A ubiquitous tire rubber additive induced serious eye injury in zebrafish (Danio rerio).

Previous studies have indicated that tire wear particles (TWPs) leachate exposure induced serious eye injury in fish through inhibiting the thyroid peroxidase (TPO) enzyme activity. However, the main TPO inhibitors in the leachate were still unknown. In this study, we identified 2-Mercaptobenzothiazole (MBT) as the potential TPO inhibitor in the TWPs leachate through references search, model prediction based on Danish QSAR and ToxCast database, molecular docking, and in vivo assay. We further explored the toxic mechanism of MBT under environmentally relevant concentrations. The decreased eye size of zebrafish larvae was mainly caused by the decreased lens diameter and cell density in the inner nuclear layer (INL) and outer nuclear layer (ONL) of the retina. Transcriptomics analysis demonstrated that the eye phototransduction function was significantly suppressed by inhibiting the photoreceptor cell proliferation process after MBT exposure. The altered opsin gene expression and decreased opsin protein levels were induced by weakening thyroid hormone signaling after MBT treatment. These results were comparable to those obtained from a known TPO inhibitor, methimazole. This study has identified MBT as the primary TPO inhibitor responsible for inducing eye impairment in zebrafish larvae exposed to TWPs leachate. It is crucial for reducing the toxicity of TWPs leachate in fish.

Chloropicrin induced ocular injury: Biomarkers, potential mechanisms, and treatments.

Ocular tissue, especially the cornea, is overly sensitive to chemical exposures. The availability and adoption of chemical threat agent chloropicrin (CP) is growing in the United States as a pesticide and fumigant; thereby increasing the risk of its use in warfare, terrorist attacks and non-intentional exposure. Exposure to CP results in immediate ocular, respiratory, and dermal injury; however, we lack knowledge on its mechanism of toxicity as well as of its breakdown products like chlorine and phosgene, and effective therapies are elusive. Herein, we have reviewed the recent findings on exposure route, toxicity and likely mechanisms of CP induced ocular toxicity based on other vesicating chemical warfare agents that cause ocular injury. We have focused on the implication of their toxicity and mechanistic outcomes in the ocular tissue, especially the cornea, which could be useful in the development of broad-spectrum effective therapeutic options. We have discussed on the potential countermeasures, overall hallmarks and challenges involved in studying ocular injuries from chemical threat agent exposures. Finally, we reviewed useful available technologies and methods that can assist in the identification of effective medical countermeasures for chemical threat agents related ocular injuries.

[Lens injury as a complication of intravitreal medication injection]. / Linsenverletzungen als Komplikation bei intravitrealer Medikamenteneingabe.

BACKGROUND: Intravitreal medication injections are an efficient and low-risk delivery technique for treating various retinal diseases. Rare serious complications include increased intraocular pressure, vitreous hemorrhage, retinal tears and detachment, intraocular inflammation and endophthalmitis. In the case series presented here, we report iatrogenic lens injuries caused by inadequate performance of intravitreal injections. METHODS: A multicenter data collection of patients treated with intravitreal injections with visible iatrogenic lens defects from 2016 to 2023 was retrospectively performed. RESULTS: Lens trauma after intravitreal injections was identified in six cases (69.3±6.5 years). While five cases were observed after anti-VEGF therapy, we identified lens injury after dexamethasone implantation in one patient. CONCLUSION: Iatrogenic lens injury during intravitreal injection is preventable with the correct injection technique. Knowledge of individual axis length and lens status also helps to avoid this complication.

Mouse Model of Nitrogen Mustard Ocular Surface Injury Characterization and Sphingolipid Signaling.

Vesicating chemicals like sulfur mustard (SM) or nitrogen mustard (NM) can cause devastating damage to the eyes, skin, and lungs. Eyes, being the most sensitive, have complicated pathologies that can manifest immediately after exposure (acute) and last for years (chronic). No FDA-approved drug is available to be used as medical counter measures (MCMs) against such injuries. Understanding the pathological mechanisms in acute and chronic response of the eye is essential for developing effective MCMs. Here, we report the clinical and histopathological characterization of a mouse model of NM-induced ocular surface injury (entire surface) developed by treating the eye with 2% (w/v) NM solution for 5 min. Unlike the existing models of specific injury, our model showed severe ocular inflammation, including the eyelids, structural deformity of the corneal epithelium and stroma, and diminished visual and retinal functions. We also observed alterations of the inflammatory markers and their expression at different phases of the injury, along with an activation of acidic sphingomyelinase (aSMase), causing an increase in bioactive sphingolipid ceramide and a reduction in sphingomyelin levels. This novel ocular surface mouse model recapitulated the injuries reported in human, rabbit, and murine SM or NM injury models. NM exposure of the entire ocular surface in mice, which is similar to accidental or deliberate exposure in humans, showed severe ocular inflammation and caused irreversible alterations to the corneal structure and significant vision loss. It also showed an intricate interplay between inflammatory markers over the injury period and alteration in sphingolipid homeostasis in the early acute phase.

Predicting clinical outcome of sulfur mustard induced ocular injury using machine learning model.

The sight-threatening sulfur mustard (SM) induced ocular injury presents specific symptoms in each clinical stage. The acute injury develops in all exposed eyes and may heal or deteriorate into chronic late pathology. Early detection of eyes at risk of developing late pathology may assist in providing unique monitoring and specific treatments only to relevant cases. In this study, we evaluated a machine-learning (ML) model for predicting the development of SM-induced late pathology based on clinical data of the acute phase in the rabbit model. Clinical data from 166 rabbit eyes exposed to SM vapor was used retrospectively. The data included a comprehensive clinical evaluation of the cornea, eyelids and conjunctiva using a semi-quantitative clinical score. A random forest classifier ML model, was trained to predict the development of corneal neovascularization four weeks post-ocular exposure to SM vapor using clinical scores recorded three weeks earlier. The overall accuracy in predicting the clinical outcome of SM-induced ocular injury was 73%. The accuracy in identifying eyes at risk of developing corneal neovascularization and future healed eyes was 75% and 59%, respectively. The most important parameters for accurate prediction were conjunctival secretion and corneal opacity at 1w and corneal erosions at 72 h post-exposure. Predicting the clinical outcome of SM-induced ocular injury based on the acute injury parameters using ML is demonstrated for the first time. Although the prediction accuracy was limited, probably due to the small dataset, it pointed out towards various parameters during the acute injury that are important for predicting SM-induced late pathology and revealing possible pathological mechanisms.

Causal factors of work-related chemical eye injuries reported to the Dutch Poisons Information Center.

This study investigated the circumstances of chemical occupational eye exposures reported to the Dutch Poisons Information Center. During a 1-year prospective study, data were collected through a telephone survey of 132 victims of acute occupational eye exposure. Victims were often exposed to industrial products (35%) or cleaning products (27%). Most patients developed no or mild symptoms. Organizational factors (such as lack of work instructions (52%)), and personal factors (such as time pressure and fatigue (50%), and not adequately using personal protective equipment (PPE, 14%), were the main causes of occupational eye exposures. Exposure often occurred during cleaning activities (34%) and personal factors were reported more often during cleaning (67%) than during other work activities (41%). Data from Poison Control Centers are a valuable source of information, enabling the identification of risk factors for chemical occupational eye exposure. This study shows that personal factors like time pressure and fatigue play a significant role, although personal factors may be related to organizational issues such as poor communication. Therefore, risk mitigation strategies should focus on technical, organizational, and personal factors. The need to follow work instructions and proper use of PPE should also have a prominent place in the education and training of workers.

A corneo-retinal hypercitrullination axis underlies ocular injury to nitrogen mustard.

The vesicant sulfur mustard (SM) is a chemical warfare agent that causes acute and chronic injury to the cornea and proximal anterior segment structures. Despite clinical evidence of SM-exposure causing unexplained retinal deficits, there have been no animal studies conducted to examine the retinal toxicity of this vesciant. The cardinal hallmark of retinal response to stressors or injury is the activation of reactive gliosis, a cellular process largely governed by Müller glia. Previously we showed that corneal exposure to sodium hydroxide elicits rapid induction of reactive gliosis and results in retinal degeneration in a dose-related manner. Based on this evidence, we hypothesized that the vesicant nitrogen mustard (NM), an analog of SM, may also elicit reactive gliosis. To test this idea, we developed a mouse model of NM ocular injury and investigated corneal and retinal effects focusing on citrullination, a posttranslational modification (PTM) of proteins. This PTM was recently linked to alkali injury and has also been shown to occur in retinal degenerative conditions. Here, we demonstrate that corneal exposure to 1% NM causes a synchronous activation of citrullination in both the cornea and retina with hypercitrullination becoming apparent temporally and manifesting with altered cellular expression characteristics. A key finding is that ocular citrullination occurs acutely as early as 1-h post-injury in both the cornea and retina, which underscores a need for expeditious interception of this acute corneal and retinal response. Moreover, exploiting dose response and temporal studies, we uncoupled NM-induced retinal citrullination from its induction of retinal gliosis. Our findings demonstrate that hypercitrullination is a common corneo-retinal mechanism that sensitizes the eye to NM injury and suggests that counteracting hypercitrullination may provide a suitable countermeasure to vesicant injury.

Eyes Instead of Ears: Eye Injuries Following Ocular Exposure to Otic Medications.

To determine the epidemiology of ocular exposures and toxicoses in dogs and cats from otic products, 79 dog and cat cases with an ocular exposure to a topical otic medication were retrieved from the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center database. Prescription products were involved in 75/79 (95%) of cases, and over-the-counter products in 4 (5%). Clinical signs included conjunctivitis, blepharospasm, epiphora, ocular discharge, and corneal ulceration. Medication error, specifically involving mistaken identification (i.e., an otic product confused with an ophthalmic product), occurred in 68/79 (86%) of cases. In 4 of these 68 cases, an otic instead of an ophthalmic medication was mistakenly dispensed to the pet owner. Unintentional delivery (i.e., accidental ocular exposure in the course of an otic application) occurred in 9/79 (11%) of cases, and 2 (3%) cases involved intentional delivery of otic products to the eyes. Because mistaken identification was the most common cause of ocular toxicoses from otic products, separate storage and/or distinctive packaging for ophthalmic versus otic products could reduce medication errors. Animal poison control center epidemiological data can be used as a source of information regarding veterinary medication errors.

Research models of sulfur mustard- and nitrogen mustard-induced ocular injuries and potential therapeutics.

Sulfur mustard (SM) is a notorious, bifunctional alkylating vesicant that was first used in warfare during World War I in 1917 and since then has been deployed in numerous skirmishes with its most recent documented use being during the Middle Eastern conflicts. Apart from its use in combat and terrorist activities, continual threat of accidental exposure from old stockpiles and improperly discarded munitions is ever present, especially to the innocent and unassuming civilian populations. SM can cause devastating injuries, depending on the dosage of SM exposure, route of exposure, as well as the physiological conditions of the individuals exposed. The most common routes of exposure are ocular, dermal, and exposure to the lungs and respiratory tissues through inhalation. Eyes are the most susceptible organ to SM-induced toxicities owing to their high moisture content and rapidly dividing cells. Additionally, ocular injury causes the most expeditious disablement of individuals even upon whole-body exposures. Therefore, it is imperative to understand the mechanisms underlying SM-induced ocular toxicity and design therapeutic interventions to prevent/mitigate ocular injuries. Ocular SM exposure may cause a wide range of symptoms such as inflammation, lacrimation, itching, dryness, photophobia, edema of the cornea/sclera/retina/iris, conjunctivitis, degradation of the corneal layer, fusion of two or more ocular layers, neovascularization, fibrosis, and temporary or permanent structural damage to one or more ocular layers. These symptoms may lead to vision impairments, resulting in partial or complete blindness that may be permanent. The highly toxic and exceedingly notorious nature of SM makes it a highly regulated chemical, requiring very expensive licensing, security, and safety requirements; thus, the more easily accessible analogue, nitrogen mustard (NM) that mimics SM-induced toxicity and injuries is employed in plethora of studies conducted in different animal models and culture systems. This review provides a comprehensive account of the injuries and symptoms that occur upon ocular SM exposures in human patients as well as studies in animal (in vivo, ex vivo) and cell (in vitro) models of SM and NM ocular exposures. Special emphasis has been laid on highlighting the strengths and lacunae in the research as well as the possible unexplored avenues of mechanisms underlying mustard-induced ocular injury that can be explored in future research endeavors. Furthermore, development of therapeutic interventions and targets of interest in the ocular system exposed to SM and NM, based on studies in human patients as well as in vivo, ex vivo, and in vitro models has been discussed in great depth, providing a valuable knowledge database to delineate pathways associated with vesicant-induced toxicity, and strategies/diagnostic tools against SM-induced toxicity.

Determining the effect of ocular chemical injuries on topical drug delivery.

Ocular chemical injuries (OCIs) commonly cause ocular damage and visual loss and treatment uses topical therapies to facilitate healing and limit complications. However, the impact of chemical injury on corneal barrier function and treatment penetration is unknown. Therefore, the aim of this study was to determine the effect of OCI on drug penetration and absorption. Porcine corneal explants were used to assess histological damage, electrical resistance, and the trans-corneal penetration/corneal adsorption of reference compounds (sodium fluorescein and rhodamine B) and dexamethasone. Corneal explants were injured with either 1 M sulfuric acid, or 1 M sodium hydroxide. Dexamethasone penetration was measured using high-performance liquid chromatography (HPLC) and that of fluorescein and rhodamine using fluorescence. Dexamethasone corneal adsorption was measured using enzyme-linked immunoabsorbant assay (ELISA). Both acid and alkaline injuries reduced trans-corneal electrical resistance. NaOH injury increased hydrophilic fluorescein penetration (NaOH 8.59 ± 1.50E-05 cm.min-1 vs. Hanks' Balanced Salt Solution (HBSS) 1.64 ± 1.01E-06 cm.min-1) with little impact on hydrophobic rhodamine B (1 M NaOH 6.55 ± 2.45E-04 cm.min-1 vs. HBSS 4.60 ± 0.972E-04 cm.min-1) and dexamethasone penetration (1 M NaOH 3.00 ± 0.853E-04 cm.min-1 vs. HBSS 2.69 ± 0.439E-04 cm.min-1). By contrast, H2SO4 decreased trans-corneal penetration of hydrophilic fluorescein (H2SO4 1.16 ± 14.2E-07 cm.min-1) and of hydrophobic dexamethasone (H2SO4 1.88 ± 0.646E-04 cm.min-1) and rhodamine B (H2SO4 4.60 ± 1.42E-05 cm.min-1). Acid and alkaline OCI differentially disrupted the corneal epithelial barrier function. Acid injury reduced penetration of hydrophobic dexamethasone and rhodamine B as well as hydrophilic fluorescein, which may translate clinically into reduced drug penetration after OCI, while alkaline injury increased fluorescein penetration, with minimal effect on dexamethasone and rhodamine B penetration.

Inter-laboratory performance of ICE histopathology scoring to identify UN GHS Category 1 surfactants and non-extreme pH detergents.

The inter-laboratory performance of Isolated Chicken Eye (ICE) histopathology scoring was assessed for predicting EU CLP/UN GHS Cat. 1 surfactants. Furthermore, the predictive capacity of ICE histopathology was evaluated for the combined dataset of surfactants and existing data for non-extreme pH (2 < pH < 11.5) detergents. Use of ICE histopathology led to increased sensitivity compared to the ICE test method alone for surfactants. When combined with the existing dataset of detergents, use of histopathology in addition to the standard ICE test method decreased the false negative rates from 64% (14/22) to 27% (6/22); increased accuracy from 53% (16/30) to 77% (23/30); and led to acceptable level of false positives (from 0/8 to 1/8 (12.5%). Moreover, good reproducibility of ICE histopathology predictions conducted on the same slides was found between pathologists and peer-reviewers from three independent laboratories (10/12 or 83%) and over time. Use of ICE histopathology was therefore found suitable to predict EU CLP/UN GHS Cat. 1 surfactants and non-extreme pH detergents. In addition, appropriate reproducibility of ICE histopathology was found, provided that i) an internal peer-review system was in place; ii) original slides were assessed to enable evaluation of three dimensional effects; and iii) appropriate training and proficiency appraisal were conducted.

[Rational use of topical drugs to avoid drug-induced ocular surface injury].

Drug-induced ocular surface injury often occurs in the clinical diagnosis and treatment of eye diseases. Because of concealed clinical manifestations, it is difficult to be distinguished, causing misdiagnosis and mistreatment, and leading to serious corneal and conjunctival damage, and even visual disfunction. In this article, we focus on the mechanism, active prevention and effective treatment of drug-induced ocular surface injury, and propose that the rational use of local eye drugs can effectively reduce or avoid drug-induced ocular surface injury and improve the clinical diagnosis and treatment of eye diseases. (Chin J Ophthalmol, 2021, 57: 561-563).

SkinEthic HCE Time-to-Toxicity on solids: A test method for distinguishing chemicals inducing serious eye damage, eye irritation and not requiring classification and labelling.

This study describes the development of a Time-to-Toxicity approach for solids (TTS) based on the SkinEthic™ HCE tissue construct, capable to distinguish chemicals that do not require classification for serious eye damage/eye irritation (No Cat.) from chemicals that require classification for eye irritation (Cat. 2), and serious eye damage (Cat. 1). Briefly, the time-to-toxicity of 69 solids was evaluated by exposing SkinEthic™ HCE tissue constructs to the test chemical for two different time periods (30-min, and 120-min). Based on the viability observed for the different exposure periods, a classification was assigned. The within laboratory reproducibility in terms of concordance in classifications (3 UN GHS categories), based on a set of 48 solids, was 93.7%. Furthermore, 73.6% Cat. 1 (N = 24), 55.6% Cat. 2 (N = 15) and 72.2% No Cat. (N = 30) were correctly identified with the SkinEthic™ HCE TTS test method. This study provides evidence that the SkinEthic™ HCE Time-to-Toxicity method (multiple exposure times) can distinguish Cat. 2 solids from Cat. 1 solids. This is an added value compared to the SkinEthic™ HCE EITS method (single exposure time) that can distinguish No Cat. chemicals from chemicals that do require classification and labelling for eye irritation/serious eye damage (Cat. 2/Cat. 1).

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

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.

Therapeutic measures for sulfur mustard-induced ocular injury.

The use of sulfur mustard (SM) in global terrorism is still a relevant threat to both civilian population and military personnel. Casualties exposed to SM may present mild, moderate or severe acute ocular lesions followed by a complete ocular resolution, chronic lesions or re-emerged ocular pathologies after a latent period. Current treatment for SM-induced ocular injury is based mainly on the clinical manifestation at the different stages of the injury and includes pharmaceutical and surgical interventions. These therapeutic measures are beneficial but not sufficient, and the ocular injury remains a continuous challenge for medical professionals. This review focuses on treatment experience carried out in humans and studied in animal models, for both SM-induced ocular acute injury and late pathology. In general, therapeutic measures are based on clinical features of the ocular injury or on the involvement of specific factors during the ocular injury that point out towards potential treatments. Anti-inflammatory treatments and limbal stem cell transplantation techniques were developed based on the clinical manifestation of the ocular injury. Optional therapies for impaired corneal innervation and endothelium are suggested for future research. Additionally, studies on potential treatments with anti-matrix metalloproteinase (MMP), anti-vascular endothelial growth factor (VEGF) and anti-IL-6 agents are discussed. Consequently, future studies may reveal the potential of additional pharmacological and biological treatments or advanced cellular and molecular biology methods to serve as novel therapeutic measures and techniques for this complicated ocular injury.

Pediatric Eye Injuries by Hydroalcoholic Gel in the Context of the Coronavirus Disease 2019 Pandemic.

Importance: The coronavirus disease 2019 (COVID-19) pandemic has made alcohol-based hand sanitizers (ABHS) widely available in public places. This may warrant determining whether cases of unintentional ocular exposure are increasing, especially in children. Objective: To describe the epidemiologic trend of pediatric eye exposures to ABHS and to report the severity of the ocular lesions. Design, Setting, and Participants: Retrospective case series conducted from April 1, 2020, to August 24, 2020. Cases were retrieved from the national database of the French Poison Control Centers (PCC) and from a pediatric ophthalmology referral hospital in Paris, France. Cases of ocular exposure to chemical agents in children younger than 18 years during the study period were reviewed. Cases of ABHS exposure were included. Exposures: The following data were collected: age, sex, circumstances of exposure, symptoms, size of the epithelial defect at first examination, time between the incident and re-epithelialization, and medical and/or surgical management. Main Outcomes and Measures: Comparison of the number of eye exposures to ABHS in children between April to August 2020 and April to August 2019. Results: Between April 1 and August 24, 2020, there were 7 times more pediatric cases of ABHS eye exposures reported in the PCC database compared with the same period in 2019 (9.9% of pediatric eye exposures in 2020 vs 1.3% in 2019; difference, 8.6%; 95% CI, 7.4-9.9; P < .001). The number of cases occurring in public places increased in 2020 (from 16.4% in May to 52.4% in August). Similarly, admissions to the eye hospital for ABHS exposure increased at the same period (16 children in 2020 including 10 boys; mean [SD] age, 3.5 [1.4] years vs 1 boy aged 16 months in 2019). Eight of them presented with a corneal and/or conjunctival ulcer, involving more than 50% of the corneal surface for 6 of them. Two cases required amniotic membrane transplant. Conclusions and Relevance: These data support the likelihood of an increasing number of unintentional ocular exposures to ABHS in the pediatric population. To maintain good public compliance with hand disinfection, these findings support that health authorities should ensure the safe use of these devices and warn the parents and caregivers about their potential danger for children.

Synthetic cannabinoid induced ocular self-injury.

Synthetic cannabinoids are a relatively new and increasingly popular recreational drug. While used for their hallucinogenic properties similar to natural cannabis, they have a greater and more serious side effect profile, including potentially severe neuropsychiatric toxicity. We report the cases of two patients with untreated schizophrenia who presented after ocular self-injury while intoxicated on K2. Both patients hallucinated that a bug was behind their eye, and in their attempts at removing the bug, damaged the periocular soft tissue. To our knowledge these are the first reports of ocular self-injury from synthetic cannabinoid intoxication.