Spelling suggestions: "subject:"achemical risk assessment"" "subject:"a.chemical risk assessment""
1 |
Automated Methods in Chemical Risk AssessmentBrown, Trevor 29 August 2011 (has links)
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.
|
2 |
Automated Methods in Chemical Risk AssessmentBrown, Trevor 29 August 2011 (has links)
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.
|
3 |
Simulations expérimentale et numérique des effets retardés d'une explosion en milieu clos et en présence de produits liquidesMunier, Laurent 12 October 2011 (has links)
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.
|
4 |
Proposta de mudança do ensino de toxicologia do médico do trabalho no Brasil, a partir da análise de erros cometidos por profissionais na condução de casos atendidos / Proposal of change in the teaching of toxicology of the occupational physician in Brazil, based on the analysis of errors made by professionals in the management of cases attendedBuschinelli, José Tarcisio Penteado 06 September 2005 (has links)
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.
|
5 |
Proposta de mudança do ensino de toxicologia do médico do trabalho no Brasil, a partir da análise de erros cometidos por profissionais na condução de casos atendidos / Proposal of change in the teaching of toxicology of the occupational physician in Brazil, based on the analysis of errors made by professionals in the management of cases attendedJosé Tarcisio Penteado Buschinelli 06 September 2005 (has links)
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.
|
6 |
Combining NMR and MS fingerprinting for fine characterization of lipid profiles. : Application to a chemical food safety issue / Caractérisation fine de profils lipidiques via la combinaison de prises d'empreintes par RMN et SdM : Application à une problématique de sécurité chimique des alimentsMarchand, Jérémy 13 December 2018 (has links)
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.
|
7 |
Integrated New Approach Methods Using Zebrafish (Danio rerio) Larvae and Transcriptomics Produce Points of Departure that are Protective of Chronic Toxicity EffectsCurry, Jory 12 December 2023 (has links)
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.
|
8 |
Sfide e prospettive nella valutazione del rischio ambientale dei prodotti fitosanitari / CHALLENGES AND PERSPECTIVES IN THE ENVIRONMENTAL RISK ASSESSMENT OF PLANT PROTECTION PRODUCTSPANIZZI, SILVIA 31 May 2017 (has links)
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.
|
9 |
Återanvändning av kemiska riskbedömningar : Förutsättningar, fördelar och svårigheter. / Reuse of chemical risk assessments : Prerequisites, advantages and difficulties.Larsen, Anna January 2019 (has links)
Kemiska arbetsmiljörisker förekommer inom ett flertal branscher och behöver förebyggas för att skydda arbetstagare mot ohälsa, sjukdom och olycksfall. Det förebyggande arbetet görs genom att identifierade risker bedöms och kontrolleras med ändamålsenliga åtgärder, med målet att riskerna minskar eller helt försvinner. Att genomföra kemiska riskbedömningar är dock ofta både svårt och komplext med många olika aspekter att beakta och kräver både tid och kunskap. Som ett sätt att förenkla och effektivisera processen kring kemisk riskbedömning önskar Skanska, ett företag inom bygg- och anläggningsbranschen, se över om det är möjligt att återanvända kemiska riskbedömningar. Syftet med detta examensarbete blev därmed att utreda möjligheten i återanvändning av redan genomförda kemiska riskbedömningar där de kemiska produkterna ska användas igen. Utredningen har fokuserat på fördelar, hinder eller svårigheter och förutsättningar för återanvändning. Europeiskt och svenskt regelverk och vetenskaplig litteratur har genomlysts och data har samlats in från intervjuer med olika nyckelpersoner på tre arbetsplatser inom Skanska samt utifrån riskbedömningar av några utsedda produkter. Resultatet har därefter jämförts med svenskt regelverk, för att därigenom dra slutsatser om möjligheten i återanvändning av kemiska riskbedömningar. Examensarbetet har resulterat i slutsatsen att återanvändning av kemiska riskbedömningar bör vara möjlig, under förutsättning att de mallar eller checklistor som används som stöd uppfyller de krav som finns för kemisk riskbedömning. Det behöver säkerställas genom ändamålsenliga rutiner av personal med rätt kompetens om kemiska arbetsmiljörisker. Det behöver också stämmas av att exempelvis arbetssätt, omgivning och tillgången av åtgärder är likvärdiga på den arbetsplats som först genomfört riskbedömningen, och den arbetsplats som därefter återanvänder riskbedömningen, eller att dessa faktorer kan bli likvärdiga genom vidtagna åtgärder. Några risker eller hinder för återanvändning har identifierats. En av de mest framträdande riskerna är att kemiska arbetsmiljörisker förbises i samband med återanvändningen och därigenom också de åtgärder som behöver vidtas. Orsaker till detta kan vara bristande kunskap och engagemang eller möjligen fusk och slarv. I situationer där arbete ska ske med farligare kemiska produkter kan det vara svårare med återanvändning av riskbedömningar. Några fördelar med återanvändning bedöms vara förkortad tidsåtgång för kemiska riskbedömningar, en effektivare hantering, samt ett ökat stöd och lärande om kemiska arbetsmiljörisker genom att man lär av varandra och tidigare riskbedömningar. Möjligen kan återanvändning också bidra till att fler riskbedömningar genomförs, för att därigenom trygga yrkesarbetarnas säkerhet och hälsa. / Chemical risks in the work environment occur in several industries, and need to be prevented to protect workers from ill-health, illness and accidents. By performing risk assessments and taking appropriate measures, it is possible to reach the goal to reduce or even eliminate chemical risks. However, performing chemical risk assessments is often a quite difficult and complex issue with several different aspects to consider, requiring both time and knowledge. As a way to simplify and streamline the process of chemical risk assessment, Skanska, a company within the construction industry, wants to investigate whether it is possible to reuse chemical risk assessments. The purpose of this thesis was thus to investigate the possibility of reusing already performed chemical risk assessments in situations where the chemical products will be used again. The investigation has focused on the advantages, obstacles or difficulties and prerequisites for reuse. European and Swedish regulations and scientific literature have been reviewed and data have been collected from interviews with managers, safety representatives and employees at three workplaces at Skanska and from performed risk assessments of some selected products. Thereafter, the results have been compared with Swedish regulations, in order to draw conclusions about the possibility of reusing chemical risk assessments. The conclusion is that it should be possible to reuse chemical risk assessments, provided that the templates or checklists used as a support meet the requirements for chemical risk assessments. This needs to be ensured through appropriate routines by personnel with the right expertise about chemical risks in the work environment. It must also be ensured that some factors, as way of working, the work environment and measures taken, need to be similar for the workplace first performing the risk assessment, and the workplace that will reuse the same risk assessment, or at least that these factors can become similar after measures taken. Some risks or obstacles of reusing chemical risk assessments have been identified. One of the most prominent risks is that chemical hazards will be missed and thereby also the measures that need to be taken. This may be due to lack of knowledge and commitment or possibly cheating or carelessness. In situations where more hazardous chemical products are being used, it may be more difficult to reuse risk assessments. Some benefits of reusing risk assessments may be less time required for chemical risk assessments, more efficient management and increased support and learning about chemical hazards by learning from each other and previous risk assessments. Possibly, reuse can also contribute to more risk assessments being carried out, thereby ensuring the safety and health of professional workers.
|
10 |
Evaluating the use of dose-response relationships based on in vitro data in establishing acceptable exposure levels in humansBloch, Sherri 09 1900 (has links)
Avec plus de 350 000 produits chimiques utilisés et de nouveaux arrivant sur le marché chaque année, des outils rapides et à coûts réduits sont nécessaires pour l'étude de ces produits. L’évaluation des risques pour ces produits est généralement faite à partir d’études animales, mais celles-ci présentent plusieurs limitations. Par exemple, évaluer le potentiel cancérogène d’une substance prendre jusqu'à trois ans et coûter six millions de dollars. En outre, il a été démontré que les modèles animaux n'ont qu'un faible pouvoir prédictif par rapport aux effets chez l’humain. Pour surmonter ces obstacles, on assiste actuellement à un mouvement mondial en faveur du développement et de l'acceptation de nouvelles approches méthodologiques (NAM) pour la priorisation des produits chimiques et l'évaluation des risques.
Notre objectif était d’élaborer et d'évaluer une nouvelle approche d’extrapolation in vitro à in vivo (IVIVE) pour établir des niveaux d'exposition acceptables chez l'homme en combinant des des études in vitro et des outils de modélisation toxicologique. À cette fin, nous avons développé et évalué un outil informatique utilisé dans l'approche IVIVE et mené des études de cas sur deux produits chimiques pour lesquels étaient disponibles des données in vitro, des modèles d'exposition, et des études épidémiologiques associant l’exposition à des effets néfastes chez l’humain.
Dans le premier article, nous avons développé et évalué un modèle de bilan de masse dynamique (IV-MBM DP v1.0) pour estimer les concentrations intracellulaires au cours d'expériences in vitro avec administration répétée, incluant une description du transport facilité. Pour évaluer la précision du modèle, nous avons paramétré et appliqué le modèle à des scénarios de dose unique et de doses répétées, et évalué les concentrations estimées aux données empiriques. En outre, nous avons simulé des scénarios de dosage répété pour des produits chimiques organiques représentant une diversité de caractéristiques physico-chimiques, et nous avons comparé leur dispersion dans le système au fil du temps. Dans l'ensemble, pour les scénarios de dosage unique et répété, la concordance entre les données simulées et expérimentales a illustré le pouvoir prédictif du modèle.
i
Dans les deuxième et troisième articles, nous nous sommes concentrés sur l'utilisation et l'évaluation de notre nouvelle approche IVIVE en faisant deux études de cas impliquant l'exposition placentaire et lactationnelle à des polluants organiques persistants. La première étape de notre méthodologie a été la sélection d'un point de départ à partir d'une étude in vitro utilisant des cellules humaines. Ensuite, nous avons appliqué la modélisation benchmark dose pour obtenir la concentration associée à un changement relatif de 5% de la réponse par rapport au contrôle. Nous avons ensuite appliqué la modélisation de de bilan de masse pour déterminer la concentration cellulaire pour un point de départ conduisant à un changement de réponse de 5%. Un modèle toxicocinétique pour le transfert placentaire et par l’allaitement a ensuite été utilisé pour calculer la dose équivalente administrée et la concentration plasmatique associée, et des facteurs d'incertitude (variabilité interindividuelle (10) et sous-chronique à chronique (10)) ont été appliqués pour calculer les apports quotidiens tolérables et les équivalents de biosurveillance. Les équivalents de biosurveillance ont été comparés aux concentrations dans le sang de la mère et du cordon ombilical mesurées dans les études épidémiologiques. Nos études de cas portaient sur la neurotoxicité développementale du 2,2',4,4'-tétrabromodiphényléther (BDE-47) et sur l'obésogénicité du dichlorodiphényldichloroéthylène (p,p'-DDE). Pour les deux études, les apports quotidiens tolérables calculés en tenant compte des facteurs d’incertitude étaient plus faibles que les valeurs toxicologiques de référence déterminées sur la base d’études animales. En outre, les deux études de cas ont produit des équivalents de biosurveillance se situant dans la gamme des concentrations maternelles et du cordon ombilical mesurées dans les études épidémiologiques.
Dans l'ensemble, l'évaluation de notre modèle de bilan de masse, ainsi que les valeurs conservatrices générées par l'approche IVIVE dans nos études de cas, renforcent la confiance dans les NAM, ce qui est essentiel pour leur adoption future par les organismes de réglementation. / With over 350,000 chemicals in use and more entering the market every year, cost-effective and time-efficient tools are necessary for the investigation of these products. Whole animal models are traditionally used and accepted by regulatory agencies; however, animal models carry multiple limitations. Specifically, animal models may take up to three years and six million dollars to investigate the carcinogenicity of a compound. Additionally, animal models have been shown to have poor predictive power for human safety. To overcome these obstacles, a global movement toward the development and acceptance of new alternative methods (NAMs) for chemical prioritization and risk assessment is taking place.
Our objective was to develop and evaluate a novel in vitro to in vivo (IVIVE) approach to establish acceptable exposure levels in humans by combining novel in vitro and biological/computational modeling technologies for chemical safety assessment. To this end, we tested and evaluated a computational tool utilized in the IVIVE approach, and conducted proof-of-concept studies on two case chemicals with publicly available in vitro data, exposure models, and epidemiological studies demonstrating adverse health effects.
In the first paper, we aimed to develop and evaluate a dynamic partitioning mass-balance model (IV-MBM DP v1.0) to estimate intracellular concentrations during in vitro experiments of repeat dosing, and incorporate facilitated transport into the model. To evaluate the model accuracy, we parametrized and applied the model to single dose and repeat dosing scenarios and assessed the output against empirical data. In addition, we simulated repeat dosing scenarios for organic chemicals with different properties and compared their dispersion within the system over time. Overall, for single and repeat dosing scenarios, concordance between simulated and experimental data illustrated the predictive power of the model.
In the second and third papers, we focused on the use and evaluation of our novel IVIVE approach through case studies involving placental and lactational exposure to persistent organic pollutants. The first step of our methodology was the selection of a point of departure from an in vitro study utilizing human cells. Next, we applied benchmark dose modeling to obtain the nominal
iv
concentration at a 5% relative change in response from control. We subsequently applied mass- balance modeling to determine the cellular concentration for the POD leading to a 5% change in response. A toxicokinetic model for placental transfer and lactation was then used to calculate the administered equivalent dose and associated maternal and cord plasma concentration, and uncertainty factors (interindividual variability (10) and subchronic to chronic (10)) were applied to calculate tolerable daily intakes and biomonitoring equivalents. Biomonitoring equivalents were compared to concentrations in maternal and cord blood measured in epidemiological studies. Our case studies were on 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) developmental neurotoxicity and dichlorodiphenyldichloroethylene (p,p’-DDE) obesogenicity. For both studies, calculated tolerable daily intakes accounting for uncertainty factors were more conservative than the reference doses determined through the use of whole animal models. Moreover, both case studies produced biomonitoring equivalents within the range of maternal and cord levels measured in epidemiological studies.
Overall, assessment of our IV-MBM DP v1.0 mass-balance model, as well as the demonstrated protective quality of the IVIVE approach in our case studies, enhances confidence in NAMs, which is essential for their future adoption by regulatory agencies.
|
Page generated in 0.111 seconds