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The design of new alerts, collections of structural features observed to result in toxicological activity, can be a slow process and may require significant input from toxicology and chemistry experts. Two methods have therefore been developed to help with alert identification by mining descriptions of activating structural features directly from toxicity datasets. The first method attempts to iteratively grow descriptions of activating substructures, by repeated ranking and combination of atom pairs to form increasingly detailed atom multiplets. This technique, although promising, proved too computation ally intensive for application to heterogeneous datasets. Attempts were made, however, to improve performance and to account for the eo-occurrence of structural features by interactively splitting heterogeneous datasets into subsets that support individual multiplets. The second method is based on emerging pattern mining (Dong and Li, 1999), a technique that is well known to computer science, but is relatively new to chemistry. The Horizon-Miner algorithm (Li et aI., 2001) and border-differential operation (Dong and Li, 2005) are applied to generate the minimal and maximal borders of a set of jumping-emerging patterns of atom pairs. Using the minimal jumping-emerging patterns it is possible to cluster toxic compounds into groups defined by the presence of shared structural features that occur exclusively in the actives. A method has been developed to identify hierarchical relationships between clusters and their associated jumping- emerging patterns, which has enabled families of structural feature descriptions to be arranged into trees. The root of each tree represents the most general and most commonly occurring structural feature description in the family. By inspecting clusters further down the tree, it is possible to extend the significant structural features to further distinguish sets of toxic compounds. The methodology has been tested on a number of datasets for Ames mutagenicity, oestrogenicity and hERG channel inhibition endpoints. These tests have shown the method to be effective at clustering the datasets around minimal jumping-emerging structural patterns and finding larger descriptions of the significant structural features. The resulting descriptions of the significant structural features have been shown to be related to some of the known alerts for all three tested endpoints.

A group of inducible sensors were characterised under a standard protocol in order to comprehensively compare them. Subsequently, the toxicity of a series of mercury anions was investigated using the suite of inducible sensors and chemical analysis. Next, the response of the inducible sensors was tested against a number of metal ions in order to determine their capacity to induce the biosensors, and against a constitutively marked biosensor to measure the toxicity of the individual metal ions. These bioluminescent data were used to determine the presence of quantitative structural activity relationships (QSARs) between the metal ions and the transcriptional switches of the sensor. Homology was identified but further characterisation is required. Finally, an assessment of a number of environmental samples was carried out using a combination of chemical analysis, toxicity-based and inducible biosensors. Soil characteristics influenced the bioavailable fraction of mercury in the extracts under investigation and the biosensors had the capacity to report on the bioavailable fraction present. Whilst the sensors could predict the bioavailable fraction of mercury in aqueous systems, it is clear in order to exploit their potential they must be used in combination with other sensors and in conjunction with chemical analysis techniques. Biosensor technology has progressed significantly in the past decade, but while there is clear evidence of their construction, there is a lack of environmental application.

Bibliography: leaves 116-138 / [14], 138 leaves, 5 leaves of plates : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical & Experimental Pharmacology, 1988

Les allergies représentent un problème majeur dans le domaine des maladies professionnelles et ont un impact sérieux sur la vie des travailleurs. Les allergies professionnelles sont principalement cutanées et respiratoires ; elles peuvent être causées par des produits chimiques de bas poids moléculaire. Dans le passé, les tests destinés à identifier les produits susceptibles d’entraîner des allergies étaient réalisés sur l’animal. Or, la législation européenne engage à limiter le recours à l’expérimentation animale pour évaluer le pouvoir sensibilisant des substances chimiques, incitant à développer des tests in vitro de substitution. C’est dans ce contexte que nous avons cherché à développer des modèles de cultures cellulaires destinés à identifier les substances sensibilisantes. Un premier modèle utilisant des cellules dendritiques dérivées de moelle osseuse (BMDC) de souris BALB/c a été développé et a donné des résultats prometteurs pour l’identification des produits sensibilisants et leur catégorisation selon leur puissance sensibilisante. De plus, la voie de signalisation Nrf2/Keap1 semble être impliquée dans la réponse de ce modèle cellulaire aux sensibilisants. Dans le but de compléter ce modèle et d’évaluer la capacité des BMDC à activer les lymphocytes T (LT), un modèle de coculture de BMDC et LT a été mis au point avec un sensibilisant de référence avant d’être testé sur un ensemble de produits de référence (sensibilisants cutanés et respiratoires, irritants et non sensibilisants). Les BMDC de notre modèle, exposées à des sensibilisants, se sont révélées capables d’activer les LT en coculture. Enfin, des essais préliminaires utilisant des cellules de souris de souche C57BL6/J dans notre modèle de coculture ont donné des résultats comparables à ceux obtenus avec des cellules issues de la souche BALB/c. Les modèles de cultures cellulaires BMDC et de coculture BMDC-LT sont prometteurs dans le cadre du développement de méthodes de substitution à l’expérimentation animale pour l’évaluation du pouvoir sensibilisant de substances chimiques / Allergies constitute an important issue in the field of occupational health and have a serious impact on the lives of workers. Occupational allergies are mainly contact and respiratory allergies and can be caused by low molecular weight chemicals. In the past, the tests that were used to identify the potential allergens were carried out on animals. However, European legislation has provided the impetus for reducing the use of animal testing to assess the sensitization potential of chemicals and promoted the development of alternative in vitro tests. In this context, we aimed to develop cell culture models to identify sensitizers. A first model using bone marrow derived dendritic cells (BMDC) from BALB/c mice was developed and showed promising results for identifying sensitizers and classify them according to their allergenic potency. Moreover, the Nrf2/Keap1 pathway seems to be involved in the response of this cell model to sensitizers. In order to supplement this model and to assess the functionality of BMDC, a BMDC-T cell (TC) coculture model was developed with a reference sensitizer before being tested on a range of reference sensitizers (cutaneous and respiratory sensitizers, irritants and non-sensitizers). The BMDC of our model, while exposed to sensitizers, were able to activate TC in coculture. Finally, preliminary tests using the cells of C57BL6/J mice in our coculture model showed that similar results to those obtained with cells from the BALB/c strain. The models of BMDC cultures and BMDC-TC coculture are promising for the development of alternative methods to animal experimentation assessing the sensitizing potential of chemicals

L’exposition prénatale à différents agents toxiques est généralement étudiée en considérant le placenta comme une barrière entre la mère et le fœtus ; nous le considérons en tant qu’organe cible des agents toxiques. Pour ce faire, nous avons sélectionné un modèle cellulaire de trophoblastes adapté aux études toxicologiques. En clinique, des pathologies de la grossesse sont associées à des modifications de la sécrétion de l’hormone placentaire lactogène hPL et de l’hormone gonadotrope chorionique hCG. Nos travaux in vitro ont permis de faire le lien entre une exposition à des micropolluants (le mono(2-ethylhexyl) phtalate, un perturbateur endocrinien, et le benzo(a)pyrene, un carcinogène) et ces observations cliniques. Les biomarqueurs de sécrétion hormonale (hPL et hCG hyperglycosylée) et de dégénérescence (activation du purinorécepteur P2X7) que nous avons identifiés permettent de détecter l’exposition et le risque suite à une exposition à des polluants. / Prenatal exposure to pollutants is commonly evaluated using placenta as a barrier between mother and fetus. Here, we consider placenta as a target organ for toxic agents. To achieve this, we selected a trophoblastic cell model, which is adapted to toxicological studies. In clinical studies, pregnancy pathologies are associated to changes in human placental lactogen (hPL) and human chorionic gonadotropin (hCG) secretions. Our in vitro work links exposure to micropollutants (mono(2-ethylhexyl)phthalate, an endocrine disruptor, and benzo(a)pyrene, a carcinogen) and clinical observations. We identified biomarkers of hormonal secretion (hPL and hyperglycosylated hCG) and degeneration (P2X7 receptor activation), which enable the evaluation of exposure and risk attached to exposure to pollutants.