATO up to 22 passages. Four of the up-regulated and 1 down-regulated genes were selected and confirmed with qRT-PCR technique. These include; Aldo-Keto Reductase family 1, member C3 (AKR1C3), Insulin Growth Factor-Like family member 1 (IGFL1), Interleukin 1 Receptor, type 2 (IL1R2) and Tumour Necrosis Factor [ligand] Super-Family, member 18 (TNFSF18), and down-regulated Regulator of G-protein Signalling 2 (RGS2). The decline in growth inhibiting gene (RGS2) and increase in AKR1C3 may be the contributory path to chronic inflammation leading to metaplasia. This pathway is proposed to be a mechanism leading to carcinogenesis in skin keratinocytes. The observed over expression of IGFL1 may be a means of triggering carcinogenesis in HaCaT keratinocytes. In conclusion, it was established that at very low doses, arsenic is genotoxic and induces aberrations in gene expression though it may appear to enhance cell proliferation. The expression of two genes encoding membrane proteins IL1R2 and TNFSF18 may serve as possible biomarkers of skin keratinocytes intoxication due to arsenic exposure. This research provides insights into previously unknown gene markers that may explain the mechanisms of arsenic-induced dermal disorders including skin cancer / Environmental Sciences / D. Phil. (Environmental science)