Afin d’améliorer au mieux le greffon placentaire, nous suggérons de réaliser sa culture d’expansion ex vivo dans des conditions proches de l’environnement des cellules souches hématopoïétiques in vivo. Ainsi, nous proposons que la co-culture de cellules CD34+ placentaires avec des cellules stromales mésenchymateuses (CSM) à basses concentrations d’O2 (BC-O2) pourrait contribuer à équilibrer les processus d’autorenouvellement et de différenciation afin d’obtenir un greffon optimisé. Sur le plan fonctionnel, nos résultats confirment un effet bénéfique de notre modèle expérimental par rapport aux conditions où figure la culture simple et/ou l’oxygénation atmosphérique (20%) en termes du maintien de progéniteurs (PH) primitifs (pré-CFC) et de cellules souches Scid-Repopulating Cells (SRC). Sur le plan quantitatif, l’amplification des cellules CD34+ et des PH engagés, bien qu’elle soit en retrait dans nos conditions de référence par rapport à la condition de 20% d’O2, elle demeure néanmoins importante. Par ailleurs, le rôle de l’IL-3 exogène se montre crucial à BC-O2 notamment en co-culture à 1,5% d’O2 où elle permet non seulement de préserver mais aussi d’amplifier le taux de SRC par rapport au témoin de cellules CD34+ de J0. Enfin, l’étude de la sécrétion des facteurs solubles et l’expression des marqueurs phénotypiques sur les CSM montre que l’IL-6, le VEGF et l’IL-8 sont plus sécrétés et les CD146, CD49a, CD54, CD200 et CD105 sont plus exprimés après incubation à 5% d’O2. Cependant, l’implication réelle de ces facteurs et antigènes dans l’effet paracrine et/ou de contact cellulaire direct menés par les CSM dans notre protocole requiert de nouvelles investigations / To optimize at best the hematopoietic engraftment, we suggest in this work to improve the ex vivo expansion conditions by moving them closer to physiology. Indeed, we propose to culture placental CD34+ (HSC/PH) on MSC layer in combination with LO2-C to ensure the amplification of HP together with the maintenance/expansion of HSC. Compared to the single culture and/or atmospheric oxygenation, our experimental model allows a better maintenance of primitive HP (Pre-CFC) and HSC together with a quite good amplification of total cells, CD34+ cells and committed HP despite of lower than control condition. Moreover, exogenous IL-3 shows crucial effect in co-culture at LO2-C (1.5% O2) since its addition better preserves and even increases the number of HSC compared to the CD34+ cells control from D0. We then studied the secretion of soluble factors in culture supernatants and found that IL-6, VEGF and IL-8 were present in larger quantities at LO2-C in both co-culture and MSC culture. Finally, the CD146, CD49a, CD54, CD200 and CD105 membrane antigens appear to be up-regulated in MSCs when incubated at 5% O2. However, the involvement of these factors and antigens in paracrine effect and/or direct cell to cell contact mechanisms at LO2-C requires further investigations. In conclusion, the combination of LO2-C and MSC would be promising in the field of HSC/PH grafts expansion to achieve its main objective of reducing the post-transplant cytopenia period together with maintaining the long-term graft potential

La pharmacogénomique (PGx) étudie le concept selon lequel les déterminants génétiques peuvent aider à prédire la réponse clinique d’un patient aux médicaments. Les concentrations plasmatiques de ces derniers sont essentielles pour déterminer l’exposition, les profils pharmacocinétiques (PK), les effets cliniques et éventuellement les doses des médicaments, dont la plupart sont métabolisés par des enzymes hépatiques, les cytochromes P450 (CYPs). Néanmoins, la plupart des découvertes en matière de PGx concernant la prédiction des profils de concentrations des médicaments ont généralement recours à des plans d’études PK traditionnels avec une approche fonctionnelle. Bien qu’utile, cette méthodologie comporte des limites pour les études PGx, notamment le nombre restreint de sujets inclus, qui réduit la puissance statistique des associations PGx et limite l’identification de nouveaux variants génétiques moins fréquents. À l’inverse, les grandes cohortes observationnelles sont largement utilisées pour identifier des marqueurs génétiques physiopathologiques. Cette thèse de doctorat visait donc à 1) synthétiser les données publiées concernant les effets cliniques des polymorphismes génétiques de l’enzyme CYP2D6 sur le traitement au métoprolol, un agent β-bloquant. Les concentrations plasmatiques de métoprolol ont montré à plusieurs reprises qu’elles étaient fortement influencées par la PGx du CYP2D6; 2) développer une nouvelle méthode bioanalytique capable de quantifier les concentrations chirales de métoprolol des patients dans un contexte clinique; 3) mener une étude clinique en utilisant une grande cohorte observationnelle, ou biobanque, comme preuve de concept pour recréer l’association précédemment établie entre les phénotypes inférés des génotypes du CYP2D6 et les concentrations plasmatiques de métoprolol. Ces projets sont présentés en tant que chapitres de thèse et sous forme de manuscrits publiés. Le premier projet consistait en une revue systématique qui a permis d’extraire toutes les études relatives à la PGx du métoprolol-CYP2D6. La synthèse qualitative a suggéré que les métaboliseurs lents du CYP2D6, dépourvus de capacité enzymatique, avaient des valeurs plus élevées concernant les réductions de la fréquence cardiaque et de tension artérielle, ainsi que la survenue d’épisodes bradycardiques relativement aux autres phénotypes. Une méta-analyse ultérieure a confirmé la significativité de ces associations. Le deuxième projet a combiné des techniques bioanalytiques telles que la dérivation, l’extraction en phase solide et la chromatographie liquide avec spectrométrie de masse en tandem. Une méthode permettant de surmonter les limites analytiques antérieures a été validée avec succès pour mesurer les concentrations plasmatiques de (S)-métoprolol, l’énantiomère pharmacologiquement actif, et de son métabolite spécifique au CYP2D6. L’applicabilité d’une telle méthode a ensuite été démontrée grâce aux échantillons d’un groupe de patients issus de la Cohorte Hospitalière de l’Institut de Cardiologie de Montréal (ICM). Puis, le troisième projet présente la réalisation de l’étude LEVEL-PGx (LEVEraging Large observational cohort studies to identify pharmacogenetic determinants of drug dosing : A proof-of-concept study in the Montreal Heart Institute Hospital Cohort). L’étude portait sur un échantillon de >1000 patients sélectionnés dans la cohorte hospitalière de l’ICM, incluant leur génotypage pour CYP2D6 et la quantification du métoprolol racémique et de son métabolite spécifique au CYP2D6 dans des échantillons provenant de la Biobanque de l’ICM. Un seul échantillon unique et aléatoire par patient a été utilisé. Le recours à des modèles multivariables a validé le concept selon lequel de grandes cohortes transversales recueillant des échantillons biologiques pouvaient être utilisées afin d’identifier des associations PGx de concentrations de médicaments et ce, à des valeurs satisfaisant les seuils de significativité d’essais pangénomiques. D’autres analyses de cette cohorte ont indiqué que cette méthodologie parvenait à identifier des associations PGx qui influençaient la fréquence cardiaque au repos et la posologie du métoprolol à-travers les phénotypes du CYP2D6 et pour les déterminants génétiques uniques, même en présence de co-médications. Cependant, ces associations PGx avec les paramètres cliniques n’ont pas atteint une significativité applicable aux seuils pangénomiques. En résumé, par la reproduction d’une association PGx préalablement démontrée, l’ensemble des travaux présentés dans cette thèse suggère que l’identification et la découverte de nouveaux déterminants génétiques prédictifs des concentrations et des doses des médicaments pourrait s’effectuer par le biais de grandes cohortes observationnelles à l’échelle du génome. Ces approches permettraient de développer des modèles prédictifs plus précis de l’exposition et de la réponse aux médicaments, ce qui pourrait favoriser les découvertes PGx et, dans certains cas, éventuellement développer le potentiel translationnel d’une approche thérapeutique personnalisée selon le profil génétique des patients. / Pharmacogenomics (PGx) studies the concept that genetic determinants can help predict a patient’s clinical response to therapies. Drug concentrations are an essential component to determining the exposure, pharmacokinetic (PK) profiles, clinical effects, and potentially drug doses, most of which are metabolized through the cytochrome P450 (CYPs) liver enzymes. Nevertheless, most PGx discoveries regarding the prediction of drug concentration profiles have generally resorted to traditional PK study designs with a functional approach. Though useful, this methodology contains limitations for gene-drug interaction studies, most notably the restricted number of subjects included, which reduces the statistical power for PGx associations and limits the identification of new, less frequent genetic variants. On the opposite, large observational cohorts have long been utilized for identifying genetic markers of disease. This doctoral thesis therefore aimed to 1) synthesize published data regarding the clinical effects of CYP2D6 genetic polymorphism on metoprolol therapy. A β-blocker, metoprolol plasma concentrations have shown repeatedly to be heavily influenced by the PGx of the CYP2D6 enzyme; 2) develop a new bioanalytical method able to quantify patients’ chiral concentrations of metoprolol in a clinical setting; 3) conduct a clinical study using a large observational cohort, or biobank, as a proof of concept to recreate the previously established association between CYP2D6 genotype-inferred phenotypes and metoprolol plasma concentrations. Those projects are presented as thesis chapters in the form of published manuscripts. The first project was a systematic review that allowed us to find all studies pertaining to the PGx of metoprolol. The qualitative synthesis suggested that CYP2D6 poor metabolizers (PMs), without enzymatic capacity, had greater values regarding reductions in heart rate, blood pressures, and occurrences in bradycardia relative to non-PMs. A subsequent meta-analysis confirmed the significance of those associations. The second project combined bioanalytical techniques such as derivatization, solid phase extraction, and liquid chromatography-tandem mass spectrometry. A method overcoming previous analytical shortcomings was successfully validated to measure (S)-metoprolol plasma concentrations and its CYP2D6-specific metabolite. Its application was later demonstrated in a group of patients from the Montreal Heart Institute (MHI) Hospital Cohort. Then, the third project presents the conduct of the LEVEL-PGx study (LEVEraging Large observational cohort studies to identify pharmacogenetic determinants of drug dosing: A proof-of-concept study in the Montreal Heart Institute Hospital Cohort). The study implicated a sample of >1000 selected patients selected from the MHI Hospital Cohort, along with the genotyping of CYP2D6, and the quantification of racemic metoprolol and its CYP2D6-specific metabolite in samples from the MHI Biobank. A single, random sample per patient was used. Multivariable modeling validated the concept that large observational cohorts collecting biospecimens could be utilized to identify PGx associations of drug concentrations with genome-wide significance. Further analyses in our cohort indicated that the tested PGx associations influenced resting heart rate and metoprolol daily drug dosage across CYP2D6 phenotypes and for single genetic determinants, regardless of interfering comedications. However, such PGx associations with clinical parameters could not achieve genome-wide significance. In summary, the body of work presented in this thesis suggested that, using a previously validated PGx association, the identification of novel genetic determinants predictive of drug concentrations and dosage could be discovered and identified at the genome-wide level with large observational cohorts. These approaches would help develop more accurate predictive models of drug exposure and response, which could favor PGx discoveries and the translational potential of a personalized approach to treatments according to a patient’s genetic profile.

Most known drug targets and metabolizing enzymes are located inside cells. Interactions with these proteins are determined by intracellular unbound drug concentrations. Assessing intracellular drug exposure is technically challenging, but essential for predicting pharmacokinetic, pharmacological, and toxicological profiles of new drugs. This thesis aims at establishing and applying a straightforward methodology to measure intracellular unbound drug concentrations. This was achieved by separately measuring cellular drug binding (fu,cell), and total intracellular drug accumulation (Kp). This allowed the calculation of intracellular drug bioavailability (Fic), which represents the fraction of the concentration added to the cells that is unbound in the cell interior. The methodology was initially developed in HEK293 cells, where the Fic of 189 drug-like compounds was measured. Binding to HEK293 cells was governed by compound lipophilicity and was correlated with binding to more complex systems, such as hepatocytes and brain. Due to negligible expression of drug transporters, Fic in this cell line was consistent with pH-dependent subcellular sequestration of lipophilic cations in low pH compartments. The methodology was then applied to study the effects of drug transporters on Fic. The uptake transporter OATP1B1 increased the Fic of its substrates in a concentration-dependent manner. In contrast, the Fic of P-gp substrates was decreased when P-gp was present. In human hepatocytes, the methodology allowed the determination of Fic without prior knowledge of transporter mechanisms or metabolic activity. Finally, the methodology was applied to measure the impact of Fic on target binding and cellular drug response. Intracellular concentrations of active metabolites of pro-drugs targeting the intracellular target thymidylate synthase were in agreement with the level of binding to this target. Further, high Fic was generally required for kinase and protease inhibitors to be active in cellular assays. In conclusion, the methodology can be used to predict if new drug candidates reach their intracellular targets in sufficient amounts. Furthermore, the methodology can improve in vitro predictions of drug clearance and drug-drug interactions, by measuring the drug available for intracellular enzymes. Finally, this work can be expanded to other xenobiotics, e.g., to predict their intracellular toxicity.

This thesis describes the optimization process for the pitchfork developed by the company Sverigegrepen. The work was done at the department of Applied Mechanics at Uppsala University. The project were handed by Ångström Materials Academy together with Sverigegrepen The work included a major prestudy of plastic construction, plastic materials, plastic injection and strength of materials. By applying the laws of beam theory, a mathematical expression could be provided, explaining the behaviour of the pitchforks teeth. By studying the pitchfork with tools such as 3D- CAD and FEA-simulations, an area where high concentrations of stress were found, an area known to have frequent issues with strength. From this data several concepts were created with an increased strength and a better distribution of stress. The plastic material was evaluated and tested to find the most valuable material characteristics. The provided information was used to isolate different functions in plastic materials, which is crucial for the pitchforks further functionality.

Mammalian estrogens and estrogen-like compounds known as xeno-estrogens are being found in and excreted into the environment in ever increasing amounts. The xeno-estrogen DDE has been found at high concentrations of 1-5 mg/kg of soil (Aislabie et. al, 1997). These estrogens and xeno-estrogens are having a devastating effect on animal-life, yet little is known or understood on the effects of estrogens on plant-life. Thus it is important to determine what effects (if any) estrogens may have on plants. Other research has shown that estrogen has an effect on plants grown in vitro (Janeczko and Skoczowski, 2005). This research aims to help increase the amount of information on what effects estrogens may have on plants. In this study, the effects of mammalian estrogens (17-β-estradiol, estrone and estriol) on the growth and tuberization of potato plants (Solanum tuberosum L. cv 'Iwa') grown in liquid tissue culture medium are presented. It was found that at even 0.1 mg/L of estrogen, root growth of the plants was diminished and at 10 mg/L of estrogen, plant deformity was apparent and callus growth induced. Acid phosphatase activity of the plants was increased with the addition of 0.1 mg/L and 1 mg/L of estrogen but then decreased with the addition of 10 mg/L of estrogen. Tuber production was slightly reduced in plants treated with estrogen compared to the control.

SIMS est une technique d'analyse sensible de la surface. La probabilité d'ionisation dépend de l'état chimique de la surface. La génération des ions positifs est améliorée par le bombardement de la surface avec des éléments électronégatifs.Sur le NanoSIMS 50 de CAMECA, dont la configuration optique nécessite une polarité opposée entre ions primaires et secondaires, l'analyse des ions positifs se fait sous bombardement d'ions O-, générés dans un duoplasmatron. La faible brillance de la source en mode O- a comme conséquence une faible résolution latérale des analyses. Pour y remédier, nous avons étudié la possibilité de générer d’autres faisceaux d’ions primaires négatifs. Dans cet objectif, nous avons étudié la génération par duoplasmatron d'ions F-, Cl-, Br- et I- en fonction du champ magnétique, du courant d'arc et de la pression totale des gaz. Le courant d'ions et le diamètre du faisceau ont été mesurés afin de déterminer la brillance de la source en mode F-, Cl-, Br- et I-. Une brillance 5 fois plus élevée en mode F- qu'en mode O- a été déterminée.En utilisant les faisceaux F-, Cl-, Br- et I-, le rendement de pulvérisation, la concentration d'ions primaires implantés et le rendement utile ont été mesurés pour des semi-conducteurs et des métaux. Suite à une faible concentration en halogène à la surface des semi-conducteurs, résultant des processus de décapage, le rendement utile sous bombardement halogène était plus faible que sous bombardement O-. Pour les métaux (p.ex. Ni, Cu et Ag) par contre, une amélioration du rendement utile sous bombardement halogène jusqu'à deux ordres de grandeurs, comparé au bombardement O-, a été mesurée / Secondary Ion Mass spectrometry (SIMS) is a powerful surface analysis technique. The ionisation probability strongly depends on the chemical surface state. The generation of positive secondary ions can be enhanced by surface bombardment with electronegative elements.Due to the optical configuration of the CAMECA NanoSIMS 50, that necessitates an opposite polarity of incoming and ejected ions, analyses of positive ions are realized with primary O- ions, generated in a duoplasmatron ion source. As a consequence of the low O- brightness of the duoplasmatron source, the lateral resolution of the analyses on the NanoSIMS 50 is not satisfactory in the positive secondary mode. In this work, we studied the feasibility of different alternative negative primary ion beams. We investigated the possibility of F-, Cl-, Br- and I- ion generation with a duoplasmatron as a function of the source parameters, notably the magnetic field strength, the arc current and the total gas pressure. The ion current and the beam diameter were measured in order to determine the F-, Cl-, Br- and I- brightness of the source. A comparative study with the O- brightness demonstrates an increase of the F- brightness by a factor of 5.By using the F-, Cl-, Br- and I- bombardment, the sputtering yield, the concentration of implanted primary ions and the useful yield of different semi-conductor and metal samples were analysed. As a consequence of a low halogen concentration, related to etching effects, no enhancement of the useful yield could be noticed for the semi-conductors. For metals however (e.g. Ni, Cu and Ag), useful yield enhancements by up to a factor of 100 compared to the O- bombardment could be demonstrated

<p>U okviru ove doktorske disertacije autor već duže vreme radi&nbsp;na razvijanju i primeni niskofonske gama-spektrometrije na&nbsp;određivanju sadržaja uranijuma i ostalih radionuklida gama&nbsp;emitera u uzorcima zemlji&scaron;ta i sedimenta, kao i na praćenju&nbsp;<br />njihove distribucije i korelacije &scaron;to je od značaja za mapiranje&nbsp;radioaktivnosti poljoprivrednog zemlji&scaron;ta. Pored toga&nbsp;doktorant se bavi proučavanjem ravnoteže u radioaktivnim&nbsp;nizovima uranijuma i torijuma, čiji gasoviti produkti radon&nbsp;²²²Rn i toron&nbsp;²²⁰Rn kao inertni gasovi difuzijom napu&scaron;taju&nbsp;mesto generisanja i na taj način obrazuju značajne&nbsp;koncentracije u zatvorenim prostorima, &scaron;to predstavlja veliki&nbsp;<br />problem za niskofonske podzemne laboratorije i radijacioni&nbsp;rizik izloženog stanovni&scaron;tva. U sklopu ovih istraživanja&nbsp;razvijen je i egzaktan matematički model za određivanje&nbsp;<br />faktora ravnoteže između radona i torona i njihovih&nbsp;kratkoživećih produkata. Dobijeni rezultati će se koristiti za&nbsp;testiranje postojećih metoda merenja radona razvijenih u&nbsp;<br />laboratoriji i primenu za merenje koncentracije aktivnosti&nbsp;radona u urbanim sredinama. Ujedno proučavanje ovih pojava&nbsp;i iznalaženje korekcija na raspad može imati primenu i u&nbsp;drugim nuklearnim analitičkim tehnikama kod kojih je period&nbsp;poluraspada mete uporediv sa vremenom merenja.</p> / <p>In this dissertation the author has been working on the&nbsp;development and application of low-level gamma spectrometry&nbsp;method to determine the content of uranium and other&nbsp;radionuclides gamma emitters in soil and sediment, as well as&nbsp;monitoring their distribution and correlation which is important&nbsp;to map the radioactivity of agricultural soil. In addition, author&nbsp;studies the equilibrium in the radioactive series of &nbsp;uranium and&nbsp;thorium, which gaseous products radon&nbsp;²²²Rn and thoron&nbsp;²²⁰Rn as inert gases leave the place of origin by diffusion and&nbsp;thus forming significant concentrations indoors, which is a&nbsp;significant problem for the low-level underground laboratories&nbsp;and population radiation risk. As part of this research an exact&nbsp;model for the determination of radon and thoron equilibrium&nbsp;was developed. The results will be used to test existing&nbsp;methods of measuring radon developed in the laboratory and&nbsp;the application of the measurement of radon activity&nbsp;concentration in urban areas. At the same time the study of&nbsp;these phenomena and decay corrections may have application&nbsp;in other nuclear analytical techniques in which the half-life of&nbsp;the target is comparable with the time of measurement.</p>

Objetivo Avaliar o perfil da exposição ocupacional a agentes químicos, em laboratórios, e verificar os impactos na avaliação de risco decorrentes das mudanças nos limites de exposição ocupacional (LEO) e na legislação federal brasileira. Metodologia Revisão de literatura relativa à exposição ocupacional a substâncias químicas, referentes a: conceituação de risco; desenho das curvas dose-resposta; identificação dos fatores que interferem na relação dose-efeito; conceitos de exposição por longo período, da exposição múltipla e em baixas concentrações; e fatores de confusão na monitoração ocupacional. Realização de estudo transversal no Centro de Pesquisas da Petrobras, para avaliar o perfil de exposição a agentes químicos de 3.000 trabalhadores, com atividades preponderantes em laboratórios, metade das quais com exposição em baixas concentrações e por longo período, tendo por base as avaliações ambientais do ano de 2004. Análise temporal dos valores de LEO da American Conferrence of Governmental Industrial Hygienists (ACGIH) e levantamento das mudanças nas legislações federal previdenciária, trabalhista e de saúde nos aspectos relacionados à exposição a agentes químicos. Resultados Foram identificadas 484 substâncias químicas em 243 postos de trabalho, resultando em 2.550 situações de exposição, com média de 3,73 substâncias químicas por local. Os 1.563 trabalhadores com exposição formaram 168 Grupos Homogêneos de Exposição (GHE), cuja composição variou de 1 a 44 trabalhadores (média de 4,55, mediana de 3 e moda de 1). Em cada local de trabalho foram identificados, em média, 4,91 GHE. Foram medidas 977 amostras. Com relação ao GHE, foi notado que em 91,9% das avaliações ocorreram resultados abaixo do nível de ação, correspondendo a 92,5% dos empregados, configurando a exposição a baixas concentrações. Verificou-se ainda que 49,6% dos GHE (49,9% dos empregados) tinham concentrações inferiores ao limite de detecção das técnicas analíticas, enquanto que em 8,1% dos GHE e 7,5% dos empregados, as concentrações estavam em nível igual ou acima do nível de ação. Comprovou-se que nos últimos dez anos foram implantados ou revisados 135 (18,5%) LEO. O número de substâncias cuja redução do LEO é igual ou superior a 50% corresponde à quase totalidade das reduções e, em todos os períodos, as maiores são iguais ou superiores a 80% ultrapassando, portanto, o nível de ação. Ainda que não exista concordância nos valores dos LEO foi constatado que, entre as diferentes agências têm ocorrido freqüentes mudanças na legislação. Estes fatos têm obrigado os profissionais a incorporarem estes conhecimentos a sua prática de trabalho. Conclusões A exposição a substâncias químicas em laboratórios é predominantemente em baixa concentração, variada e múltiplas. Na proteção da saúde de trabalhadores, a aceitação do risco quando a concentração ambiental da substância química é abaixo do nível de ação, deve ser usado com parcimônia, pois os valores de LEO têm apresentado tendência de redução e exclui parcela significativa da população. Nesta se incluem os hipersensíveis, os expostos a substâncias com efeito estocástico, misturas com efeitos aditivos e com curva dose-resposta bifásica / Objective The aim of this study was to assess the profile of occupational exposure to chemicals in laboratories and check the impacts on risk assessment that derive from changes in occupational exposure limits (OEL) and in Brazilian federal laws applicable thereto. Methodology Review of publications on occupational exposure to chemicals concerning the following: risk concept, dose-response curve drawing, identifying factors that interfere with dose-effect relationship; concepts of lengthy exposure, multiple exposure, and low concentration exposure; confusing factors in occupational monitoring. A transversal study was carried out at the Petrobras Research Center in order to assess the profile of exposure to chemicals among 3,000 employees whose job was predominantly performed inside a laboratory, half of which were low concentration, lengthy exposures (the study was based on environmental assessments carried out in 2004). Time analysis of American Conference of Governmental Industrial Hygienists (ACGIH) OEL values. Survey on the changes made in security, labor, and health federal laws as relates to exposure to chemicals. Results 484 chemicals were identified in 243 workplaces. This resulted in 2,550 exposure situations with an average of 3.73 chemicals per location. The 1,563 workers under exposure were divided into 168 Homogeneous Exposure Groups (HEG) comprised by 1 to 44 subjects (mean = 4.55; median = 3; mode = 1). On average, 4.91 HEG were identified in each workplace. 977 samples were measured. Regarding the HEG, it was observed that 91.9% of the assessments showed results below action level. This is equivalent to 92.5% of the amount of workers and fits into the low concentration exposure category. It was also observed that 49.6% of HEG (i.e. 49.9% of workers) showed concentrations lower than detection limit in analytical techniques, whereas concentrations were equal to or greater than action level among 8.1% of HEG and 7.5% of workers. 135 (i.e. 18.5%) OEL were proven to have been implemented or revised. The amount of chemicals whose OEL decrease is equal to or greater than 50% is equivalent to nearly all decreases. Moreover, the highest decreases are equal to or greater than 80%, and therefore exceeded action level. Although there is no common agreement on OEL values, it was observed that applicable laws have been changed by several agencies on a regular basis. These facts have led professionals into considering such information in their work practice. Conclusions Exposure to chemicals in laboratories occurs basically under low, varied, multiple concentration. In the field of workers healthcare, one should be careful while considering a risk for environmental concentration of a chemical below action level. This is because OEL levels have shown to be prone to decrease and thus exclude a significant part of the population. Such part includes hypersensitive individuals, people exposed to chemicals with stochastic effect, mixtures with additive effects and biphasic dose-response curve

Submitted by Ricardo Cedraz Duque Moliterno (ricardo.moliterno@uefs.br) on 2018-01-29T22:57:17Z No. of bitstreams: 1 Disserta??o Monise da Silva Pereira.pdf: 3743767 bytes, checksum: 4d2068c2083642fa8f904e5754b23885 (MD5) / Made available in DSpace on 2018-01-29T22:57:17Z (GMT). No. of bitstreams: 1 Disserta??o Monise da Silva Pereira.pdf: 3743767 bytes, checksum: 4d2068c2083642fa8f904e5754b23885 (MD5) Previous issue date: 2016-04-27 / This study aimed to quantify and spatialise the chemical elements copper (Cu), zinc (Zn), nickel (Ni), lead (Pb), cadmium (Cd), arsenic (As), chromium (Cr), tin (Sn), iron (Fe), manganese (Mn), aluminium (Al), beryllium (Be), barium (Ba), lithium (Li), cobalt (Co) and vanadium (V) in surface sediments of the Serinah?m river estuary. For quantification Inductively Coupled Plasma- Optical Emission Spectrometry (ICP/OES) was used. It was observed that, in general, the chemicals do not exceed the limitrophe Brazilian reference values, indicating the quality of the estuary waters. Moreover, anthropogenic activities along the drainage basin did not seem to affect the environmental dynamics of the Serinah?m river estuary, not demonstrating risks to human health or the environment. It is noteworthy that most of the quantified elements showed, with spatialization, a decrease in concentration toward the mouth of the estuary, concentrating upstream, after the river discharge point. When compared to other estuarine environments the Serinah?m river estuary showed low concentrations, highlighting the higher concentrations for the chemical elements Al, Fe and Mn, that are elements found in high concentrations in the lithology of the estuary basin. With respect to the particle size concentration, the first segment showed the highest concentration of chemical elements (Fe, Al, Co, Cr, Ni, V, Zn, Mn e Cu), since, due to the presence of mangrove areas, river islands become sediment retention barriers and the presence of small tributaries help in the transport of sediments that accumulate in this region. / Este estudo objetivou quantificar e espacializar os elementos qu?micos Cobre (Cu), Zinco (Zn), N?quel (Ni), Chumbo (Pb), C?dmio (Cd), Ars?nio (As), Cromo (Cr), Estanho (Sn), Ferro (Fe), Mangan?s (Mn), Alum?nio (Al), Ber?lio (Be), B?rio ( Ba), L?tio (Li), Cobalto (Co) e Van?dio (V), em sedimentos superficiais do estu?rio do rio Serinha?m. Para a quantifica??o foi utilizado a Espectrometria de Emiss?o ?ptica por Plasma Acoplado Indutivamente ? ICP/OES. Observou-se que, de forma geral, nenhum dos elementos qu?micos ultrapassa os valores lim?trofes referenciais brasileiros, indicando a qualidade das ?guas do estu?rio. Al?m disso, as atividades antr?picas desenvolvidas ao longo da bacia de drenagem parecem n?o afetar a din?mica ambiental do estu?rio do rio Serinha?m, n?o demonstrando riscos ? sa?de humana ou ao ambiente de forma ampla. Ressalta-se que a maioria dos elementos quantificados demonstrou, com a espacializa??o, um decr?scimo da concentra??o em dire??o ? foz do estu?rio, ou seja, concentrando-se a montante, logo ap?s o ponto de descarga fluvial. Quando comparado a outros ambientes estuarinos o estu?rio do rio Serinha?m apresentou concentra??es baixas, destacando as maiores concentra??es para os elementos qu?micos Al, Fe e Mn que s?o elementos encontrados em altas concentra??es na litologia da bacia do estu?rio do rio Serinha?m. Com rela??o ? concentra??o granulom?trica, o 1? segmento apresentou a maior concentra??o de elementos qu?micos (Fe, Al, Co, Cr, Ni, V, Zn, Mn e Cu), visto que devido ? presen?a de ?reas de manguezais, ilhas fluviais se tornam uma barreira de reten??o de sedimentos, e a presen?a de pequenos tribut?rios ajuda no transporte de sedimentos que se acumulam nessa regi?o.

Objetivo Avaliar o perfil da exposição ocupacional a agentes químicos, em laboratórios, e verificar os impactos na avaliação de risco decorrentes das mudanças nos limites de exposição ocupacional (LEO) e na legislação federal brasileira. Metodologia Revisão de literatura relativa à exposição ocupacional a substâncias químicas, referentes a: conceituação de risco; desenho das curvas dose-resposta; identificação dos fatores que interferem na relação dose-efeito; conceitos de exposição por longo período, da exposição múltipla e em baixas concentrações; e fatores de confusão na monitoração ocupacional. Realização de estudo transversal no Centro de Pesquisas da Petrobras, para avaliar o perfil de exposição a agentes químicos de 3.000 trabalhadores, com atividades preponderantes em laboratórios, metade das quais com exposição em baixas concentrações e por longo período, tendo por base as avaliações ambientais do ano de 2004. Análise temporal dos valores de LEO da American Conferrence of Governmental Industrial Hygienists (ACGIH) e levantamento das mudanças nas legislações federal previdenciária, trabalhista e de saúde nos aspectos relacionados à exposição a agentes químicos. Resultados Foram identificadas 484 substâncias químicas em 243 postos de trabalho, resultando em 2.550 situações de exposição, com média de 3,73 substâncias químicas por local. Os 1.563 trabalhadores com exposição formaram 168 Grupos Homogêneos de Exposição (GHE), cuja composição variou de 1 a 44 trabalhadores (média de 4,55, mediana de 3 e moda de 1). Em cada local de trabalho foram identificados, em média, 4,91 GHE. Foram medidas 977 amostras. Com relação ao GHE, foi notado que em 91,9% das avaliações ocorreram resultados abaixo do nível de ação, correspondendo a 92,5% dos empregados, configurando a exposição a baixas concentrações. Verificou-se ainda que 49,6% dos GHE (49,9% dos empregados) tinham concentrações inferiores ao limite de detecção das técnicas analíticas, enquanto que em 8,1% dos GHE e 7,5% dos empregados, as concentrações estavam em nível igual ou acima do nível de ação. Comprovou-se que nos últimos dez anos foram implantados ou revisados 135 (18,5%) LEO. O número de substâncias cuja redução do LEO é igual ou superior a 50% corresponde à quase totalidade das reduções e, em todos os períodos, as maiores são iguais ou superiores a 80% ultrapassando, portanto, o nível de ação. Ainda que não exista concordância nos valores dos LEO foi constatado que, entre as diferentes agências têm ocorrido freqüentes mudanças na legislação. Estes fatos têm obrigado os profissionais a incorporarem estes conhecimentos a sua prática de trabalho. Conclusões A exposição a substâncias químicas em laboratórios é predominantemente em baixa concentração, variada e múltiplas. Na proteção da saúde de trabalhadores, a aceitação do risco quando a concentração ambiental da substância química é abaixo do nível de ação, deve ser usado com parcimônia, pois os valores de LEO têm apresentado tendência de redução e exclui parcela significativa da população. Nesta se incluem os hipersensíveis, os expostos a substâncias com efeito estocástico, misturas com efeitos aditivos e com curva dose-resposta bifásica / Objective The aim of this study was to assess the profile of occupational exposure to chemicals in laboratories and check the impacts on risk assessment that derive from changes in occupational exposure limits (OEL) and in Brazilian federal laws applicable thereto. Methodology Review of publications on occupational exposure to chemicals concerning the following: risk concept, dose-response curve drawing, identifying factors that interfere with dose-effect relationship; concepts of lengthy exposure, multiple exposure, and low concentration exposure; confusing factors in occupational monitoring. A transversal study was carried out at the Petrobras Research Center in order to assess the profile of exposure to chemicals among 3,000 employees whose job was predominantly performed inside a laboratory, half of which were low concentration, lengthy exposures (the study was based on environmental assessments carried out in 2004). Time analysis of American Conference of Governmental Industrial Hygienists (ACGIH) OEL values. Survey on the changes made in security, labor, and health federal laws as relates to exposure to chemicals. Results 484 chemicals were identified in 243 workplaces. This resulted in 2,550 exposure situations with an average of 3.73 chemicals per location. The 1,563 workers under exposure were divided into 168 Homogeneous Exposure Groups (HEG) comprised by 1 to 44 subjects (mean = 4.55; median = 3; mode = 1). On average, 4.91 HEG were identified in each workplace. 977 samples were measured. Regarding the HEG, it was observed that 91.9% of the assessments showed results below action level. This is equivalent to 92.5% of the amount of workers and fits into the low concentration exposure category. It was also observed that 49.6% of HEG (i.e. 49.9% of workers) showed concentrations lower than detection limit in analytical techniques, whereas concentrations were equal to or greater than action level among 8.1% of HEG and 7.5% of workers. 135 (i.e. 18.5%) OEL were proven to have been implemented or revised. The amount of chemicals whose OEL decrease is equal to or greater than 50% is equivalent to nearly all decreases. Moreover, the highest decreases are equal to or greater than 80%, and therefore exceeded action level. Although there is no common agreement on OEL values, it was observed that applicable laws have been changed by several agencies on a regular basis. These facts have led professionals into considering such information in their work practice. Conclusions Exposure to chemicals in laboratories occurs basically under low, varied, multiple concentration. In the field of workers healthcare, one should be careful while considering a risk for environmental concentration of a chemical below action level. This is because OEL levels have shown to be prone to decrease and thus exclude a significant part of the population. Such part includes hypersensitive individuals, people exposed to chemicals with stochastic effect, mixtures with additive effects and biphasic dose-response curve