In this thesis, topics in chemical hazard and risk assessment are explored through the use of multimedia mass balance models and high-throughput chemical property prediction methods. Chemical hazard metrics, as calculated by environmental fate and transport simulations, are investigated to determine the validity of two common simplifying assumptions in the underlying models; the use of octanol as a surrogate for organic matter and the use of environmental parameters that do not vary in time. A major finding is that the use of these common simplifying assumptions in multimedia mass balance models has little effect on chemical risk assessment, provided that chemicals are ranked relative to each other rather than a predetermined cutoff value. Chemical properties relevant to hazard and risk are collected, and applied in a large-scale chemical hazard assessment to derive a short list of potential Arctic contaminants. Several further data needs are identified; these are widely applicable and easily calculable metrics for chemical biodegradation, toxicity and emissions. A new method of predicting chemical properties is presented to assist in meeting these data needs. The method automatically creates predictive, quantitative relationships between the structures and properties of chemicals that are comparable to similar relationships created with expert judgement.

In this thesis, topics in chemical hazard and risk assessment are explored through the use of multimedia mass balance models and high-throughput chemical property prediction methods. Chemical hazard metrics, as calculated by environmental fate and transport simulations, are investigated to determine the validity of two common simplifying assumptions in the underlying models; the use of octanol as a surrogate for organic matter and the use of environmental parameters that do not vary in time. A major finding is that the use of these common simplifying assumptions in multimedia mass balance models has little effect on chemical risk assessment, provided that chemicals are ranked relative to each other rather than a predetermined cutoff value. Chemical properties relevant to hazard and risk are collected, and applied in a large-scale chemical hazard assessment to derive a short list of potential Arctic contaminants. Several further data needs are identified; these are widely applicable and easily calculable metrics for chemical biodegradation, toxicity and emissions. A new method of predicting chemical properties is presented to assist in meeting these data needs. The method automatically creates predictive, quantitative relationships between the structures and properties of chemicals that are comparable to similar relationships created with expert judgement.

Peut-on modéliser de manière fiable les effets collatéraux (en termes de quantité ou concentration de produits éjectés) et les conséquences d’une explosion en milieu clos, et en présence de produits chimiques liquides ? Pour répondre à cette vaste question, qui soulève spontanément de nombreux sous-problèmes, les travaux de thèse se sont déroulés en trois temps : 1/une étude qualitative et semi-quantitative du scénario général, afin de comprendre le déroulement chronologique des évènements, et d’émettre les hypothèses nécessaires à une modélisation, 2 /L’étude systématique des effets d’une explosion en milieu clos, en présence ou non de produits liquides. Avant de modéliser la dégradation du produit liquide soumis à une température et à une pression élevées, les expérimentations préliminaires ont en effet fait apparaître la nécessité de quantifier dans le temps et dans l’espace, les effets thermiques et mécaniques d’une explosion à volume constant, 3/L’élaboration de modèles 0D(t) à partir des conclusions précédentes afin, d’une part, d’estimer la durée de vie d’une phase liquide dans un environnement thermodynamique contraint et, d’autre part, de démontrer la possibilité de modéliser le problème global de manière réduite. En effet, le terme source d’un tel évènement ne peut être modélisé par une libération ponctuelle de produit : il s’agit d’une libération étendue dans le temps, par le biais d’un écoulement chaud a priori diphasique et de débit variable. Les couplages des phénomènes, observés expérimentalement, rendent nécessaires : 1 - Une modélisation instationnaire de l’évolution de la pression et une estimation du niveau de température atteint dans le volume d’étude, après détonation d’une charge explosive, 2 - Une modélisation de la libération de la phase liquide dans l’enceinte, sous forme de gouttes millimétriques ou de gouttelettes microniques 3 - Une modélisation instationnaire des transferts couplés de masse et d’énergie entre la phase liquide et la phase gazeuse en présence et prise en compte d’éventuelles réactions chimiques à haute pression et haute température 4 - Et enfin, une modélisation instationnaire des rejets à la brèche. L’étude d’une explosion à volume constant a montré qu’il est possible de modéliser de manière simple la montée continue en pression de l’enceinte par une fonction exponentielle croissante. Pour une configuration de référence donnée – explosion d’une sphère d’explosif dans un parallélépipède – la valeur maximale de pression est directement proportionnelle au taux de chargement en explosif, sur l’intervalle [0,01 – 0,6] kg/m3. Le passage à une géométrie différente ou plus complexe demande l’introduction d’un coefficient correctif pour traduire l’amplification (ou l’atténuation) de la combustion turbulente des produits de détonation avec l’air ambiant. En ce qui concerne le champ de température par contre, notre analyse a montré qu’il coexiste des zones chaudes et des zones dites « froides » et que la valeur de température homogène finale calculée à partir d’un code thermochimique ne peut constituer qu’une simple indication. Seule une estimation du volume respectif de ces zones a été proposée ici. Nous avons établi que les propriétés physico-chimiques des produits stockés sont un point clef du problème et on suppose ces données connues pour une gamme de produits chimiques liquides à pression ambiante, communément utilisés dans l’industrie. Seul le phénomène d’évaporation a été développé dans ce mémoire. L’introduction de réactions chimiques entre constituants se traduirait dans les modèles par des termes sources supplémentaires liés à l’apparition ou la disparition d’espèces. / Is it possible to model collateral effects due to an explosion (on a chemical facility for instance) occuring in a closed volume containing liquid chemical products storage units ?This thesis deals with a zerodimensionnal modelisation of such a 3D complex problem to asses the final thermodynamic state of chemical products released in the atmosphere. Developped sub-models take into account:- the unsteady time histories of the internal overpressure and temperature,- the unsteady liquid ejection (droplets sizes)- the unsteady modelisation of the local heat and mass transfers between the gas phase and the liquid phase- the unsteady ejection process of the resulting multiphase mixture in the environment.Models and sub-models are validated thanks to many experimental results.

Em um universo de centenas de casos envolvendo problemas de toxicologia ocupacional atendidos ao longo de 17 anos (1984 a 2001) por uma instituição governamental especializada em Saúde e Trabalho, foi constado que a grande maioria deles tinha sido anteriormente conduzido de forma equivocada pelos médicos do trabalho. Isto mostrou uma falha no ensino deste conhecimento a estes profissionais, e a partir deste fato, o ensino de toxicologia para os médicos, e especialmente para os médicos do trabalho, foi estudado, assim como os conceitos fundamentais das boas práticas da toxicologia ocupacional. A fim de se propor maneiras objetivas de melhoria dos cursos, foram analisados em profundidade dez casos extraídos do universo existente através do método qualitativo de estudos de casos, muito utilizado na área de educação, e a partir da compreensão das causas que levaram aos conceitos equivocados, e que tiveram suas conseqüências nos erros cometidos, foram elaboradas propostas de mudança da forma de se ministrar o conhecimento de toxicologia aos médicos do trabalho no Brasil. / In a universe of hundreds of cases related to occupational toxicology, assisted over 17 years (from 1984 to 2001) in a governmental institution specialized in Occupational Health, it was observed that the great majority of them had been inadequately managed by the occupational physicians previously. This fact showed a flaw in the knowledge to these professionals. Based on this finding, a study was designed to evaluate the teaching of toxicology for physicians, particularly occupational physicians, as well as to assess the essential concepts of the good practices of occupational toxicology. In order to suggest objective measures to improve the courses, ten cases were deeply analyzed using a case study, a qualitative research methodology frequently used in the Education area. Based on the understanding of the causes responsible by the equivocal concepts, a set of proposals for changing the teaching of toxicology to occupational physicians in Brazil has been created.

Em um universo de centenas de casos envolvendo problemas de toxicologia ocupacional atendidos ao longo de 17 anos (1984 a 2001) por uma instituição governamental especializada em Saúde e Trabalho, foi constado que a grande maioria deles tinha sido anteriormente conduzido de forma equivocada pelos médicos do trabalho. Isto mostrou uma falha no ensino deste conhecimento a estes profissionais, e a partir deste fato, o ensino de toxicologia para os médicos, e especialmente para os médicos do trabalho, foi estudado, assim como os conceitos fundamentais das boas práticas da toxicologia ocupacional. A fim de se propor maneiras objetivas de melhoria dos cursos, foram analisados em profundidade dez casos extraídos do universo existente através do método qualitativo de estudos de casos, muito utilizado na área de educação, e a partir da compreensão das causas que levaram aos conceitos equivocados, e que tiveram suas conseqüências nos erros cometidos, foram elaboradas propostas de mudança da forma de se ministrar o conhecimento de toxicologia aos médicos do trabalho no Brasil. / In a universe of hundreds of cases related to occupational toxicology, assisted over 17 years (from 1984 to 2001) in a governmental institution specialized in Occupational Health, it was observed that the great majority of them had been inadequately managed by the occupational physicians previously. This fact showed a flaw in the knowledge to these professionals. Based on this finding, a study was designed to evaluate the teaching of toxicology for physicians, particularly occupational physicians, as well as to assess the essential concepts of the good practices of occupational toxicology. In order to suggest objective measures to improve the courses, ten cases were deeply analyzed using a case study, a qualitative research methodology frequently used in the Education area. Based on the understanding of the causes responsible by the equivocal concepts, a set of proposals for changing the teaching of toxicology to occupational physicians in Brazil has been created.

Dans un contexte réglementaire contraignant (REACh), ce projet a pour but de développer une méthode permettant d'évaluer, le plus amont possible du processus de conception, le risque chimique potentiellement présenté par un équipement aéronautique depuis sa livraison jusqu'à sa fin de vie. Le résultat s'intègre dans l'ensemble des paramètres gérés par les concepteurs, dans un but d'amélioration de la traçabilité des substances dangereuses et de maîtrise du risque chimique présenté par l'équipement. Le développement de la méthode s'appuie tant sur l'analyse des modes d'évaluation classiques de risques chimiques, pour différents périmètres, que sur celle des pratiques de conception aéronautiques. En parallèle, des tests in situ en Bureaux d'Etudes sont réalisés itérativement, permettant de définir des outils d'évaluation et d'aide à la décision adaptés aux besoins identifiés des concepteurs. Les travaux aboutissent à la proposition d'une méthode permettant au concepteur de répondre à la problématique risque chimique à partir des seules données issues du processus de conception, rendant cette nouvelle approche miscible à ses activités quotidiennes. / In a restrictive context (REACh regulation), this project aims at developping a method enabling one to evaluate, as soon as possible in the design process, the potential chemical risk related to any aeronautic equipment' s part during their different life cycle steps (from delivery to end of life). Assesment results is integrated among the numerous data that are by designers, in order to improve hazardous substances traceability and equipment's chemical risk control. The method's development lays on the analysis of different chemical risk assessments modes (different perimeters) and the understanding of aeronautical design practices. In situ tests (design offices) have been run in an iterative way, in order to define assessment ans decision making tools responding to designers identified needs. The work done leads to the proposal of a method which enables the designer to cope with chemical risk problematics, only from the data resulting from design process : this new approach can be considered as miscible in designer's daily activities.

Pour garantir au consommateur des aliments sûrs, l'emploi d'anabolisants chez les animaux de production est prohibée au sein de l'Union Européenne depuis la fin des années 1980. Bien que performantes, les méthodes de contrôle classiques ciblées font face à de nouveaux défis auxquels des stratégies alternatives (non ciblées),visant à identifier des biomarqueurs métaboliques caractéristiques de l'effet associé à ces pratiques, offrent des solutions innovantes. Le lipidome en particulier constitue une fraction d'intérêt pour l'étude des effets liés aux agents de répartition. La Spectrométrie de Masse (SdM) et la Résonance Magnétique Nucléaire (RMN) sont alors classiquement utilisées, indépendamment. Ce travail propose d'évaluer leur combinaison, bénéficiant des niveaux d'information différents associés, et les conséquences en termes de gain de prédiction ou d'identification des biomarqueurs. Comme modèle d'étude, des échantillons sanguins provenant d'animaux traités avec un agent de répartition connu pour perturber les profils lipidiques,ont été caractérisés. L'analyse du lipidome sérique par SdM a impliqué trois plateformes offrant des angles de vue différents afin de fournir une couverture étendue; l'étude de leur cohérence et complémentarité constituant l'un des objectifs de cette thèse. En parallèle, l'analyse par RMN a requis le développement d'une procédure complète, de l'optimisation des conditions de préparation d'échantillon aux paramètres d'acquisition, incluant des approches de RMN 2D rapides récentes. Enfin, le verrou associé à l'analyse des données issues des différentes sources a permis d'évaluer des approches statistiques innovantes, notamment multibloc. / Ln order to ensure safe food products for the consumer, the use of growth promoters in livestock farming has been prohibited in European Union since the end of the 80s. Although efficient, the conventional targeted control methods face new challenges to which alternative strategies (untargeted), aiming at identifying metabolic biomarkers characteristic of the effects induced by such practices, provide innovative solutions. In particular, the lipidome is an area of interest to investigate the effects associated with repartition agents. Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) are then classically used independently. This PhD work intends to evaluate their combination benefiting from the different levels of associated information and the consequences in terms of enhanced prediction or biomarker identification. As a study model, blood samples from animals treated with a repartition agent known to disrupt lipid profiles were characterized. The investigation of the serum lipidome with MS involved three distinct platforms providing different outlooks in order ta generate extended coverage; the study of their consistency and complementarity constituting one of the objectives of this PhD. In parallel, the analysis with NMR prompted the development of a complete workflow, from the optimization of the sample preparation conditions to acquisition parameters -including recent fast 2D NMR approaches. Finally, the challenge associated with the analysis of data from multiple sources allowed ta evaluate innovative statistical approaches such as multiblock analysis.

There is growing concern that current toxicological test methods are too slow and expensive to evaluate the safety of the thousands of chemicals in the Canadian economy. In this thesis, a novel zebrafish embryo test, with integrated behaviour, energy expenditure and gene transcription assays, was used to assess the hazard of a diverse suite of 29 chemicals. I hypothesized that points of departure (PODs) from the integrated test would be protective of the long-term toxic effects of these chemicals. I found that: 1) integrating alternative test methods enhanced the sensitivity of the zebrafish embryo acute toxicity (FET) test, 2) integrated results provided a holistic understanding of potential mechanisms of action and effects, and 3) transcriptional PODs were protective of PODs from traditional long-term and short-term juvenile and adult fish toxicity tests reported in the literature. This integrated zebrafish embryo test is a sensitive, informative and protective chemical hazard screening tool.

El objertivo principal de la presente investigación es aplicar el método simplificado Control Banding en una empresa de pinturas en Lima, con el fin de reducir el riesgo a la exposición directa de los trabajadores a Agentes Químicos Peligrosos (AQP), utilizados en la fabricación de pinturas y thinner. El enfoque de la investigación es pre experimental con pre y post test. El método se apoya en el cuestionario la norma española NTP 749 para realizar la evaluación de los riesgos en las diferentes áreas afectadas, como son almacenaje, transporte y producción, los resultados de la aplicacion del cuestionario inicialmente mostraron deficiencias, resultando en el nivel 4 con una puntuación 1440 en el rango de 600 a 4000, encontrándose en el Nivel de Riesgo Deficiente, que requería realizar una corrección urgente. El control banding asigna una letra para caracterizar de acuerdo a su peligrosidad y disponibilidad a los 09 solventes, Acetato de Butilo, Solvesso 100, HAS, Acetato de Metilo, Xileno, Metanol, Metil Etil Cetona, Tolueno y Butil Glicol. Con el apoyo en las hojas de seguridad HDS y utilizando las hojas de control del Programa de Seguridad y Salud en el Trabajo y Medio Ambiente de la OIT. Los resultados muestran solventes mutagénicos, cancerígenos como son: el Solvesso 100 y el Has, categorizados con la banda de control E por lo que deben ser reemplazados y los demás categorizados dentro de la banda de control C y S, que pueden ser controlados a través de las hojas de control de la OIT correspondiente. Aplicado el método se procedieron a establecer parcialmente las medidas, como la adquisición de una maquina de trasegó con sistema de transferencia cerrada, el almacenamiento de solventes en un lugar ventilado y separado del resto etc. Posteriormente se aplicó nuevamente el cuestionario de la NTP 749 y establecio el Nivel de Riesgo 3 con una puntuación 980 en el rango de 800 a 1200 estos resultados finales nos ubicaron dentro de la tabla en Mejorable y redujeron el nivel de riesgo en 31.94%. El método del Control banding es una herramienta complementaria preliminar que basada en los estudios y conocimiento de la mayoría de agentes químicos peligrosos por organismos internacionales coadyuvan en el control y reducción de los riesgos. / The main objective of this research is to apply the simplified Control Banding method in a paint company in Lima, in order to reduce the risk of direct exposure of workers to Hazardous Chemical Agents (AQP), used in the manufacture of paints and thinner. The research approach is pre-experimental with pre- and post-test. The method is based on the questionnaire of the Spanish standard NTP 749 to carry out the evaluation of the risks in the different affected areas, such as storage, transportation and production. The results of the application of the questionnaire initially showed deficiencies, resulting in level 4 with a score of 1440 in the range of 600 to 4000, being in the Poor Risk Level, which required urgent correction. The banding control assigns a letter to characterize according to its danger and availability to the 09 solvents, Butyl Acetate, Solvesso 100, HAS, Methyl Acetate, Xylene, Methanol, Methyl Ethyl Ketone, Toluene and Butyl Glycol. With the support of the HDS safety sheets and using the control sheets of the Occupational Safety and Health and Environment Program of the ILO. The results show mutagenic, carcinogenic solvents such as: Solvesso 100 and Has, categorized with the control band E so they must be replaced and the others categorized within the control band C and S, which can be controlled through of the corresponding ILO control sheets. Once the method was applied, the measures were partially established, such as the acquisition of a decanting machine with a closed transfer system, the storage of solvents in a ventilated place and separated from the rest, etc. Subsequently, the NTP 749 questionnaire was applied again and established Risk Level 3 with a score of 980 in the range of 800 to 1200. These final results placed us within the Improvable table and reduced the risk level by 31.94%. The Control banding method is a preliminary complementary tool that, based on studies and knowledge of the majority of dangerous chemical agents by international organizations, contributes to the control and reduction of risks.

La prima parte dell’elaborato presenta le origini e lo sviluppo delle politiche di valutazione del rischio per le sostanze chimiche. Dopo un primo inquadramento storico, l’attenzione è stata dedicata a temi emergenti come la valutazione delle incertezze, la necessità di integrazione delle valutazioni del rischio per l’uomo e per l'ambiente. La seconda parte presenta l’evoluzione delle politiche di valutazione del rischio dei prodotti fitosanitari, soprattutto a livello europeo (dall’applicazione della direttiva 91/414 all’attuale regolamento 1107/2009), con particolare attenzione all’applicazione del principio di precauzione. Il terzo capitolo approfondisce le fasi e gli approcci delle attuali procedure di valutazione ambientale del rischio dei pesticidi usati a livello europeo e americano; è stato in particolar modo esplorato il tema dell’individuazione degli obiettivi specifici di protezione in fase preliminare di valutazione del rischio. Il quarto capitolo tratta di un tema attualmente molto dibattuto, ovvero la valutazione dei potenziali effetti combinati sugli organismi non bersaglio esposti a più sostanze attive simultaneamente. Infine, l’obiettivo del quinto capitolo è quello di valutare la contaminazione ambientale dovuta all’applicazione di fungicidi a base rame su melo. A tale scopo è stato testato un nuovo modello per il calcolo integrato dell’esposizioni umana e ambientale MERLIN – Expo, sviluppato grazie al progetto europeo 4FUN. I risultati ottenuti per le acque superficiali e il sedimento sono stati confrontati con i risultati degli attuali modelli usati in Unione Europea, i modelli FOCUS. Le simulazioni probabilistiche hanno anche permesso di effettuare valutazioni di incertezza e sensitività sui parametri utilizzati nelle simulazioni. / This PhD thesis is a multidisciplinary work on the risk assessment of plant protection products including both legislative and scientific aspects. The first part of the thesis introduces the origin of risk assessment procedures with a wide glance on the whole process of risk analysis to protect the humans and the environment. The accent is put on emerging issues and trends, such as the uncertainties appraisal, the necessity of integration between human and environmental impacts without ignoring socio- economic and behavioural factors. The second chapter deals with the origin and development of global risk assessment policies on pesticides. It focuses in particular on European policies, from the original Directive 91/414 to the current Regulation 1107/2009 and the application of the precautionary principle. A brief comparison with US approaches for risk assessment is also presented. The third chapter gives an overview on the risk assessment procedures that nowadays provide the highest achievable protection for the environment, starting with the definition of clear and specific protection goals. The fourth chapter addresses the issue of combined risk assessment of pesticides: current approaches for the evaluation of effects on non-target organisms are analysed. The last chapter is dedicated to the estimation of the environmental contamination following the application of copper –based fungicides sprayed on orchards by using MERLIN - Expo, which is a multimedia model developed in the frame of the FP7 EU project 4FUN. The performance of the MERLIN- Expo software in estimating the contamination of the metal is also analysed through a comparison with the currently used FOCUS standard models for the calculation of pesticides concentrations in surface water and sediment. Both deterministic and probabilistic simulations have been run; the latter has allowed to perform uncertainty and sensitivity assessment.