Certaines espèces de phytoplanctons produisent des métabolites secondaires hautement toxiques appelés phycotoxines. Ces phycotoxines peuvent contaminer les fruits et mer et poser un risque sanitaire pour l'homme. Elles sont responsables d'effets néfastes chez l'homme et peuvent provoquer des diarrhées, des nausées et des douleurs abdominales. Pour améliorer l'évaluation du risque sanitaire lié à la présence de phycotoxines dans les coquillages, une meilleure caractérisation du potentiel toxique est indispensable. Aussi, l'objectif de ce doctorat a été d'étudier les effets cytotoxiques des phycotoxines lipophiles seules et en mélange à l'aide de nouvelles approches in vitro en toxicologie. Nos études ont montrées que si les analogues de l'acide okadaïque (AO) induisaient tous l'apoptose, la génotoxicité, l'inflammation cellulaire et la perturbation du cycle cellulaire, sur les lignées intestinales Caco-2 et HT29-MTX, ces effets se produisaient à des concentrations différentes en fonction des toxines. Ensuite, nos recherches sur la lignée hépatique humaine HepaRG ont montrées l'implication des enzymes de phase I dans le processus de détoxication de l'AO et de ses analogues les dinophysistoxines (DTX), et de la pectenotoxin-2 (PTX-2). Pour finir, l'utilisation de la méthode des index de combinaison pour l'étude de la toxicité des mélanges binaires de toxines sur des lignées intestinales a mis en évidence des effets synergiques du mélange Azaspiracide-1/ Yessotoxine. / Some species of phytoplankton produce highly toxic secondary metabolites called phycotoxins. Phycotoxins can contaminate seafood and pose a health risk to humans. They can cause several adverse effects in humans, including diarrhea, nausea and abdominal pain. To improve risk assessment associated with the presence of lipophilic phycotoxins in shellfish, a better characterization of the toxic potential is essential. The aim of this PhD was to study the cytotoxic effects of single and mixed lipophilic shellfish toxins using new approaches in in vitro toxicology. Our studies have shown that, analogs of okadaic acid (OA) induced apoptosis, genotoxicity, cellular inflammation and disturbance of the cell cycle, on intestinal cell lines Caco-2 and HT29-MTX, and that this effects occurred at different concentrations depending on the toxin. Then, our researches on human hepatic lineage HepaRG have shown the involvement of phase I enzymes in the detoxification of the pectenotoxin-2 (PTX-2), and OA and its analogues the dinophysistoxins (DTX). Finally, the use of the combination index method for studying the toxicity of binary mixtures of phycotoxins on intestinal cell lines showed synergistic effects of azaspiracid-1 / yessotoxin mixture.

Self-propagating High-temperature Synthesis (SHS) is the synthesis of solid materials by a reaction wave propagating into the initial reactants, typically two metals, which can alloy exothermically. Typically, experiments are performed with the reactants in powder form, with relatively low density. Recent experiments by Bacciochini et al. revealed much larger flame speeds in densified powders near TMD (theoritical maximum density), obtained by the cold spray process. The present thesis investigates why the flame speed increases dramatically with an increase in density of the powders. The investigation rests on the analytical model formulated by Makino by controlling how the variables are affected by changes in density. Flame speed measurements were performed in mixtures of nickel (Ni) and aluminum (Al) at different initial densities. The density was varied by controlling the cold-pressing of the samples inside metallic channels and tubes. Experiments were also performed in ball-milled powders, in order to permit comparison with the experiments performed by Bacciochini in these mixtures at nearly maximum densities. The measurements revealed that the flame speed increases with the initial density, with a discontinuous transition occurring at approximately 60% theoretical maximum density (TMD). This transition also corresponds to the point where the powders deform plastically during the compaction process, suggesting that the intimate contact between the particles is responsible for the flame speed increase. The flame speed dependence on powder density is attributed to the changes in the heat conductivity of the pressed powders. At high densities, where the powders have plastically deformed, the continuous structure yields conductivities close to the idealized solid matrix. At these high densities, the conductivity was modeled using the Effective Medium Theory (EMT). Analytical predictions of the flame speed, using available thermo-chemical data for the Al-Ni system were found in good agreement with the present experiments at high densities. At low densities, since Al-Ni is a mixture of loose powders, the EMT model is no longer applicable. Thus, the thermal conductivity was experimentally measured and then was fitted using the semi-empirical model suggested by Aivazov. Using this data, Makino's model predicts the correct flame speed dependence observed experimentally. The present thesis has thus established that the dependence of flame speed on density is due mainly to the changes in the structure and thermal conductivity of the powders.

Human exposures to polycyclic aromatic hydrocarbons (PAHs) occur as components of complex mixtures. Evaluations of health risks posed by complex mixtures containing PAHs rely on the toxicological knowledge of prioritized PAH mixture components, assuming that these PAHs share a common mode of action and that the sum of the contributions of these PAHs equals the toxic potency of the mixture (i.e., additivity). Traditional toxicity testing methods emphasizing apical endpoints have had limited success at evaluating the validity of these assumptions. Toxicogenomic tools that are able to rapidly generate toxicologically-relevant and mechanistic information have gained acceptance in the regulatory arena for individual chemicals; however, the applicability of these tools for chemical mixtures has been inadequately addressed. This thesis used toxicogenomic tools to (1) improve the understanding of mechanisms underlying the adverse, toxicological responses induced by individual PAHs and (2) evaluate the contention that transcriptional profiles and pathway information can be used to critically examine interactions between individual PAHs in PAH-containing mixtures, and the assumption of additivity. Microarrays were used to profile gene expression changes (transcriptomes) in forestomach, liver, and lung tissues (targets of PAH exposure) from mice orally exposed to three doses of eight individual PAHs, two defined PAH mixtures, and one complex PAH-containing mixture (coal tar). The results revealed that each PAH induced transcriptional changes that were significantly associated with several pathways implicated in carcinogenesis. However, despite a uniform ability to induce DNA damage (i.e., DNA adducts), mutations, and increases in enzyme activity, the pathways differ across PAHs and tissues. A novel strategy that employs single-PAH transcriptome data to models of additivity revealed that the assumption of additivity in PAH mixtures is valid at the pathway level; however, the independent action model of additivity yielded better estimates compared to concentration addition (used in human health risk assessment of PAH mixtures) or generalized concentration addition. Additionally, predicted and observed coal tar-induced transcriptional benchmark doses were comparable to those derived from previously published coal tar-induced murine lung tumour incidence data. Overall, this thesis demonstrates the utility of toxicogenomic data to expand the current understanding regarding the toxic potential of individual PAHs and PAH-containing complex mixtures.

Les expositions environnementales aux pesticides chez la femme enceinte sont une préoccupation de santé publique. L’association d’analyses métabolomiques par RMN chez l’Homme et l’animal a permis de tester l’utilité de cet outil dans l’étude des mélanges complexes. Les empreintes métaboliques proviennent des urines et du sang de cordon de plus de 300 femmes de la cohorte PELAGIE (Bretagne) et des urines, sang, foie et cerveaux de rates et de leurs fœtus exposés par voie orale durant la gestation à 8 pesticides représentatifs des expositions humaines. Une discrimination des profils métaboliques a été observée chez l’Homme en fonction de l’exposition estimée par la part de cultures de céréales dans la commune. Les modifications métaboliques suggèrent un mécanisme osmo-protecteur lié à un stress oxydant. Les données animales ont confirmé ces observations avec des modifications évoquant un dysfonctionnement mitochondrial. Les conséquences sanitaires associées restent à étudier. / Environmental exposure to pesticides is of growing interest in public health, especially in pregnant women. The combination of metabolomics analyses both in human and animal allows testing the utility of this tool in the study of complex mixtures and low-dose exposures. 1H NMR metabolic profiling was carried out on urinary samples collected at the first trimester of pregnancy and cord blood samples at birth for more than 300 women included in the PELAGIE cohort (Britany, France) and on urine, blood, liver and brain from rats and their fetuses orally exposed during the gestation to 8 pesticides representative of human exposures. Based on PLS-DA analyses, a good separation of the metabolic profiles was observed in human according to the percentage of area devoted to cereal crops in the town of residence. The metabolic modifications suggest an osmo-protective mechanism associated with an oxidative stress. Animal data confirmed this hypothesis with plasmatic, liver and brain metabolic changes suggesting a mitochondrial dysfunction. The associated health impacts are yet to be studied.

Previous thread rolling methods for the plastic limit are shown to be inadequate and inaccurate. Alternative methods for the plastic limit are shown to be imprecise and unreliable. The strength-based concept and use of the fall-cone test to determine the plastic limit are shown to be flawed. An apparatus that replicates Atterberg’s rolling technique, devised and developed by the author, is described, referred to as the Barnes Apparatus. A thread of soil is rolled between two plates configured to permit extrusion and reduction of diameter with much less operator interference than with the standard test and judgement of the crumbling condition is eliminated. Using a loading device nominal stresses are derived and from dial gauge readings diametral strains are determined for each rolling traverse of the soil thread. Toughness has previously only been studied in an empirical or qualitative manner. From plots of nominal stress vs. strain the workability or toughness of the plastic soil is determined as the work/unit volume. The apparatus and test are appropriate to a wide range of soils. Threads are tested over a range of water contents from near the sticky limit to the brittle state. Good correlations between toughness and water content display an abrupt ductile-brittle transition and give an accurate definition of the plastic limit. From the correlations useful properties are obtained such as the maximum toughness at the plastic limit, the toughness limit, the water content at zero toughness, the stiffness transition, the toughness coefficients, the toughness index and the workability index. An investigation into the significance of the soil thread diameter of 3 mm in the standard plastic limit test has found that as the water content of a soil reduces it undergoes a transition from fully plastic, to cracked, to brittle, largely regardless of the diameter of the thread. It is recommended that the 3 mm diameter requirement is withdrawn from the standard test procedure as unnecessary and emphasis placed on observing the behaviour of the soil thread as it is rolled by hand. A review of the relationship between the clay matrix and the granular particles in a soil has found that the linear law of mixtures and activity index are appropriate only at high clay contents. The terms granular spacing ratio and matrix porosity are introduced to explain the effect of the granular particles on the toughness and plastic limit. An analysis confirms that with small diameter soil threads large granular particles affect the results disproportionately. An aggregation ratio term is introduced to explain the change in toughness in the clay matrix as its water content reduces towards the plastic limit. To assess the effect of granular particles in a clay matrix on the toughness and plastic limit the results of tests conducted on mixtures of a high plasticity clay and silt, and sand particles of two different sizes are discussed. Smaller particle sizes are found to have a greater effect on reducing the toughness and the plastic limit of the clay. In the ceramics industry mixing different clays together to obtain suitable properties is common. The toughness and plastic limits of two pairs of mixed clays do not follow the linear law of mixtures but are dependent on the total clay content and the content of a dominant clay mineral.

Além do interesse intrínseco pelos seus aspectos mecanísticos, as reações de hidrólise de compostos carbonílicos apresentam também a interessante particularidade da reação pelo próprio solvente, a água. Dentre estas reações, conhecidas como \"reações de água\" (Robertson, 1967; Johnson, 1967), estudou-se neste trabalho a hidrólise de carbonatos, através do cálculo das energias de transferência da fase gasosa para o solvente, de reagentes (R), estado de transição (ET) e produtos (P). O estudo da solvatação de modelos moleculares para R e ET indica uma correlação entre reatividade e estrutura molecular. Os resultados usando o enfoque de \"super-molécula\" mostram maior concordância com os dados experimentais do que o cálculo de solvatação da molécula simples e indicam que a solvatação dos modelos de ET é mais eficiente que para R e, portanto, há um aumento da reatividade. O estudo mais detalhado das estruturas de R, ET e P, em misturas água/acetonitrila para carbonatos de difenila e bis(2,4-dinitrofenila), sugere a existência de duas ligações de hidrogênio: entre o oxigênio da água do \"cluster\" e um dos hidrogênios dos anéis aromáticos (CF e CDNF), e entre o hidrogênio da água e o oxigênio do grupo nitro do outro anel aromático (CDNF). A consequente diminuição da liberdade conformacional em relação à fase gasosa, provocada por estas ligações de hidrogênio (CF e CDNF), expõe um dos hemisférios da carbonila ao ataque da água, provocando então uma aceleração entrópica do processo. Os efeitos eletrônicos, devidos às ligações de hidrogênio, estão de acordo com a maior acidez esperada dos hidrogênios dos anéis do CDNF em relação ao CF. Também mostram uma compensação no CDNF, pouco contribuindo para alterar a densidade eletrônica no seu carbono carbonílico, enquanto que indica uma soma de efeitos no CF, contribuindo então para um aumento desta densidade eletrônica no CF, de acordo com sua conhecida baixa reatividade. O trabalho permite ainda concluir sobre o relativo sucesso do uso de método semi-empírico PM3 e modelo relativamente simples de solvatação (Cramer & Truhlar, 1991), para o cálculo de energia de transferência em misturas de água/acetonitrila, na faixa de fração molar da água (0,40 a 1,00) onde o método apresenta resultados concordantes com os valores experimentais. / In addition to their intrinsic mechanistic interest, hydrolysis reactions of carbonyl compounds in aqueous media exhibit the interesting peculiarity of direct reaction with the solvent itself, i.e., water. In the present work, we have investigated a representative example of one of these \"water reactions\" (Robertson, 1967; Johnson, 1967), the hydrolysis of carbonates, via quantum chemical ca1culation of the free energies of transfer of the reagents (R), the transition state (TS) and the products (P) from the gas phase to water. A model study of the solvation of R and TS points to a correlation between reactivity and molecular structure. Results using the \"super-molecule\" approach show greater agreement with experiment than solvation ca1culations on the isolated molecule and imply that the solvation of the TS is more effective than that of R in increasing reactivity. A more detailed study of the structures of R, TS and P for diphenyl- (DPC) and bis(2,4-dinitrophenyl)carbonates (DNPC) in acetonitrile/water mixtures suggests the existence of two possible types of hydrogen bonds, i.e., between oxygen of the water c1uster and an aromatic ring hydrogen (DPC and DNPC) or, in the case of DNPC, between the protons of water and the oxygens of the nitro group of the second aromatic ring. The decrease in conformational degrees of freedom reI ative to the gas phase provoked by these hydrogen bonds exposes one of the hemispheres of the carbonyl group to attack by water, resulting in an entropic acceleration of the reaction. The electronic effects on the hydrogen bonds are in line with the greater acidity of the aromatic ring hydrogens of DNPC relative to those of DNP. In DNPC, there is a compensation effect, with very little alteration of the electron density on the carbonyl carbon, while in DPC a sum of effects increases the electron density on the carbonyl carbon, in line with the known lower reactivity of the latter. This work points to the relative success of the semi-empirical PM3 method combined with relatively simple solvation models (Cramer & Truhlar, 1991) for ca1culating free energies of transfer involving acetonitrile/water mixtures in the water mole fraction range from 0.40-1.00.

<div>Nitrous oxide (N₂O) has gained popularity as a unique oxidizer due to its ability to decompose exothermically, producing nitrogen and oxygen. Additionally, there are concerns about the safety of nitrous oxide in the nuclear industry where it has been observed that stored nuclear waste generates and retains large amounts of flammable</div><div>gases such as hydrogen and ammonia along with nitrous oxide. These gases are at risk of explosion even in the presence of a weak ignition source which can result in detonations more violent than those initiated directly. Nitrous oxide is also finding an application in the geothermal industry where it is being tested in combination with ethylene as a stimulant mixture to fracture rock. The detonations initiated in this mixture have the ability to produced a network of fractures in the rock formation. In the rocket industry, nitrous oxide has been used for propulsion in multiple systems, but never in a detonative mode. In order to use nitrous oxide in these areas, its detonation properties in combination with a fuel require quantification. Available literature on nitrous oxide-hydrocarbon detonations is mainly restricted to initial pressures below one atm or with dilution. Therefore, detonations with nitrous oxide as the oxidizer are far from being completely characterized. In addition to this lack of general knowledge, understanding of nitrous oxide-fuel detonations at higher pressures, more typical of practical combustion systems is either extremely limited or</div><div>non-existent.</div><div><br></div><div>In the current work, the flame acceleration, deflagration-to-detonation transition (DDT), and detonation properties of a bipropellant mixture of ethylene (C₂H₄) and N₂O are studied as a function of initial pressures. These properties are compared to those in mixtures of ethylene-oxygen (O₂). these detonations are investigated in a combustion tube designed and fabricated in-house. The performances of these two mixtures are also investigated using theoretical Chapman-Jouguet detonation calculations as a basis of comparison with the measured properties. Additionally, detonation properties in a mixture of acetylene (C₂H₂) and nitrous oxide are also investigated to compare the two fuels. While C₂H₂ is a highly energetic fuel with theoretically high performance, it presents serious practical storage concerns when considered for propulsion applications. These practical issues motivates the investigation of C₂H₄as a potential alternative fuel, which is relatively easy to manage. </div><div><br></div><div>A critical requirement for the application of bipropellant mixtures to detonation systems is rapid flame acceleration to achieve significant chamber pressure rise in a short distance with the potential for a prompt transition to detonation. This DDT behavior of mixtures using N₂O and O₂ with C₂H₄ and C₂H₂ is investigated for increasing initial pressures in the experimental portion of this work. This behavior is quantified by measuring the run-up distances leading to DDT. The pre-compression of the bipropellant mixtures during flame acceleration caused by the accelerating flame is also estimated and directly measured using appropriate instrumentation. These direct measurements of pre-compression are further used to estimate the path of the</div><div>accelerating flame in the combustion tube. These estimates are compared with the flame tracked by high-speed imaging in an optically accessible combustion tube.</div>

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The key results of this thesis are (1) an extension of N-mixture models to incorporate the additional layer of obfuscation brought by observing counts from a related auxiliary population (rather than the target population), (2) an extension of N-mixture models to allow for grouped counts, the purpose being two-fold: to extend the applicability of N-mixtures to larger population sizes, and to allow for the use of coarse counts in fitting N-mixture models, (3) a new R package allowing the easy application of the new N-mixture models, (4) a new R package allowing for optimization of multi-parameter functions using arbitrary precision arithmetic, which was a necessary tool for optimization of the likelihood in large population abundance N-mixture models, as well as (5) simulation studies validating the new grouped count models and comparing them to the classic N-mixtures models. / Graduate

Mass transfer in a porous solid, partially saturated with asingle solvent and multicomponent liquid mixtures, has beenexperimentally and theoretically studied. A porous materialcontaining single liquids and mixtures of organic solvents wasisothermally dried. Experiments were performed using a jacketedwind tunnel, through which a humidity andtemperature-controlled air stream flowed. The wetted porousmaterial was placed in a cylindrical vessel, whose top isexposed to the air stream until the material became dried to acertain extent. Drying experiments with the single solventswater, methanol, ethanol and 2-propanol, were performed atdifferent temperatures and transient liquid content profileswere determined. In isothermal drying experiments with liquidmixtures,the transient concentration profiles of thecomponents along the cylindrical sample as well as the totalliquid content were determined. The liquid mixtures examinedwere water-methanolethanol and isopropanol-methanol-ethanol.Two different temperatures and initial compositions were usedin the experiments. Mathematical models that describe nonsteadystate isothermal drying of a solid containing single liquidsand multicomponent liquid mixtures were developed. In the solidwetted with a single liquid, capillary movement of the liquidwas the main mechanism responsible for mass transfer. In thesolid containing liquid mixtures, interactive diffusion inliquid phase was superimposed to the capillary movement of theliquid mixture. In addition, interactive diffusion of thevapours in empty pores was considered. The parameters todescribe the retention properties of the solid and thecapillary movement of the liquid were determined by comparingtheoretical and experimental liquid content profiles obtainedduring drying of the solid wetted with single liquids. Tosimulate the transport of the liquid mixtures these parameterswhere weighed according to liquid composition. A fairly goodagreement between theoretical and experimental liquidcomposition profiles was obtained if axial dispersion isincluded in the model when the moisture consists of amixture. Keywords:Internal mass transfer, capillary flow,multicomponent, diffusion, solvent mixtures