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dc.contributor.authorMcCanna, David
dc.date.accessioned2009-04-27 14:06:30 (GMT)
dc.date.available2009-04-27 14:06:30 (GMT)
dc.date.issued2009-04-27T14:06:30Z
dc.date.submitted2009
dc.identifier.urihttp://hdl.handle.net/10012/4338
dc.description.abstractThe 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.en
dc.language.isoenen
dc.publisherUniversity of Waterlooen
dc.subjectin vitroen
dc.subjectAlternative Methodsen
dc.subjectalamarBlueen
dc.subjectrhodamineen
dc.subjecttight junctionsen
dc.subjectbovine lensen
dc.subjectviabilityen
dc.subjecttoxicityen
dc.subjectmitochondriaen
dc.subjectmitochondria integrityen
dc.subjectbenzalkonium chlorideen
dc.subjectsodium dodecyl sulphateen
dc.subjectsodium lauryl sulfateen
dc.subjectscanning electron microscopyen
dc.subjectDraizeen
dc.subjectDraize maximal average scoresen
dc.subjectzonula occludensen
dc.subjectcosmetic directiveen
dc.subjectPETAen
dc.subjecthumane societyen
dc.subjectanimal leagueen
dc.subjectpeople for the ethical treatment of animalsen
dc.subjectinteragency coordinating committee on the validation of alternative methodsen
dc.subjectICCVAMen
dc.subjectECVAMen
dc.subjectJaCVAMen
dc.subjectBCOPen
dc.subjectbovine corneaen
dc.subjectocular irritantsen
dc.subjectocular irritationen
dc.subjectocular toxicityen
dc.subjecthuman corneal epithelial cellsen
dc.subjectvitroen
dc.subjectconfocalen
dc.subjectconfocal microscopyen
dc.subjectmetabolic activityen
dc.subjectoptical qualityen
dc.subjectreactive oxygen speciesen
dc.subjectcontact lensen
dc.subjectcontact lens care solutionsen
dc.subjectbarrier functionen
dc.subjectmicrobial keratitisen
dc.subjectmulitipurpose solutionsen
dc.subjecttight junctionen
dc.subjectcell damageen
dc.subjectclaudinen
dc.subjectZO-1en
dc.subjectoccludinen
dc.subjectMDCKen
dc.subjectMadinen
dc.subjectMadin-Darbyen
dc.subjectcanine kidney cellsen
dc.subjectcorneaen
dc.subjecthuman corneaen
dc.subjecthuman corneal epitheliumen
dc.subjectepithelial cell lineen
dc.subjecthuman corneal epithelial cell lineen
dc.subjectsodium fluoresceinen
dc.subjectsodium fluorescein permeabilityen
dc.subjectfluorescein permeabilityen
dc.subjectocular surfaceen
dc.subjectcell monolayeren
dc.subjectAraki-Sasakien
dc.subjectcell physiologyen
dc.subjectrisk assessmenten
dc.subjectsafety assessmenten
dc.subjectScanToxen
dc.subjectscanning laseren
dc.subjectlens epitheliumen
dc.subjectcorneal cellsen
dc.subjectin vitro modelen
dc.subjectophthalmic formulationsen
dc.subjectmultiple instillationen
dc.subjectback vertexen
dc.subjectanimal testingen
dc.subjectrabbit testingen
dc.subjectalternatives to animal testingen
dc.subjectcultured bovine lensen
dc.subjecttoxicity of chemicalsen
dc.subjectirritationen
dc.subjectirritantsen
dc.subjectlaser scanneren
dc.subjectorgan cultureen
dc.subjectdelayed toxicityen
dc.subjecttoxinsen
dc.subjecthydrogen peroxideen
dc.subjectcornea toxicityen
dc.subjectcornea toxicity modelsen
dc.subjectprediction of human toxicityen
dc.subjectno observable adverse effect levelen
dc.subjectlowest observable adverse effect levelen
dc.subjectNOAELen
dc.subjectLOAELen
dc.subjecttoxicity thresholdsen
dc.subjectsafety factorsen
dc.subjectcorneaen
dc.subjectuncertainty factorsen
dc.subjectpreservativesen
dc.subjectdisinfectantsen
dc.subjectophthalmic productsen
dc.subjectpreclinicalen
dc.subjectpreclinical testingen
dc.subjectepithelial barrieren
dc.subjectdrug penetrationen
dc.subjectclinical confocal microscopyen
dc.subjectanimal rightsen
dc.subjectrabbit corneaen
dc.subjecthuman corneaen
dc.subjecthuman clinical effectsen
dc.subjecttoxicen
dc.subjectanimal rights activisten
dc.subjectsensitive measuresen
dc.subjecttoxic effecten
dc.subjecttoxicity thresholden
dc.subjectagar overlayen
dc.subjectagar diffusionen
dc.subjectagar overlay methoden
dc.subjectagar diffusion methoden
dc.subjectcytochromeen
dc.subjectcytochrome cen
dc.subjectapoptosisen
dc.subjectnecroticen
dc.subjectapoptoticen
dc.subjectnecrosisen
dc.subjectcaspaseen
dc.subjectrhodamine 123en
dc.subjectresazuranen
dc.subjectresorufinen
dc.subjectcell deathen
dc.subjectcell viabilityen
dc.subjectmetabolic dyeen
dc.subjectmicrosomalen
dc.subjectmicrosomal enzymesen
dc.subjectcytotoxicityen
dc.subjectcytotoxicen
dc.subjectcytotoxic effecten
dc.subjectMTTen
dc.subjectXTTen
dc.subjectWST-1en
dc.subjectplasma membraneen
dc.subjectmitochondrialen
dc.subjectmitochondrial morphologyen
dc.subjectocular toxicity potentialen
dc.subjectocular toxicityen
dc.subjecthuman corneal epithelialen
dc.subjectcell lineen
dc.subjectconfocal analysisen
dc.subjectcorneal epitheliumen
dc.subjectcell fluorescenceen
dc.subjectalamarBlue assayen
dc.subjectrhodamine dyeen
dc.subjectanimal welfareen
dc.subjecttoxic injuryen
dc.subjectdegraded mitochondriaen
dc.subjectepithelial monolayeren
dc.subjectdisinfectantsen
dc.subjectmembrane integrityen
dc.subjecteye toxicityen
dc.subjecteyeen
dc.subjectviability dyeen
dc.subjecttoxicity in humansen
dc.subjecthuman toxicityen
dc.subjecteffects on the mitochondriaen
dc.subjectmitochondrial toxicityen
dc.subjectin vitro batteryen
dc.subjectin vitro test batteryen
dc.subjectophthalmic eye dropen
dc.subjectdirect contacten
dc.subjectproduct safetyen
dc.subjectcytotoxicity potentialen
dc.subjectmolecularen
dc.subjectmolecular biologyen
dc.subjectrefine reduce replaceen
dc.subjectsensitivity and relevanceen
dc.subjectsensitivityen
dc.subjectrelevanceen
dc.subjectrabbit ocular irritation testen
dc.subjectproduct developmenten
dc.subjectcytotoxicity modelsen
dc.subjectcytotoxicity alternative methodsen
dc.subjectreplacements for animal testingen
dc.subjectthree r'sen
dc.subjectbeagleen
dc.subjecttiered testingen
dc.subjecttiered testing strategyen
dc.subjectreplacements animal testingen
dc.subjectmechanistic toxicityen
dc.subjectcornea mitochondriaen
dc.subjectdose responseen
dc.subjectthresholden
dc.titleDevelopment of Sensitive In Vitro Assays to Assess the Ocular Toxicity Potential of Chemicals and Ophthalmic Productsen
dc.typeDoctoral Thesisen
dc.pendingfalseen
dc.subject.programVision Science and Biologyen
uws-etd.degree.departmentSchool of Optometryen
uws-etd.degreeDoctor of Philosophyen
uws.typeOfResourceTexten
uws.peerReviewStatusUnrevieweden
uws.scholarLevelGraduateen


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