Global ETD Search

41	Valutazione della sicurezza di Enterococcus faecium nella catena alimentare / SAFETY ASSESSMENT OF ENTEROCOCCUS FAECIUM IN THE FOOD CHAIN PIETTA, ESTER 28 January 2015 (has links) Enterococcus faecium è un componente fondamentale del microbiota di diversi alimenti fermentati quali formaggi e salumi e viene spesso isolato in alto numero in alimenti pronti al consumo. É inoltre largamente utilizzato come probiotico sia per l’uomo che per gli animali. Allo stesso tempo, però, questa specie batterica rappresenta una delle cause principali di infezioni nosocomiali quali endocarditi ed infezioni al tratto urinario. Studi recenti hanno dimostato che la specie E. faecium è costituita da due sub-popolazioni principali: la prima è denominate hospital associated (HA) clade “A” ed include la maggior parte dei ceppi responsabili di infezioni umane; la seconda è chiamata community associated (CA) clade “B”, e contiene principalmente ceppi commensali dell’uomo. Analisi più approfondite hanno rivelato un ulteriore suddivisione all’interno del clade A, nel sub-clade A1 (che raggruppa la maggioranza dei ceppi clinici) e nel sub-clade A2, associato agli animali e più sporadicamente ad infezioni umane. Nel 2012, EFSA ha redatto una linea guida per la valutazione della sicurezza di E. faecium usato come probiotico per gli animali, concludendo che i cepi appartenenti all’hospital-associated clade non devono essere utilizzati in nutrizione animale. Comunque, la distinzione tra le due sub-popolazioni è stata fatta utilizzando dati ottenuti prevalentemente da isolati umani e animali e solo un numero limitato di ceppi isolati dagli alimenti è stato considerato. Obiettivo di questa tesi di dottorato è stato quello di valutare la sicurezza di E. faecium negli alimenti fermentati, considerando ceppi isolati da formaggi artigianali e prodotti carnei e utilizzando sia tecniche di genomica che analisi fisiologiche. Nessuno dei ceppi alimentari studiati è risultato parte del clade A1, ma un ceppo isolato da un salame stagionato pronto al consumo ha rivelato diversi tratti tipici dei ceppi A1, tra cui particolari IS, transposase e geni di resistenza agli antibiotici. Questi risultati, così come altri dati, sottolineano la necessità di approfondire le conoscenze circa il ruolo dei ceppi di E. faecium isolati da alimenti come fattore di rischio per la salute umana. / Enterococcus faecium is commonly found in high numbers in ready to eat foods, being a member of the bacterial communities of a variety of fermented foods, including cheese and sausages, and is widely used as human and animal probiotic. However, this bacterial species is a leading cause of nosocomial infection, mainly endocarditis and urinary tract infections. Recent studies have demonstrated that E. faecium species consists of two very distinct clades: the hospital associated (HA) clade “A”, which includes most of the strains responsible for human infections, and the community associated (CA) clade “B”, that contains primarily human commensal isolates. Deeper analysis revealed a further split within clade A into sub-clade A1 (which groups the vast majority of clinical isolates), and sub-clade A2, associated with animals and sporadic human infections. In 2012, the European Food Safety Authority has issued a guideline for the safety assessment of E. faecium used as animal probiotics, concluding the strains belonging to the hospital-associated clade should not be used in animal nutrition. However, the differentiation of the two clades has been performed using data mainly deriving from human and animal isolates, and only a limited number of strains from the food chain were considered. Aim of this doctoral thesis was to assess the safety of E. faecium in fermented food, considering strains isolated from artisanal cheese and meat products, and using both whole genome-based techniques and physiological studies. None of the food isolates studied in this work belong to the epidemic clade A1, however a strain isolated from a ready to eat salami revealed several A1-specific traits, such as specific IS, transposases and antibiotic resistance genes. These results, as well as other data, underline the emergency of deeper understanding the role of E. faecium isolated from fermented foods as risk factor for human health. AGR/15: SCIENZE E TECNOLOGIE ALIMENTARI BIO/19: MICROBIOLOGIA GENERALE AGR/16: MICROBIOLOGIA AGRARIA
42	An Artificial Intelligence-Driven Model-Based Analysis of System Requirements for Exposing Off-Nominal Behaviors Madala, Kaushik 05 1900 (has links) With the advent of autonomous systems and deep learning systems, safety pertaining to these systems has become a major concern. The existing failure analysis techniques are not enough to thoroughly analyze the safety in these systems. Moreover, because these systems are created to operate in various conditions, they are susceptible to unknown safety issues. Hence, we need mechanisms which can take into account the complexity of operational design domains, identify safety issues other than failures, and expose unknown safety issues. Moreover, existing safety analysis approaches require a lot of effort and time for analysis and do not consider machine learning (ML) safety. To address these limitations, in this dissertation, we discuss an artificial-intelligence driven model-based methodology that aids in identifying unknown safety issues and analyzing ML safety. Our methodology consists of 4 major tasks: 1) automated model generation, 2) automated analysis of component state transition model specification, 3) undesired states analysis, and 4) causal factor analysis. In our methodology we identify unknown safety issues by finding undesired combinations of components' states and environmental entities' states as well as causes resulting in these undesired combinations. In our methodology, we refer to the behaviors that occur because of undesired combinations as off-nominal behaviors (ONBs). To identify undesired combinations and ONBs that aid in exposing unknown safety issues with less effort and time we proposed various approaches for each of the task and performed corresponding empirical studies. We also discussed machine learning safety analysis from the perspective of machine learning engineers as well as system and software safety engineers. The results of studies conducted as part of our research shows that our proposed methodology helps in identifying unknown safety issues effectively. Our results also show that combinatorial methods are effective in reducing effort and time for analysis of off-nominal behaviors without overlooking any dependencies among components and environmental entities of a system. We also found that safety analysis of machine learning components is different from analysis of conventional software components and detail the aspects we need to consider for ML safety. Intelligent system safety Safety assurance Machine learning safety Safety assessment, Unknown safety issues Combinatorial analysis Automated model generation Property-driven analysis Association-driven analysis Autonomous systems
43	Seismic probabilistic safety assessment and risk control of nuclear power plants in Northwest Europe Medel Vera, Carlos Pablo January 2016 (has links) Nuclear power plays a crucial role in energy supply in the world: around 15% of the electricity generated worldwide is provided from nuclear stations avoiding around 2.5 billion tonnes of CO2 emissions. As of January 2016, 442 reactors that generated 380+ GW were in operation and 66 new reactors were under construction. The seismic design of new nuclear power plants (NPPs) has gained much interest after the high-profile Fukushima Dai-ichi accident. In the UK, a tectonically stable continental region that possesses medium-to-low seismic activity, strong earthquakes capable of jeopardising the structural integrity of NPPs, although infrequent, can still occur. Despite that no NPP has been built in Great Britain after 1995, a New Build Programme intended to build 16 GW of new nuclear capacity by 2030 is currently under way. This PhD project provides a state-of-the-art framework for seismic probabilistic safety assessment and risk control of NPPs in Northwest Europe with particular application to the British Isles. It includes three progressive levels: (i) seismic input, (ii) seismic risk analysis, and (iii) seismic risk control. For seismic input, a suitable model to rationally define inputs in the context of risk assessments is proposed. Such a model is based on the stochastic simulation of accelerograms that are compatible with seismic scenarios defined by magnitude 4 < Mw < 6.5, epicentral distance 10 km < Repi < 100 km, and different types of soil (rock, stiff soil and soft soil). It was found to be a rational approach that streamlines the simulation of accelerograms to conduct nonlinear dynamic analyses for safety assessments. The model is a function of a few variables customarily known in structural engineering projects. In terms of PGA, PGV and spectral accelerations, the simulated accelerograms were validated by GMPEs calibrated for the UK, Europe and the Middle East, and other stable continental regions. For seismic risk analysis, a straightforward and logical approach to probabilistically assess the risk of NPPs based on the stochastic simulation of accelerograms is studied. It effectively simplifies traditional approaches: for seismic inputs, it avoids the use of selecting/scaling procedures and GMPEs; for structural outputs, it does not use Monte Carlo algorithms to simulate the damage state. However, it demands more expensive computational resources as a large number of nonlinear dynamic analyses are needed. For seismic risk control, strategies to control the risk using seismic protection systems are analysed. This is based on recent experience reported elsewhere of seismically protected nuclear reactor buildings in other areas of medium-to-low seismic activity. Finally, a scenario-based incremental dynamic analysis (IDA) is proposed aimed at the generation of surfaces for unacceptable performance of NPPs as function of earthquake magnitude and distance. It was found that viscous-based devices are more efficient than hysteretic-based devices in controlling the seismic risk of NPPs in the UK. Finally, using the proposed scenario-based IDA, it was found that when considering all controlling scenarios for a representative UK nuclear site, the risk is significantly reduced ranging from 3 to 5 orders of magnitude when using viscous-based devices. 621.48
44	Dopravník obrobků / Workpiece conveyor Vaníček, David January 2018 (has links) This master‘s thesis is focused on the design of manipulator for crankshaft handling in flexible production lines. The first part describes the types of production lines and possible ways of inter-operative manipulation. With regard to the suitability of their use, a suitable variant is selected, which is then conceptually processed and verified by technical calculations. The final conclusion is the verification of the design in terms of safety. Part of the master‘s thesis is technical drawing documentation.
45	Posouzení bezpečnosti činností obsluhy u vodorovné vyvrtávačky WHN 13 CNC / Safety assessment of operator activities for WHN 13 CNC horizontal boring machine Nohavica, Radek January 2020 (has links) The diploma’s thesis deals with the current state of requirements for products resulting from directives of the European Parliament and the European Council. The aim of the thesis is a system analysis of the issue, proposal and justification of the chosen procedure for solving the objectives. Furthermore, the analysis of requirements of current standards and safety analysis related to the work of machine operators in the areas of operation, service and maintenance of horizontal boring machine WHN 13 CNC. The analysis is followed by a proposal for preventive measures for hazards where the value of risks and criticality is unacceptable, leading to their reduction.
46	Ingénierie système et Sûreté de fonctionnement : Méthodologie de synchronisation des modèles d'architecture et d'analyse de risques / System engineering and dependability : methodology synchronization of models Legendre, Anthony 15 December 2017 (has links) L'organisation classique en silos disciplinaires des industries atteint ses limites pour maîtriser la complexité. Les problèmes sont découverts trop tard et le manque de communication entre les experts empêche l'émergence précoce de solutions. C'est pourquoi, il est urgent de fournir de nouvelles approches collaboratives et des moyens d' interactions entre les disciplines d'ingénierie, au début et tout au long du cycle de développement. Dans ce contexte, nous avons étudié l'approche synchronisation de modèles entre deux domaines d'ingénierie : la conception d'architecture de systèmes et la sûreté de fonctionnement. Elle a pour but de construire et maintenir la cohérence entre les modèles.Ces travaux proposent, étudient et analysent une démarche collaborative de synchronisation de modèles. Ils tiennent compte des contextes d’études, des processus, des méthodes appliqués et des points de vue produits par les ingénieurs. Les contributions répondent à des problématiques au niveau des pratiques, des concepts, de la mise en œuvre, des applications et l’implémentation de la synchronisation de modèles. / Classical organization in disciplinary silos in the industry reaches its limits to manage and control complexity. Problems are discovered too late and the lack of communication between experts prevents the early emergence of solutions. This is why it is urgent to provide new collaborative approaches and ways to exchange the models contents between various engineering fields, early and all along the development cycle. In this context, we are particularly interested in a synchronization approach of models between two engineering fields: system architecture design and dependability analysis.This work proposes a collaborative approach of synchronization of models. It takes into account the study contexts, applied processes, applied methods and viewpoint produced by engineers. Contributions address issues at levels of practices, concepts, implementation, applications and implementation of model synchronization. Synchronisation de modèles Cohérence Approche collaborative Models synchronization Consistency Model based system engineering Model based safety assessment Collaborative approach
47	Reliability Assessment of Passive ICS in an SMR as part of the PSA Analysis / Tillförlitligsanalys av passiv ICS i en SMR som en led i PSA analysen Trundle, Graeme January 2023 (has links) Passive safety systems are increasingly being utilized in prospective nuclear power plant designs. Indeed, the use of safety systems driven by natural phenomena might be seen as an unmitigated virtue. However, the low magnitude of the forces involved in such systems, combined with the uncertainty inherent in the factors which affect them, pose a problem in the assessment of their reliability when compared to their active counterparts. Hence, the purpose of this thesis is to investigate and apply a state-of-the-art technique in passive reliability assessment, known as the Reliability Methods of Passive Systems (RMPS) methodology, to the isolation condenser system (ICS) of the prospective BWRX-300 small modular reactor (SMR) design. The ICS is a safety system driven by natural circulation which provides emergency core cooling, residual heat removal, and pressure control for the BWRX-300. Using RMPS to analyze the effect that uncertainties in thermal characteristics of the fuel have on ICS operation, the reliability of natural circulation was quantified with a confidence of 99%. This yielded an immeasurably small failure probability. Considering residual uncertainty, an engineering judgment assigned a failure probability of 1.00E-07. This finding was integrated into a Level 1 probabilistic safety assessment, involving analysis of initiating events, event tree analysis, and failure mode and effect analysis (FMEA) of safety systems, including natural circulation. Analysis of sequences leading to core damage resulted in a core damage frequency of 1.23E-07 yr-1. / Passiva säkerhetssystem används i allt större utsträckning i innovativa kärnkraftverkskonstruktioner. Faktum är att användningen av säkerhetssystem som drivs av naturfenomen kan ses som en oförminskad dygd. Den låga storleken på de krafter som är involverade i sådana system, i kombination med den osäkerhet som är inneboende i de faktorer som påverkar dem, utgör ett problem vid bedömningen av deras tillförlitlighet jämfört med deras aktiva motsvarigheter. Därför är syftet med denna avhandling att undersöka och tillämpa en toppmodern teknik inom passiv tillförlitlighetsbedömning, känd som Reliability Methods of Passive Systems (RMPS) metodologi, på isolationskondensorsystemet (ICS) hos den potentiella BWRX-300 liten modulär reaktor (SMR) design. ICS är ett säkerhetssystem som drivs av naturlig cirkulation som ger nödkylning av kärnan, avlägsnande av restvärme och tryckkontroll för BWRX-300. Med hjälp av RMPS kvantifierades den naturliga cirkulationens tillförlitlighet med en konfidens på 99 %, vilket gav en omätligt liten sannolikhet för misslyckande. Med hänsyn till kvarvarande osäkerhet tilldelade en teknisk dom en felsannolikhet på 1.00E-07. Detta fynd integrerades i en nivå 1 probabilistisk säkerhetsbedömning, som involverade analys av initierande händelser, händelseträdsanalys och felläges- och effektanalys (FMEA) av säkerhetssystem, inklusive naturlig cirkulation. Analys av sekvenser som leder till härdskada resulterade i en härdskadafrekvens på 1,23E-07 år-1. Passive system reliability Probabilistic safety assessment Reliability Methods of Passive Systems Natural circulation TRACE RiskSpectrum Passiv systemtillförlitlighet Probabilistisk säkerhetsbedömning Reliability Methods of Passive Systems Naturlig cirkulation TRACE RiskSpectrum Physical Sciences Fysik
48	Posouzení bezpečnosti činností obsluhy u vertikálního obráběcího centra MCFV 1260 / Safety assessment of operator's activities at MCFV 1260 vertical machining center Valc, Lukáš January 2020 (has links) This diploma thesis deals with the safety assessment of operator’s activities at the MCFV 1260 vertical machining center. Then a system analysis of the issue is created with a proposal and justification of the chosen procedure. In the second part of the thesis there is solved the failure risk analysis, which is focused on the operations of the operator in the area of maintenance, service and during the operation of the vertical machining center located in the company TAJMAC – ZPS Zlín. The result of this thesis is the design and recommendation of preventive measures to reduce unacceptable risks in the relevant operations at the machining center.
49	Development of Sensitive In Vitro Assays to Assess the Ocular Toxicity Potential of Chemicals and Ophthalmic Products McCanna, David January 2009 (has links) The utilization of in vitro tests with a tiered testing strategy for detection of mild ocular irritants can reduce the use of animals for testing, provide mechanistic data on toxic effects, and reduce the uncertainty associated with dose selection for clinical trials. The first section of this thesis describes how in vitro methods can be used to improve the prediction of the toxicity of chemicals and ophthalmic products. The proper utilization of in vitro methods can accurately predict toxic threshold levels and reduce animal use in product development. Sections two, three and four describe the development of new sensitive in vitro methods for predicting ocular toxicity. Maintaining the barrier function of the cornea is critical for the prevention of the penetration of infections microorganisms and irritating chemicals into the eye. Chapter 2 describes the development of a method for assessing the effects of chemicals on tight junctions using a human corneal epithelial and canine kidney epithelial cell line. In Chapter 3 a method that uses a primary organ culture for assessing single instillation and multiple instillation toxic effects is described. The ScanTox system was shown to be an ideal system to monitor the toxic effects over time as multiple readings can be taken of treated bovine lenses using the nondestructive method of assessing for the lens optical quality. Confirmations of toxic effects were made with the utilization of the viability dye alamarBlue. Chapter 4 describes the development of sensitive in vitro assays for detecting ocular toxicity by measuring the effects of chemicals on the mitochondrial integrity of bovine cornea, bovine lens epithelium and corneal epithelial cells, using fluorescent dyes. The goal of this research was to develop an in vitro test battery that can be used to accurately predict the ocular toxicity of new chemicals and ophthalmic formulations. By comparing the toxicity seen in vivo animals and humans with the toxicity response in these new in vitro methods, it was demonstrated that these in vitro methods can be utilized in a tiered testing strategy in the development of new chemicals and ophthalmic formulations. in vitro Alternative Methods alamarBlue rhodamine tight junctions bovine lens viability toxicity mitochondria mitochondria integrity benzalkonium chloride sodium dodecyl sulphate sodium lauryl sulfate scanning electron microscopy Draize Draize maximal average scores zonula occludens cosmetic directive PETA humane society animal league ICCVAM ECVAM JaCVAM BCOP bovine cornea ocular irritants ocular irritation ocular toxicity human corneal epithelial cells vitro confocal confocal microscopy metabolic activity optical quality reactive oxygen species contact lens contact lens care solutions barrier function microbial keratitis mulitipurpose solutions tight junction cell damage claudin ZO-1 occludin MDCK Madin Madin-Darby canine kidney cells cornea human cornea human corneal epithelium epithelial cell line human corneal epithelial cell line sodium fluorescein sodium fluorescein permeability fluorescein permeability ocular surface cell monolayer Araki-Sasaki cell physiology risk assessment safety assessment ScanTox scanning laser lens epithelium corneal cells in vitro model ophthalmic formulations multiple instillation back vertex animal testing rabbit testing alternatives to animal testing cultured bovine lens toxicity of chemicals irritation irritants laser scanner organ culture delayed toxicity toxins hydrogen peroxide cornea toxicity cornea toxicity models prediction of human toxicity no observable adverse effect level lowest observable adverse effect level NOAEL LOAEL toxicity thresholds safety factors cornea uncertainty factors preservatives disinfectants ophthalmic products preclinical preclinical testing epithelial barrier drug penetration clinical confocal microscopy animal rights rabbit cornea human cornea human clinical effects toxic animal rights activist sensitive measures toxic effect toxicity threshold agar overlay agar diffusion agar overlay method agar diffusion method cytochrome cytochrome c apoptosis necrotic apoptotic necrosis caspase rhodamine 123 resazuran resorufin cell death cell viability metabolic dye microsomal microsomal enzymes cytotoxicity cytotoxic cytotoxic effect MTT XTT WST-1 plasma membrane mitochondrial mitochondrial morphology ocular toxicity potential ocular toxicity human corneal epithelial cell line confocal analysis corneal epithelium cell fluorescence alamarBlue assay rhodamine dye animal welfare toxic injury degraded mitochondria epithelial monolayer disinfectants membrane integrity eye toxicity eye viability dye toxicity in humans human toxicity effects on the mitochondria mitochondrial toxicity in vitro battery in vitro test battery ophthalmic eye drop direct contact product safety cytotoxicity potential molecular molecular biology refine reduce replace sensitivity and relevance sensitivity relevance rabbit ocular irritation test product development cytotoxicity models cytotoxicity alternative methods replacements for animal testing three r's beagle tiered testing tiered testing strategy replacements animal testing mechanistic toxicity cornea mitochondria dose response threshold Vision Science and Biology
50	Development of Sensitive In Vitro Assays to Assess the Ocular Toxicity Potential of Chemicals and Ophthalmic Products McCanna, David January 2009 (has links) The utilization of in vitro tests with a tiered testing strategy for detection of mild ocular irritants can reduce the use of animals for testing, provide mechanistic data on toxic effects, and reduce the uncertainty associated with dose selection for clinical trials. The first section of this thesis describes how in vitro methods can be used to improve the prediction of the toxicity of chemicals and ophthalmic products. The proper utilization of in vitro methods can accurately predict toxic threshold levels and reduce animal use in product development. Sections two, three and four describe the development of new sensitive in vitro methods for predicting ocular toxicity. Maintaining the barrier function of the cornea is critical for the prevention of the penetration of infections microorganisms and irritating chemicals into the eye. Chapter 2 describes the development of a method for assessing the effects of chemicals on tight junctions using a human corneal epithelial and canine kidney epithelial cell line. In Chapter 3 a method that uses a primary organ culture for assessing single instillation and multiple instillation toxic effects is described. The ScanTox system was shown to be an ideal system to monitor the toxic effects over time as multiple readings can be taken of treated bovine lenses using the nondestructive method of assessing for the lens optical quality. Confirmations of toxic effects were made with the utilization of the viability dye alamarBlue. Chapter 4 describes the development of sensitive in vitro assays for detecting ocular toxicity by measuring the effects of chemicals on the mitochondrial integrity of bovine cornea, bovine lens epithelium and corneal epithelial cells, using fluorescent dyes. The goal of this research was to develop an in vitro test battery that can be used to accurately predict the ocular toxicity of new chemicals and ophthalmic formulations. By comparing the toxicity seen in vivo animals and humans with the toxicity response in these new in vitro methods, it was demonstrated that these in vitro methods can be utilized in a tiered testing strategy in the development of new chemicals and ophthalmic formulations. in vitro Alternative Methods alamarBlue rhodamine tight junctions bovine lens viability toxicity mitochondria mitochondria integrity benzalkonium chloride sodium dodecyl sulphate sodium lauryl sulfate scanning electron microscopy Draize Draize maximal average scores zonula occludens cosmetic directive PETA humane society animal league ICCVAM ECVAM JaCVAM BCOP bovine cornea ocular irritants ocular irritation ocular toxicity human corneal epithelial cells vitro confocal confocal microscopy metabolic activity optical quality reactive oxygen species contact lens contact lens care solutions barrier function microbial keratitis mulitipurpose solutions tight junction cell damage claudin ZO-1 occludin MDCK Madin Madin-Darby canine kidney cells cornea human cornea human corneal epithelium epithelial cell line human corneal epithelial cell line sodium fluorescein sodium fluorescein permeability fluorescein permeability ocular surface cell monolayer Araki-Sasaki cell physiology risk assessment safety assessment ScanTox scanning laser lens epithelium corneal cells in vitro model ophthalmic formulations multiple instillation back vertex animal testing rabbit testing alternatives to animal testing cultured bovine lens toxicity of chemicals irritation irritants laser scanner organ culture delayed toxicity toxins hydrogen peroxide cornea toxicity cornea toxicity models prediction of human toxicity no observable adverse effect level lowest observable adverse effect level NOAEL LOAEL toxicity thresholds safety factors cornea uncertainty factors preservatives disinfectants ophthalmic products preclinical preclinical testing epithelial barrier drug penetration clinical confocal microscopy animal rights rabbit cornea human cornea human clinical effects toxic animal rights activist sensitive measures toxic effect toxicity threshold agar overlay agar diffusion agar overlay method agar diffusion method cytochrome cytochrome c apoptosis necrotic apoptotic necrosis caspase rhodamine 123 resazuran resorufin cell death cell viability metabolic dye microsomal microsomal enzymes cytotoxicity cytotoxic cytotoxic effect MTT XTT WST-1 plasma membrane mitochondrial mitochondrial morphology ocular toxicity potential ocular toxicity human corneal epithelial cell line confocal analysis corneal epithelium cell fluorescence alamarBlue assay rhodamine dye animal welfare toxic injury degraded mitochondria epithelial monolayer disinfectants membrane integrity eye toxicity eye viability dye toxicity in humans human toxicity effects on the mitochondria mitochondrial toxicity in vitro battery in vitro test battery ophthalmic eye drop direct contact product safety cytotoxicity potential molecular molecular biology refine reduce replace sensitivity and relevance sensitivity relevance rabbit ocular irritation test product development cytotoxicity models cytotoxicity alternative methods replacements for animal testing three r's beagle tiered testing tiered testing strategy replacements animal testing mechanistic toxicity cornea mitochondria dose response threshold Vision Science and Biology

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