Dissertations / Theses on the topic 'Toxicodynamie'

Les biomarqueurs sont des outils d'un grand intérêt mis en oeuvre pour établir un diagnostic de risque environnemental pour les écosystèmes aquatiques. Néanmoins, la mesure de ces marqueurs sub-individuels présentent encore certaines limitations pour l'évaluation de la qualité des écosystèmes, parmi lesquelles la caractérisation des dynamiques parfois complexes de réponses de ces effets non-léthaux en fonction du temps ou de la dose ou encore l'extrapolation des réponses d'une échelle d'organisation biologique à une autre. Une des solutions semblant prometteuses pour caractériser la dynamique de ces réponses dans une optique de changement d’échelle serait d’intégrer les biomarqueurs à des modèles mécanistiques permettant de prédire cette dynamique et d’expliquer les mécanismes sous-jacents à l’apparition des effets. Ainsi, ce travail de thèse propose de construire des modèles mécanistiques de toxicocinétique et toxicodynamie à base physiologique (PBTK-TD) pour mieux caractériser et mieux comprendre les dynamiques de réponse des biomarqueurs. Dans ce cadre, pour aborder cette problématique, une stratégie décomposée en deux sous-parties a été utilisée. Tout d’abord une étude de la partie « toxico-cinétique » ou TK a permis de relier la dose externe, présente dans l’environnement, à la dose interne, présente dans l’organisme. Puis, la partie « toxico-dynamique » ou TD a été développé pour faire le lien entre la dose interne et l’effet. Dans un premier temps, ce travail de thèse a consisté à collecter un ensemble de données TK et TD chez notre espèce-modèle, l’épinoche à trois épines, sur une famille de molécules, les bisphénols, et plus particulièrement, le BPA, le BPS et le BPF. Ces données récoltées à partir d’expositions de courte durée (sept jours de contamination et sept jours de dépuration) et d’une exposition de longue durée (21 jours) ont tout d’abord permis de comparer les effets de modulation des bisphénols sur les biomarqueurs. Les marqueurs de l’immunité innée ont notamment été fortement impactés par ces substances. Des différences de cinétique entre le BPA et le BPS ont par ailleurs été mise en avant. Par la suite, les données collectées au cours des expositions ont été utilisée pour construire un modèle TK à base physiologique (PBTK) pour le BPA, puis un modèle PBTK couplé à des sous-modèles TD (PBTK-TD) décrivant la dynamique de certains immunomarqueurs. Enfin, un dernier modèle PBTK-TD a été construit pour démontrer la faisabilité de cette démarche de modélisation pour intégrer des conditions d’exposition plus représentatives de celles du milieu naturel, i.e. pour un mélange de substances. Considéré dans son ensemble, ce travail de thèse démontre l’attractivité du couplage entre l’approche expérimentale par la mesure de biomarqueurs et la modélisation
Biomarkers are useful tools for the diagnosis of environmental risk in aquatic ecosystems. Nevertheless, the measurement of these sub-individual markers still presents some limitations for the assessment of ecosystem health, including the characterisation of the complex dynamics of responses of these non-lethal effects as a function of time or dose, or the extrapolation of responses from one scale of biological organisation to another. One of the solutions that seems promising for characterising the dynamics of these responses from a change of scale perspective would be to integrate the biomarkers into mechanistic models that make it possible to predict these dynamics and explain the mechanisms underlying the effects. This thesis proposes to build mechanistic models of physiologically based toxicokinetics and toxicodynamics (PBTK-TD) to better characterise and understand the response dynamics of biomarkers. In this context, the problem of biomarker dynamics was divided in two. First, the "toxico-kinetic" or TK makes it possible to link the external dose, present in the environment, to the internal dose, present in the organism. Second, the "toxico-dynamic" or TD, makes the link between the internal dose and the effect. Accordingly, the first step in this thesis was to collect a set of TK and TD data in our model species, the three-spined stickleback, on a family of compounds, the bisphenols, and more specifically, BPA, BPS and BPF. These data, collected from short-term exposures (seven days of contamination and seven days of depuration) and long-term exposure (21 days), were used to compare the modulating effects of bisphenols on biomarkers. In particular, markers of innate immunity were strongly impacted by these substances. Differences in kinetics between BPA and BPS were also highlighted. Subsequently, the data collected during the exposures were used to build a physiologically based TK model (PBTK) for BPA, then a PBTK model coupled with TD sub-models (PBTK-TD) describing the dynamics of certain immunomarkers in the stickleback. Finally, a last PBTK-TD model was built to demonstrate the feasibility of this modelling approach for integrating exposure conditions more representative of those in the natural environment, i.e. for a mixture of substances. Taken as a whole, this thesis demonstrates the attractiveness of coupling the experimental approach consisting in measuring biomarkers and modelling

En 2000, la Directive Cadre sur l’Eau a exigé le retour au bon état chimique et écologique des cours d’eau. Elle a notamment classé 45 substances comme étant prioritaires pour cette évaluation (directive 2013/39/UE), dont en grande partie des pesticides. En effet, en raison de leur utilisation massive, on retrouve aujourd’hui ces contaminants dans tous les compartiments de l’environnement. Par ailleurs, au vu de sa capacité à intégrer les contaminations, le biofilm est considéré comme un excellent bioindicateur pour l’évaluation de la qualité de l’eau. Celui-ci est à la base de la chaine trophique dans les milieux aquatiques et se compose de microorganismes (microalgues, bactéries, champignons, etc…) enchâssés dans une matrice de substances polymériques extracellulaires (EPS).Cette thèse porte sur l’étude des mécanismes de transfert et de distribution des pesticides dans les biofilms en lien avec les effets toxiques associés. Ces travaux ont été réalisés avec une approche toxicocinétique par laquelle la bioaccumulation du diuron (un herbicide inhibiteur de la photosynthèse) a été suivie dans les différents compartiments du biofilm. Ce suivi a été réalisé sous plusieurs conditions abiotiques (vitesses de courant, températures et photopériodes) pour différentes durées d’exposition. En parallèle des descripteurs fonctionnels et structuraux ont été mesurés comme des activités photosynthétique (pour les communautés autotrophes) et enzymatiques (pour les communautés hétérotrophes), ainsi que la biomasse totale, la production de protéines et de polysaccharides.L’ensemble des expérimentations menées au cours de cette thèse a permis de décrire les mécanismes de sorption du diuron dans les biofilms, à savoir des processus d’absorption par les cellules et d’adsorption par la matrice EPS. Puis l’influence des différents paramètres environnementaux étudiés a pu être mise en avant. Ces travaux démontrent la pertinence de l’approche toxicocinétique-toxicodynamique pour l’étude de l’impact des pesticides sur les biofilms fluviaux
In 2000, the Water Framework Directive required the return of rivers to good chemical and ecological status. In particular, it has classified 45 substances as priority for this assessment (Directive 2013/39/EU), including a large proportion of pesticides. Indeed, due to their massive use, these contaminants are now found in all compartments of the environment. In addition, given its ability to integrate contamination, biofilm is considered an excellent bioindicator for water quality assessment. It is at the base of the trophic chain in aquatic environments and is composed of microorganisms (microalgae, bacteria, fungi, etc...) embedded in a matrix of extracellular polymeric substances (EPS).This thesis focused on the analysis of mechanisms of pesticide transfer and distribution in biofilms related to toxic impacts. This work was carried out using a toxicokinetic approach whereby the bioaccumulation of diuron (a photosynthesis inhibitor herbicide) was monitored in the different compartments of the biofilm. This assessment was carried out under several abiotic conditions (flow velocity, temperatures and photoperiods) under varying exposure durations. In parallel, functional and structural descriptors were measured as photosynthetic (for autotrophic communities) and enzymatic (for heterotrophic communities) activities, as well as biofilm biomass and protein and polysaccharide production.All the experiments performed during this thesis made it possible to highlight the sorption mechanisms of diuron in biofilm, i.e. absorption processes by cells and adsorption phenomenon within the EPS matrix. Then the influence of the different environmental parameters studied was emphasized. This work demonstrates the relevance of the toxicokinetic-toxicodynamic approach to the study of the impact of pesticides on fluvial biofilms

Inotropic support for the failing myocardium as the therapy for xi congestive heart failure (CHF) is intended to achieve an increase in cardiac output via positive responses in myocardial contractility and vasodilation. A novel approach to differentiate these two responses is the use of an animal with an implanted total artificial heart (TAH). Three inotropic drugs, dobutamine, enoximone, and pimobendan, were tested in eight animals with their natural heart intact and five animals implanted with a TAH. Baseline values of the TAH and natural heart (NH) were compared to determine their hemodynamic similarities. Each of the three drugs was given randomly to the animals in dosages similar to human clinical doses. Peak responses were recorded and analyzed. All three drugs caused an increase in contractility and cardiac output in the NH animals. Dobutamine and pimobendan also caused a significant increase in heart rate at higher dosages whereas enoximone did not. Dobutamine caused an increase in left ventricle work, as did pimobendan at the first dose given; at higher doses of pimobendan, the left ventricular work returned to baseline. However, at the doses tested, the left ventricular stroke work during enoximone administration decreased. Vasodilation (the only drug stimulation response in the TAH model) was also observed with the administration of the drugs in T AH animals, and all three caused decreases in systemic and pulmonary vascular resistance. Dobutamine and pimobendan caused an increase in left and right atrial pressures (because of the mechanical heart not being adjusted to compensate the increased return). There was also a reduction in systemic and pulmonary resistance. Enoximone caused severe pulmonary hypertension in the TAH animals, possibly due to stimulus of platelets to release vasoconstrictive substances. Thus, dobutamine, enoximone, and pimobendan significantly contribute to increases in output by vasodilation in animals with a natural heart. Similarly, dobutamine and pimobendan's vasodilatory action is identified in an animal with a TAH. However, enoximone's hypertensive action on the pulmonary vasculature of a TAH animal may offer an insight to the toxicity of enoximone when used after recent surgery.

Toxicity of pesticides to non-target organisms determines their impact on natural environments. And to find pesticides with a new, target-specific mode of action, which are safe to farmers and organisms in the surrounding environment, is important when developing new pesticides.In this study, toxicity of the insecticide chlorantraniliprole to the Collembola Folsomia candida was investigated, showing that the test animals were adversely affected by the compound. Toxicity was tested in two experiments; a reproduction test in four soils with different organic matter content, following the OECD Guideline 232, and a toxicodynamic test where mortality, mobility, reproduction and morphological changes were recorded.The reproduction test showed a lower toxicity of chlorantraniliprole in the high-organic soils compared to the low-organic. When organic matter content increased two times, the difference between the lowest and the highest EC50 and EC10 values was a factor of 5.3 and 8.4, respectively. pH did not seem to significantly affect toxicity, and organic matter content did not seem to affect the total number of juveniles produced.The toxicodynamic test showed a fast mode of action on mobility of F. candida, but not on mortality. Mobility decreased at the highest treatments of chlorantraniliprole already one day after the animals were introduced to the test vessels, but significant mortality was still not seen after almost three weeks. Reproduction was also adversely affected with a decline in the total number of juveniles produced at the higher treatments. The animals at the higher treatments also showed a possible compound induced reproduction stress, with faster egg laying. Morphological changes, such as affected antennas, increased steadily over time.Chlorantraniliprole shows high toxicity to some non-target organisms but is, with its new mode of action, still important in the development of more environmentally safe pesticides.

The green sea turtle, Chelonia mydas, spends a considerable part of its life in coastal waters foraging on seagrass and/or algae, which brings it close to anthropogenic pollutant sources. Elevated concentrations of chemical contaminants from urban, industrial and agricultural run-off accumulate in coastal environments. These pollutants have the potential to cause serious harm to C. mydas populations. However, exposure and toxicity data are challenging to obtain for free-ranging, protected wildlife species like C. mydas. Furthermore, a lack of quantitative tools linking long-term external contaminant exposure, the uptake and tissue distribution of chemicals (toxicokinetics), and the biological pathway perturbations related to adverse health outcomes (toxicodynamics) hamper efforts by scientists and policymakers to quantify the risk of pollutants adversely affecting C. mydas health. Changes in C. mydas population abundance, in turn, may affect the marine seagrass ecosystems, which, by extension, could potentially also impact human health and animals that rely on seagrass habitats. The present thesis provided the means to research the hypothesis that land-based contaminants adversely impact the health of Australia’s resident green turtle populations. The following chapters in this thesis investigate the validity of this hypothesis. Valuable experimental toxicokinetic and toxicodynamic data are collected and described in Chapters 2 and 3. Chapter 4 used data from Chapter 3 to develop tools to confirm the initial hypothesis. Overall, this thesis describes the development of tools to aid risk assessors and policymakers in setting safe chemical exposure levels for green sea populations.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
Full Text

Ce travail a consisté à analyser, par des approches toxicocinétiques (TK) et mécanistiques, les effets oestrogéniques du Bisphenol A (BPA) sur un biomarqueur précoce et sensible : la sécrétion de l'hormone lutéinisante (LH) chez la brebis prépubère ovariectomisée. La plus faible concentration plasmatique en BPA induisant une inhibition de LH s'est avérée proche des concentrations maximales décrites chez l'Homme. Cette inhibition de LH pourrait impliquer une inhibition des systèmes neuronaux à kisspeptine. L'approche TK comparative d'espèces a montré que la clairance du BPA est toujours élevée, proche du débit sanguin hépatique. Pour une exposition à la dose journalière admissible, cette approche permet de prédire chez l'Homme des concentrations en BPA très inférieures à celles associées à une inhibition de LH dans notre modèle
The goal of this thesis was to analyse through toxicokinetic (TK) and mechanistic approaches the estrogeno-mimetic effects of bisphenol A (BPA) on a precocious and sensitive biomarker: LH secretion in ovariectomized female lambs. The lowest plasma BPA concentrations associated to an inhibition of LH secretion appeared to be close to the highest one reported in human. LH suppression could be mediated by an inhibition of hypothalamic kisspeptin systems. The multispecies TK approach showed that BPA clearance is always high and equivalent to the liver blood flow. For an exposure scheme corresponding to the tolerable daily intake, this approach allows to predict human BPA concentration much lower than the one associated to LH inhibition in our highly sensitive lamb model

The contamination of seafood with methylmercury (MeHg) is a global health issue, as MeHg is a well known neurotoxin. Since dietary nutrients may interact with MeHg toxicity, and oxidative stress is one of the primary mechanisms underlying MeHg neurotoxicity, we characterized dietary antioxidant-MeHg interactions. Firstly, we used an ethnobotanical study to confirm the antioxidant activity of Northern Labrador Tea, Rhododendron tomentosum ssp. subarcticum (Tea), for the Canadian Inuit, a population with elevated MeHg exposure. Secondly, we determined the ability of Tea to ameliorate MeHg-induced toxicity in a rat perinatal exposure study. MeHg exposure (2 mg/KgBW/d) was associated with perturbed development and behaviour, elevated brain N-methyl-D-aspartate receptors, and serum lipid peroxidation. Surprisingly, Tea co-exposure (100 mg/KgBW/d) modulated MeHg’s effects on brain NMDA-R levels and lipid peroxidation, but also increased mercury serum concentrations. Thirdly, using a toxicogenomics approach we determined that MeHg exposure caused the down-regulation of Nr4a2 and its protein product Nurr1. These novel MeHg targets are implicated in developmental learning functions and were corrected with MeHg + Tea co-exposure. Lastly, we conducted a risk assessment survey and cross-sectional dietary epidemiology study in Costa Rica to further investigate dietary nutrient-MeHg interactions. Costa Rica is a Central American country with multiple sources of Hg and a high per capital fish consumption. Here, 5 of the 14 populations we studied exceeded the recommended MeHg provisional tolerable daily intake (pTDI) of 0.2 µg/KgBW/d. In Heredia the pTDI was exceeded by 34% of woman participants, primarily associated with canned tuna consumption. Interestingly, we detected that Hg body burden was significantly reduced by the consumption of antioxidant-rich dietary items. Considering our collective results, we hypothesized that MeHg toxicokinetics may be altered by dietary nutrients at the site of intestinal absorption from the disruption of gut flora, or at the site of cellular demethylation in tissues from the improvement of cellular redox state. The interaction of dietary nutrients on MeHg outcomes has a large impact on risk assessment and may provide a public health approach for managing the risk associated with MeHg exposure without reducing local fish consumption.

Das Schutzziel in der Ökotoxikologie ist die Population. Un­ter­suchungen zur Wirkung von subletalen Konzentrationen einer Umweltchemikalie auf Populationsebene, zum Beispiel mit künst­lichen Fließgewässersystemen (Mikrokosmen) können aussagekräftigere Beiträge zur ökotoxikologischen Bewertung einer Umweltchemikalie liefern. Außerdem können bei solchen Untersuchungen mögliche indirekte Effekte erfaßt werden. Über die Reaktion von Fließgewässer-Biozönosen gegenüber Um­welt­chemikalien ist relativ wenig bekannt. Die überwiegende Zahl der Untersuchungen zur Abschätzung des Ge­fähr­dungs­po­tentials von Umweltchemikalien wurde mit Testsystemen für Lebensgemeinschaften in stehenden Gewässern untersucht. Die Übertragbarkeit der Ergebnisse dieser Tests auf Fließgewässer-Lebensgemeinschaften ist meist nicht gegeben. Daher ist es notwendig Testsysteme zu etablieren, mit denen die Wirkung von Umweltchemikalien auf Fließgewässer-Le­bens­ge­mein­schaf­ten untersucht werden kann. In einem Gewächshaus wurden fünf Fließrinnen etabliert, mit denen die physikalisch-chemischen Bedingungen in einem Bach simuliert werden können. Im Ge­gensatz zu Untersuchungen einer komplexen Le­bens­ge­mein­schaft mit hoher Variabilität, wie sie sich beispielsweise durch das Einbringen von na­tür­lich­em Sediment aus Fließgewässern einstellt, wurde in diesen Experimenten die Wirkung von Che­mikalien auf eine einfache Lebensgemeinschaft untersucht. Die Le­bens­ge­mein­schaft in den Fließrinnen bestand deshalb aus wenigen, aus­ge­wählten Arten. Untersucht wurden die Kon­zen­tra­tionen 0,6, 6, 60 und 600 µg/l (Terbutryn) und 0,05, 0,5, 5 und 50 µg/l (Fenoxycarb). Gegenstand der vorliegenden Arbeit waren die Untersuchungen mit Gammarus fossarum. In einem akuten Toxizitätstest wurde die LC50 von Terbutryn für adulte und juvenile Gammariden ermittelt. In den Fließ­rin­nen­ex­perimenten mit Terbutryn und Fenoxycarb wurden po­pu­la­tions­relevante Pa­ra­meter der Gammaridenpopulationen untersucht. Ob und in welchem Um­fang sich Effekte, die mit den Stan­dard­tests gemessen wurden, auf bestimmte öko­toxi­ko­lo­gi­sche End­punkte der Population auswirken, kann nicht immer unmittelbar abgeleitet werden. Eine Möglichkeit wäre die aufwendige Durchführung von Po­pu­la­tionsexperimenten mit einfachen oder komplexeren Mo­dell­öko­systemen über eine lange Zeit. Eine andere Möglichkeit ist die Nutzung mathematischer Modelle zur Beschreibung der Populationsdynamik. Das begleitend zu den Untersuchungen entwickelte individuenbasierte Re­pro­duk­tions­modell GamMod bildet die Populationsdynamik einer ab­ge­schlos­senen Population von Gammarus fossarum in künstlichen Fließgewässersystemen ab. Es wird die Struktur und Dy­na­mik des realen Systems (Populationsdynamik) unter Ein­beziehung der Kenntnisse des Reproduktionszyklus modelliert. Mo­dell­szenarien sollen Aus­sagen über den Einfluß der Än­der­ung einer Variablen bezüglich der Populationsdynamik liefern.

Das Schutzziel in der Ökotoxikologie ist die Population. Un­ter­suchungen zur Wirkung von subletalen Konzentrationen einer Umweltchemikalie auf Populationsebene, zum Beispiel mit künst­lichen Fließgewässersystemen (Mikrokosmen) können aussagekräftigere Beiträge zur ökotoxikologischen Bewertung einer Umweltchemikalie liefern. Außerdem können bei solchen Untersuchungen mögliche indirekte Effekte erfaßt werden. Über die Reaktion von Fließgewässer-Biozönosen gegenüber Um­welt­chemikalien ist relativ wenig bekannt. Die überwiegende Zahl der Untersuchungen zur Abschätzung des Ge­fähr­dungs­po­tentials von Umweltchemikalien wurde mit Testsystemen für Lebensgemeinschaften in stehenden Gewässern untersucht. Die Übertragbarkeit der Ergebnisse dieser Tests auf Fließgewässer-Lebensgemeinschaften ist meist nicht gegeben. Daher ist es notwendig Testsysteme zu etablieren, mit denen die Wirkung von Umweltchemikalien auf Fließgewässer-Le­bens­ge­mein­schaf­ten untersucht werden kann. In einem Gewächshaus wurden fünf Fließrinnen etabliert, mit denen die physikalisch-chemischen Bedingungen in einem Bach simuliert werden können. Im Ge­gensatz zu Untersuchungen einer komplexen Le­bens­ge­mein­schaft mit hoher Variabilität, wie sie sich beispielsweise durch das Einbringen von na­tür­lich­em Sediment aus Fließgewässern einstellt, wurde in diesen Experimenten die Wirkung von Che­mikalien auf eine einfache Lebensgemeinschaft untersucht. Die Le­bens­ge­mein­schaft in den Fließrinnen bestand deshalb aus wenigen, aus­ge­wählten Arten. Untersucht wurden die Kon­zen­tra­tionen 0,6, 6, 60 und 600 µg/l (Terbutryn) und 0,05, 0,5, 5 und 50 µg/l (Fenoxycarb). Gegenstand der vorliegenden Arbeit waren die Untersuchungen mit Gammarus fossarum. In einem akuten Toxizitätstest wurde die LC50 von Terbutryn für adulte und juvenile Gammariden ermittelt. In den Fließ­rin­nen­ex­perimenten mit Terbutryn und Fenoxycarb wurden po­pu­la­tions­relevante Pa­ra­meter der Gammaridenpopulationen untersucht. Ob und in welchem Um­fang sich Effekte, die mit den Stan­dard­tests gemessen wurden, auf bestimmte öko­toxi­ko­lo­gi­sche End­punkte der Population auswirken, kann nicht immer unmittelbar abgeleitet werden. Eine Möglichkeit wäre die aufwendige Durchführung von Po­pu­la­tionsexperimenten mit einfachen oder komplexeren Mo­dell­öko­systemen über eine lange Zeit. Eine andere Möglichkeit ist die Nutzung mathematischer Modelle zur Beschreibung der Populationsdynamik. Das begleitend zu den Untersuchungen entwickelte individuenbasierte Re­pro­duk­tions­modell GamMod bildet die Populationsdynamik einer ab­ge­schlos­senen Population von Gammarus fossarum in künstlichen Fließgewässersystemen ab. Es wird die Struktur und Dy­na­mik des realen Systems (Populationsdynamik) unter Ein­beziehung der Kenntnisse des Reproduktionszyklus modelliert. Mo­dell­szenarien sollen Aus­sagen über den Einfluß der Än­der­ung einer Variablen bezüglich der Populationsdynamik liefern.

碩士
國立臺灣大學
生物環境系統工程學研究所
107
Microplastics (MPs), are defined as tiny plastics with particle size less than 5 mm. Ecological concerns and health risks of MPs contamination have been attracting a worldwide attention within a decade. While a large body of literature has shown that MPs are highly likely to be accumulated in aquatic and terrestrial biota, information about the toxic interactions of MPs on organisms from a mechanistic point of view is more limited. This thesis filled this knowledge gap by assessing polystyrene (PS)-MPs in zebrafish, red tilapia, and mice systems based on a toxicokinetic/toxicodynamic (TK/TD) modeling to quantify organ-bioaccumulation and biomarker responses appraised with published datasets. Exposure risks for aquatic model organisms including bivalves were also presented by utilizing the published environmentally relevant concentration data of PS-MPs in marine and freshwater ecosystems. The organ-specific TK-parameters and mean residence times for zebrafish, red tilapia, and mice posed by size-specific PS-MPs could be obtained. The highest uptake rates were in the liver of zebrafish, in the gut of red tilapia and mice, respectively. Results showed that steady-state bioconcentration factors (BCFsss) of PS-MPs among all organs were much greater than 1, indicating the bioaccumulating potential of PS-MPs in animals. In comparison to mice, zebrafish have commonly much greater BCFsss in organs. The sensitivities of biomarkers regarding immunological response, oxidative stress, detoxification, and energy and lipid metabolisms to PS-MPs in liver of organisms were determined by the TD assessment. These concentration-effect relationships based on the Hill model varied with species used, exposure time, and particle size of PS-MPs in each system. As the result, toxicity thresholds of PS-MPs were in a large variability. Results demonstrated that the most sensitive biomarkers in bivalves, zebrafish, red tilapia, and mice systems, based on strict threshold concentrations, were phagocytic cells, superoxide dismutase (SOD), 7-ethoxyresorufin O-deethylase, and SOD, respectively. A risk-based probabilistic model was further used to characterize the potential hazards of marine bivalves and freshwater fish in response to predicted environmental concentrations of PS-MPs quantified by exceedance risks and risk quotients. Among five global plastic-filled gyres, the highest and lowest risks were occurred in the North Pacific and South Pacific Oceans for bivalves, respectively. For freshwater fish, the Winyah Bay in USA appeared to be the greatest risks among the selected local areas. The present results warranted further attention on worldwide MPs pollution posing hazards to aquatic organisms, particularly sensitive species like zebrafish taking the brunt of the long-term toxicity risk. Moreover, the mice-based TK parameters and threshold criteria greatly assist in designing robust researches to evaluate MPs consumption by humans. An extrapolation framework was proposed for mechanistically estimating toxicity thresholds of MPs from mice to humans in a health risk assessment perspective. Overall, results derived from the TK/TD assessment, the Weibull threshold model, and the ecotoxicological risk assessment could be adopted to rapidly evaluate MPs-induced toxicities at various concentrations. The strict thresholds could be recommended as criteria for environmental management of MPs and offer a tool-kit in establishing the scheme for risk assessment of human consumption.

博士
國立臺灣大學
生物環境系統工程學研究所
100
Recently, subcellular metal partitioning has been used for assessing metal toxicity in aquatic organisms. In reality, the environmental metal concentration is tended to be fluctuation and pulse as a result of the site-specific water chemistry conditions. But little researches have been studied by using the subcellular partitioning for aquatic organisms exposed to pulsed metals in the field of ecotoxicology. Hence, the purposes of this dissertation were: (i) to develop an integrated toxicological model by linking subcellular partitioning and toxicokinetic/toxicodynamic (TK/TD) models with the experimental data of pulsed copper (Cu)-tilapia (Oreochromis mossambicus) system and published data of cadmium (Cd)-rainbow trout (Oncorhynchus mykiss) system, (ii) to investigate the trade-offs among ecophysiological parameters related to metals bioaccumulation, subcellular partitioning, and susceptibility in farmed fish of tilapia and rainbow trout, and (iii) to provide a probabilistic risk approach to assess susceptibility risks for farmed fish exposed to metals stressors. A 28-day pulsed Cu exposure experiment was conducted to provide the information on the subcellular partitioning of Cu in tilapia. The Cu bioaccumulation and the distributions of Cu in metabolically active (MAP) and detoxified pools (MDP) can be obtained from the pulsed Cu exposure experiment. The published data of rainbow trout exposed to waterborne and dietborne Cd were adopted to reanalyze and estimate susceptibility and detoxified capacity. This study estimated bioavailability, bioaccumulation, and internal damage of tilapia and rainbow trout in response to pulsed Cu and Cd, respectively. Toxicokinetic parameters of uptake rate (k1), elimination rate (k2), and detoxification rate constants (kd) were derived for tissues in tilapia (gill and muscle) and rainbow trout (gill, liver, and gut). The damage assessment model (DAM) was used to fit to data of time-varying percentage of metal in MAP to estimate killing rate constant (kk), recovery rate constant (kr), and susceptibility. A physiological-based TK model was used to predict tissue burdens for rainbow trout exposed to environmentally relevant Cd concentrations and tissue-specific susceptibility risks can be estimated. A probabilistic risk assessment model was presented to assess the metal exposure risks for tilapia and rainbow trout. The experimental results indicated that the percentage of Cu in MAP increased with time from 23% to 57% for gill, whereas for muscle, the percentage of Cu in MAP slightly decreased with time from 35% to 28% for tilapia in response to pulsed Cu exposure. Results showed that toxicokinetic parameters of k1s, k2s, and kds were 8.38 and 0.408 mL g-1 d-1, 0.244 and 0.031 d-1, and 0.178 and 0.033 d-1, respectively, for gill and muscle of tilapia exposed to pulsed waterborne Cu. Results showed that k2, kd, and kr ranged from 0.32 – 0.46 d-1, 0.45 – 1.72 d-1, and 1.08 – 1.45 d-1, respectively, for gill of rainbow trout exposed to waterborne Cd (5 – 50 ug L-1), whereas 0.07 – 0.19 d-1, 2.24 – 87.75 d-1, and 1.02×10-6 – 1.37×10-2 d-1, respectively, for gut exposed to dietborne Cd (0.6 – 30.3 ug g-1). This study implicated no significant susceptibility risk for tilapia exposed to waterborne Cu concentrations. The probability that 50% or more of the susceptibility risk in response to Cu exposure for tilapia was only 33.2% Cu in MAP. For rainbow trout exposed to Cd, a most likely probability of % Cd in MAP of gill and liver exceeding 47 – 49%. In contrast with gill and liver, gut had a relative lower Cd susceptibility risk (15 – 17% Cd in MAP). The trade-offs between elimination and detoxification in rainbow trout exposed to Cd, Cu, and zinc (Zn) based on recently published data were also examined. Results indicated that the relationships between k2 and kd were negative for rainbow trout. However, the relationships between kd and % metal in MDP were found to be positive. Results also indicated that rainbow trout had the higher accumulation (~ 60 – 90 %) in MAP when exposed to essential metals of Cu and Zn and had only 10 – 50 % accumulation in response to non-essential metal of Cd. This study found that metal accumulations of tissues varied with the patterns of exposure metal concentration in farmed fish. An integrated model to assess the susceptibility for farmed fish exposed to metal stressors was provided in this study. The trade-offs between elimination and detoxification were also quantified for providing the valuable insights into the ecotoxicology of farmed species. In conclusion, this study used exposed laboratory data of Cu and Cd to investigate the bioaccumulation, bioavailability, and metal distribution of subcellular partitioning for understanding of the susceptibility risks in framed fish of tilapia and rainbow trout. Hence, the probabilistic risk assessment framework linking with the proposed integrated ecotoxicological model can provide an advice for helping government based bioassessment and biomonitoring programs to protect the farmed fish from metal exposures.

博士
國立臺灣大學
生物環境系統工程學研究所
93
This dissertation proposes a physiologically and bioenergetics based algorithm to relate acute and chronic metal toxicities to the internal effect concentration (IEC) of arsenic (As) in tilapia Oreochromis mossambicus. The relationships among As exposure, uptake, accumulation, and toxicity to tilapia are investigated using toxicokinetic (TK) and toxicodynamic (TD) modeling. A 7-d exposure bioassay reveals that the organ-specific bioconcentration factor (BCF) values of tilapia are all above 1 (1.04 – 3.05), indicating that the tilapia is capable of accumulating waterborne As. The As acute toxicity is analyzed by determining the median external effect concentration (LC50) at different integration times, indicating that 96-h LC50 and LC50(∞) for tilapia are 28.68 (95% CI: 24.92-32.44) and 12.04 µg mL-1, respectively. To determine the mode of action (MOA) governing the As acute toxicity, this study assesses the proposed mechanistics base acute toxicity models, including the critical body residue (CBR) model, the critical area under the curve (CAUC) model, and the recently proposed damage assessment model (DAM). This study test the 3 toxicity models with observed data of tilapia exposed to As, to compare the observed and predicted LC50 and median internal effect concentration (CL,50). Result suggests that the DAM characterizes As acute toxicity well and indicates that the intrinsic MOA of As toxicity might act through the reversible reaction between As and specific receptors in target sites. A physiologically based toxicokinetic (PBTK) model is constructed to elucidate the major mechanisms, accounting for the organ-specific selected accumulation of As in tilapia and then utilize the model to predict the behavior of As in tilapia under different exposure scenarios. This study links kinetically DAM with IEC-based Hill equation model to derive dose-response relationships between equilibrium organ-specific As burdens and mortality effects. Organ-specific dose-response relationships suggest that the gill can be used as a surrogate to assess the As toxicity due to its higher sensibility to toxic effects. To assess As chronic toxicity to tilapia, a bioenergetics-based approach is presented to analyze effects and the MOA of growth inhibition when tilapia are chronically exposed to waterborne As. A 28-d growth bioassay is conducted to quantitatively determine the relationships between As exposures and the magnitudes of growth inhibition. A bioenergetics-based ontogenetic growth model is incorporated with the DEBtox theory to explore the MOA of As growth toxicity. Result shows that the specific growth rates are inversely proportional to As concentrations and are calculated to be 0.76 % d-1 in 0 µg mL-1, 0.54 % d-1 in 1 µg mL-1, 0.26 % d-1 in 2 µg mL-1, and 0.017 % d-1 in 4 µg mL-1, respectively. This study indicates that decreasing of feeding accounts for the As growth inhibition in the case of feeding ad libitum condition. The bioenergetics-based growth model also illustrates the growth trajectories of tilapia in the entire life cycle, suggesting that the maximum biomass of tilapia are 1100.82 g in uncontaminated water, 924.00 g in 1 µg mL-1, 421.51 g in 2 µg mL-1, and 352.13 g in 4 µg mL-1, respectively. The study shows that the proposed physiologically and bioenergetics-based assessment framework successfully links As exposure to TK and TD under varied exposure scenarios. This study also suggests that considering MOAs in ecotoxicology not only improves our understanding of the toxicities of chemicals but also is useful in setting up models and avoiding pitfalls in species- and site-specific environmental risk assessment. This study also supports the suggestion that replacing external concentrations by IECs is a first step toward a measurement for chemical toxicity and can be used to improve the construction of future environmental quality criteria programs, aimed at protecting and restoring the rapidly degrading aquacultural ecosystems.