An in vitro depth of injury prediction model for a histopathologic classification of EPA and GHS eye irritants

Lebrun, Stewart J.; Xie, Yong; Chavez, Sara; Chan, Roxanne; Jester, James V.

doi:10.1016/j.tiv.2019.104628

Cited by 11 publications

(7 citation statements)

References 21 publications

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“…In general, cell or tissue injury occurring progressively deeper into the cornea results in increasingly worse injuries. Whereas numerous attempts have been reported [45,46,74,[89][90][91][92] using various histopathology methods to determine the thresholds delineating the DOI between irritation categories in ex vivo/in vitro corneal systems, not surprisingly some overlap in the DOI between categories is observed. The following summarizes generalized findings on the depth of injuries, relative to chemical irritation potentials.…”

Section: Depth Of Injury Conceptmentioning

confidence: 99%

“…In comparison, the category II materials tended to induce stromal injuries notably deeper into the stroma. It should be noted that some overlap was measured in the DOI, particularly among the category II and III chemicals [91]; however, this overlap is not unexpected given the variability of the rabbit response, particularly for chemicals that are classified as mild and moderate [18]. Epithelial permeability increases if substances injure or destroy the epithelial barrier function initially by injuring tight junctions or desmosomes and progressively by necrosis of the epithelial layers.…”

Section: Depth Of Injury Conceptmentioning

confidence: 99%

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Human-relevant approaches to assess eye corrosion/irritation potential of agrochemical formulations

Clippinger¹,

Raabe

Allen

et al. 2021

Cutaneous and Ocular Toxicology

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There are multiple in vitro and ex vivo eye irritation and corrosion test methods that are available as internationally harmonized test guidelines for regulatory use. Despite their demonstrated usefulness to a broad range of substances through inter-laboratory validation studies, they have not been widely adopted for testing agrochemical formulations due to a lack of concordance with parallel results from the traditional regulatory test method for this endpoint, the rabbit eye test. The inherent variability of the rabbit test, differences in the anatomy of the rabbit and human eyes, and differences in modelling exposures in rabbit eyes relative to human eyes contribute to this lack of concordance. Ultimately, the regulatory purpose for these tests is protection of human health, and, thus, there is a need for a testing approach based on human biology. This paper reviews the available in vivo, in vitro and ex vivo test methods with respect to their relevance to human ocular anatomy, anticipated exposure scenarios, and the mechanisms of eye irritation/corrosion in humans. Each of the in vitro and ex vivo methods described is generally appropriate for identifying non-irritants. To discriminate among eye irritants, the human three-dimensional epithelial and full thickness corneal models provide the most detailed information about the severity of irritation. Consideration of the mechanisms of eye irritation, and the strengths and limitations of the in vivo, in vitro and ex vivo test methods, show that the in vitro/ex vivo methods are as or more reflective of human biology and less variable than the currently used rabbit approach. Suggestions are made for further optimizing the most promising methods to distinguish between severe (corrosive), moderate, mild and non-irritants and provide information about the reversibility of effects. Also considered is the utility of including additional information (e.g. physical chemical properties), consistent with the Organization for Economic Cooperation and Development's guidance document on an integrated approach to testing and assessment of potential eye irritation. Combining structural and functional information about a test substance with test results from human-relevant methods will ensure the best protection of humans following accidental eye exposure to agrochemicals.

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Section: Depth Of Injury Conceptmentioning

confidence: 99%

Section: Depth Of Injury Conceptmentioning

confidence: 99%

Human-relevant approaches to assess eye corrosion/irritation potential of agrochemical formulations

Clippinger¹,

Raabe

Allen

et al. 2021

Cutaneous and Ocular Toxicology

View full text Add to dashboard Cite

show abstract

“…Currently, there are two approaches concerning the requirements and the suitability of the in vitro tissue models to study ocular irritation, drug transport, and wound healing. Many investigators believe that an in vitro corneal culture model should be as complex as possible to mimic the function of the in vivo cornea as close as possible (Lotz et al 2016;Shafaie et al 2016;Lebrun et al 2019). The ideal culture model should be able to recapitulate the in vivo defense systems, barrier function, and metabolic activity.…”

Section: Requirements For In Vitro Reconstructed 3d Corneal Tissue Modelsmentioning

confidence: 99%

“…Damage to the basement membrane correlated with stromal injury and significant delay or prevention of recovery (Ljubimov and Saghizadeh 2015). In addition, damage to the basement membrane and the stroma can lead to activation of quiescent keratocytes, the formation of fibrotic tissue leading to corneal haze or scarring, and eventually loss of sight (Lebrun et al 2019). Hence, the regeneration of the corneal epithelial basement membrane may be a critical factor for determining corneal healing time and may be one of the key major drivers for classification of ocular irritation (Lebrun et al 2019).…”

Section: Drivers Of Classification and Tiered Testing Approaches In Eye Irritation Testingmentioning

confidence: 99%

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Kaluzhny

Klausner

2021

In Vitro Cell.Dev.Biol.-Animal

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Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the improvements in primary cell isolation, cell culture techniques, and media, which have led to improved in vitro corneal tissue models and test methods. Most in vitro models for ocular toxicology attempt to reproduce the corneal epithelial tissue which consists of 4-5 layers of non-keratinized corneal epithelial cells that form tight junctions, thereby limiting the penetration of chemicals, xenobiotics, and pharmaceuticals. Also, significant efforts have been directed toward the development of more complex threedimensional (3D) equivalents to study wound healing, drug permeation, and bioavailability. This review focuses on in vitro reconstructed 3D corneal tissue models and their utilization in ocular toxicology as well as their application to pharmacology and ophthalmic research. Current human 3D corneal epithelial cell culture models have replaced in vivo animal eye irritation tests for many applications, and substantial validation efforts are in progress to verify and approve alternative eye irritation tests for widespread use. The validation of drug absorption models and further development of models and test methods for many ophthalmic and ocular disease applications is required.

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“…These eyes were organ cultured for either 3 hours or overnight using previously reported methods. 37 Corneas were then fixed in 2% paraformaldehyde and then processed for phalloidin (1:100) and propidium iodide (0.01 mg/mL) staining to assess corneal cell viability posttreatment.…”

Section: Treatmentmentioning

confidence: 99%

Enhanced Transepithelial Riboflavin Delivery Using Femtosecond Laser-Machined Epithelial Microchannels

Bradford

Mikula

Xie

et al. 2020

Trans. Vis. Sci. Tech.

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This study describes a femtosecond laser (FS) approach to machine corneal epithelial microchannels for enhancing riboflavin (Rf) penetration into the cornea prior to corneal crosslinking (CXL). Methods: Using a 1030-nm FS laser with 5-to 10-μJ pulse energy, the corneal epithelium of slaughterhouse rabbit eyes was machined to create 2-μm-diameter by 25-μmlong microchannels at a density of 100 or 400 channels/mm 2. Rf penetration through the microchannels was then determined by applying 1% Rf in phosphate-buffered saline for 30 minutes followed by removal of the cornea and extraction from the central stromal button. Stromal Rf concentrations were then compared to those obtained using standard epithelial debridement or 0.01% benzalkonium chloride (BAK) to disrupt the epithelial barrier. Results: Microchannels formed using a 5-μJ/pulse at a density of 400 channels/mm 2 achieved a stromal Rf concentration that was 50% of that achieved by removal of the corneal epithelium and imbibing with 1% Rf. Stromal Rf levels were also equal to that of debrided corneas soaked with 0.5% Rf, threefold higher than those soaked with 0.1% Rf, and twofold higher than corneas soaked in BAK without epithelial debridement. Organ culture of treated corneas showed a normal corneal epithelium following FS machining while BAK-treated corneas showed extensive epithelial and stromal damage at 24 hours posttreatment. Conclusions: FS corneal epithelial machining can be used to enhance penetration of Rf into the stroma for corneal CXL. Translational Relevance: The creation of epithelial microchannels allows for stromal Rf concentrations high enough to perform true transepithelial crosslinking.

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An in vitro depth of injury prediction model for a histopathologic classification of EPA and GHS eye irritants

Cited by 11 publications

References 21 publications

Human-relevant approaches to assess eye corrosion/irritation potential of agrochemical formulations

Human-relevant approaches to assess eye corrosion/irritation potential of agrochemical formulations

In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Enhanced Transepithelial Riboflavin Delivery Using Femtosecond Laser-Machined Epithelial Microchannels

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