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PURPOSE: OptiSafe is an in chemico test method that identifies potential eye irritants based on macromolecular damage following test chemical exposure. The OptiSafe protocol includes a pre-screen assessment that identifies test chemicals that are outside the applicability domain of the test method and thus determines the optimal procedure. We assessed the usefulness and limitations of the OptiSafe test method for identifying chemicals not requiring classification for ocular irritation (i.e., bottom-up testing strategy). MATERIALS AND METHODS: Seventeen chemicals were selected by the lead laboratory and tested as an independent study. Ninety-five unique coded chemicals were selected by a validation management team to assess the intra- and inter-laboratory reproducibility and accuracy of OptiSafe in a multi-laboratory, three-phased validation study. Three laboratories (lead laboratory and two naive laboratories) evaluated 35 chemicals, with the remaining 60 chemicals evaluated by the lead laboratory only. Test method performance was assessed by comparing classifications based on OptiSafe results to classifications based on available retrospective in vivo data, using both the EPA and GHS eye irritation hazard classification systems. No prospective in vivo testing was conducted. RESULTS: Phase I testing of five chemicals showed that the method could be transferred to naive laboratories; within-lab reproducibility ranged from 93% to 100% for both classification systems. Thirty coded chemicals were evaluated in Phase II of the validation study to demonstrate both intra- and inter-laboratory reproducibility. Intralaboratory reproducibility for both EPA and GHS classification systems for Phase II of the validation study ranged from 93% to 99%, while interlaboratory reproducibility was 91% for both systems. Test method accuracy for the EPA and GHS classification systems based on results from individual laboratories ranged from 82% to 88% and from 78% to 88%, respectively, among the three laboratories; false negative rates ranged from 0% to 7% (EPA) and 0% to 15% (GHS). When results across all three laboratories were combined based on the majority classification, test method accuracy and false negative rates were 89% and 0%, respectively, for both classification systems, while false positive rates were 25% and 23% for the EPA and GHS classification systems, respectively. Validation study Phase III evaluation of an additional 60 chemicals by the lead laboratory provided a comprehensive assessment of test method accuracy and defined the applicability domain of the method. Based on chemicals tested in Phases II and III by the lead laboratory, test method accuracy was 83% and 79% for the EPA and GHS classification systems, respectively; false negative rates were 4% (EPA) and 0% (GHS); and false positive rates were 40% (EPA) and 42% (GHS). Potential causes of false positives in certain chemical (e.g., ethers and alcohols) or hazard classes are being further investigated. CONCLUSION: The OptiSafe test method is useful for identifying non-surfactant substances not requiring classification for ocular irritancy. OptiSafe represents a new tool for the in vitro assessment of ocular toxicity in a tiered-testing strategy where chemicals can be initially tested and identified as not requiring hazard classification.

Propylene glycol (PG) is a widely used solvent, chemical intermediate and carrier substance for foods, pharmaceutical and cosmetic products. Professional and occupational exposure to PG aerosol and vapor may occur from theatrical smoke generators and during application of deicing products to airplanes. While PG is considered to have low toxicity, the results of one study suggested that brief (1-min) exposure to PG mist elicited ocular and respiratory effects in humans. Because the high concentrations and brief exposure duration in that study were not representative of most occupational exposures, a controlled experimental exposure study was conducted to clarify or confirm the earlier findings.Ten males and 10 females were exposed to PG aerosol for 4 hrs at 20 and 100 mg/mObjective measures of pulmonary function and ocular irritation did not reveal any exposure-related changes. Exposure-related changes in symptom reporting were observed; however, the highest symptom ratings did not exceed "slight" on the scale.The results indicate at the concentrations and acute durations tested, PG does not affect human respiratory function or produce ocular irritation.

Context: A stable topical ophthalmic curcumin formulation with high solubility, stability, and efficacy is needed for pharmaceutical use in clinics. Objectives: The objective of this article was to describe a novel curcumin containing a nanomicelle formulation using a polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol (PVCL–PVA–PEG) graft copolymer. Methods: Nanomicelle curcumin was formulated and optimized and then further evaluated for in vitro cytotoxicity/in vivo ocular irritation, in vitro cellular uptake/in vivo corneal permeation, and in vitro antioxidant activity/in vivo anti-inflammatory efficacy. Results: The solubility, chemical stability, and antioxidant activity were greatly improved after the encapsulation of the PVCL–PVA–PEG nanomicelles. The nanomicelle curcumin ophthalmic solution was simple to prepare and the nanomicelles are stable to the storage conditions, and it had good cellular tolerance. Nanomicelle curcumin also had excellent ocular tolerance in rabbits. The use of nanomicelles significantly improved in vitro cellular uptake and in vivo corneal permeation as well as improved anti-inflammatory efficacy when compared with a free curcumin solution. Conclusions: These findings indicate that nanomicelles could be promising topical delivery systems for the ocular administration of curcumin.

Purpose To describe an unusual case of unilateral, chronic symptoms and signs of dry eye, and recurrent episodes of ocular irritation related to pinguecula, which were refractory to prior medical treatments, successfully treated with argon laser photocoagulation. Methods A 36-year-old man presented with an elevated yellowish mass on his conjunctiva in his left eye, which was associated with dry eye symptoms and general discomfort, such as "tightening sensation" and "stiffness". On clinical assessment, the left eye revealed a mild conjunctival injection, a fluorescein break-up time (FBUT) of 3.5 s, an abnormal fluorescein staining, and a Schirmer I test of 5 mm. Optical coherence tomography (OCT) imaging evidenced a height at the most elevated point of the pinguecula of 740 µm. The patient underwent argon-laser photocoagulation. Results After 2 weeks postoperatively, no residual of pinguecula or focal injection of the conjunctiva was detected by slit-lamp biomicroscopy and there was a significant improvement of clinical symptoms and signs: Schirmer I test and FBUT increased to 12 mm and >10 s, respectively, and fluorescein staining was absent. OCT imaging revealed a smooth structure of conjunctival contour, with a height of 404 µm. According to an ex juvantibus line of reasoning, definitive diagnosis was pinguecula-related dry eye disease. Conclusion Based on the concept that tear film instability and inflammation are two key components of the pathogenesis of dry eye, we coined the term "pinguecula-related dry eye disease," which can be successfully treated by a complete, accurate removal of the lesion with argon laser photocoagulation.

To explore the use of oleic acid (OA) in ocular drug delivery.Six compounds, namely rhodamine B, sodium-fluorescein, fluorescein isothiocyanate (FITC) dextrans of 4, 10, 20 and 40 kDa were selected as model drugs. The effect of OA on the corneal permeability of drugs was evaluated in vitro, using isolated rabbit corneas by a Franz diffusion cell. The safety of OA was assessed on the basis of corneal hydration level. The ocular irritation of OA was also tested in rabbits in vivo using the Draize eye test.In the presence of OA, at a concentration of 0.02-0.1%, the maximum increase in the apparent permeability coefficient (Papp) was 3.21-, 1.76- and 1.57-fold for rhodamine B, sodium-fluorescein and FITC-dextran of 4 kDa, respectively. However, no significant permeability enhancement of FITC-dextrans of 4, 10, 20 and 40 kDa was found in the presence of OA. It enhanced the corneal penetration of model compounds in a concentration-dependent manner. The Papp values of rhodamine B decreased with increasing concentration of OA, while the Papp values of sodium-fluorescein and FITC-dextrans of 4 kDa increased. The Papp enhanced by 0.1% OA was logarithmically correlated to the molecular weight of model drugs (R(2) = 0.9991). With the 0.02%, 0.05% and 0.1% oleic application, the corneal hydration values were83%, and Draize scores were4.OA may have potential clinical benefits in improving the ocular drug delivery of both hydrophilic and lipophilic compounds.

In the present work, we assessed the relationship between alkyl carbon chain length and ocular irritation potentials using the hen's egg test-chorioallantoic membrane (HET-CAM) and bovine corneal opacity and permeability (BCOP) assays using 5 commercial alkyl polyglucoside surfactants with different compositions of alkyl chain lengths (C(6)-C(16)). With HET-CAM, there was a good correlation between the proportion of C(10) alkyl polyglucoside and the eye irritation potential Q score (r(2) = 0.912, p = .011). There were no significant differences between the proportion of C(10) alkyl polyglucoside and corneal opacity in BCOP assays; however, there was a relatively high positive correlation between the proportion of C(10) alkyl carbon chain lengths and corneal permeability (r(2) = 0.736, p = .063).

A large database has demonstrated a robust relationship between the chorioallantonic membrane (CAM) and the Draize rabbit eye tests. The precision, sensitivity, and direct correlation of the CAM with human eye evaluations were critically appraised in this work. A total of 24 studies, including 12 CAM assays and 12 human clinical studies were conducted. Both the CAM assay and the human tests demonstrated good interassay precision and a robust correlation between the CAM scores and the inflammatory responses of human eye bulbar conjunctiva, palpebral conjunctiva and scleral vessels. This provided sound evidence that the CAM assay could be a predictive screen for eye irritation assessment for personal wash products and a key element of the tiered scientific approach in supporting labeling claims such as "tear free".

Although sulfur mustard (SM) has been used as a chemical warfare agent since the early twentieth century, it has reemerged in the past decade as a major threat around the world. This agent injured over 100,000 Iranians and one-third is suffering from late effects until today. Mustard affects many organs such as the skin, eyes, and lungs, as well as the gastrointestinal, endocrine, and hematopoietic system. In this study we focused on review of the late Cutaneous and ocular complications caused by exposure to SM. All studies regarding long-term ocular and cutaneous effects, which have been done on Iranian population, were collected from domestic and international sources. Pruritus is the most common complain and a malignant change is the most important lesion, which has to be considered. Also this agent is causes of chronic and delayed destructive lesions in the ocular surface and cornea, leading to progressive visual deterioration and ocular irritation.

Purpose. Previous studies have shown that repetitive administrations of Cyclosporine A (CsA) eye drops to the rabbit eye caused a long-lasting miosis, accompanied by conjunctival hyperemia, anterior humor flare, and fibrin formation in the anterior chamber. The aim of the present study was to clarify the mechanism of these findings. Methods. One drop of 0.1% CsA eye drops was applied once or six times every 30 minutes for 2.5 hours. The eyes were examined by slit-lamp microscope, and IOP and anterior humor flare were measured prior to the studies and at 0, 1, 3, 6, 12, and 24 hours after administration of CsA or vehicle. While anterior chamber aqueous flare was increasing, aqueous humor and anterior segment of the eye were taken and analyzed. The entry of plasma proteins into the aqueous humor was studied by using Evans blue dye. Result. Conjunctival hyperemia, anterior humor flare and IOP rise miosis and fibrin formation in the anterior chamber were shown after six CsA administration ipsilaterall...

Among the most fundamental assessments of the safety of a product or, indeed, of any material that has the potential to be in contact with a significant number of people in our society, are tests i...

In this study, we investigated the time course effect of sensory eye irritation in 16 subjects exposed (i.e., eye only) to n-butanol and 1-octene. Half the subjects were exposed to n-butanol, and the remaining subjects were exposed to 1-octene. Each subject was studied on 5 different days; during each day each subject was exposed in three runs (i.e., run 1, run 2, and run 3) to a constant concentration of either n-butanol or 1-octene. We performed run 1 and run 3, both of which lasted 15 min each, to evaluate persistence in "sensitization." We performed run 2, which lasted 60 min, to study the time course of sensory irritation. Ratings of ocular irritation intensity were obtained continuously during all three runs. The exposure concentrations for n-butanol were 0 mg/m3, 300 mg/m3, 900 mg/m3, and 3 000 mg/m3, and the exposure concentrations for 1-octene were 0 mg/m3, 6 000 mg/m3, 10 400 mg/m3, and 18 000 mg/m3. During run 2, we observed a slight increase in perceived eye irritation intensity for the lower concentrations of 1-octene and for all exposure concentrations of n-butanol. However, the threshold for irritation was clearly exceeded for only the 1-octene 10 400-mg/m3 and 18 000-mg/m3 exposures. During these two exposures, the response increased 10-fold following 20-40 min of exposure during run 2, after which the response remained constant. We investigated the existence of persistence in "sensitization" by comparing intensity of responses between run 1 and run 3. Persistence in "sensitization" was apparent for only the 1-octene exposure.

Hemoglobin denaturation was used as a test method to evaluate the potential ocular irritation induced by surfactants in four categories; anionic, cationic, nonionic, and amphoteric and manufactured products containing surfactants. We have proposed a plot representation of the results in order to determine the irritation potential of a substance. The results obtained by this method were compared to the Draize ocular test in vivo. A good correlation was found between the results obtained in vitro and in vivo for some of the surfactants and manufactured products. There was one false-negative result among the surfactants. Two surfactants and one manufactured product produced false-positive results. The method is easy, rapid, economical, and provides enough information about the possible irritant action of surfactants and manufactured products with surfactants in their formulation. Nevertheless, the method is not completely satisfactory and it is necessary to perform more than one alternative method to...

In a newly built workplace a high proportion of the staff experienced nasal, pharyngeal, and ocular irritation; tiredness; and headache. They suspected the glue in the new flooring to be the cause of the symptoms. The present study was designed to investigate whether the components of the floor were responsible for the symptoms reported by the staff. The study design was experimental. Using a mobile exposure chamber (0.5 m3), three workers were exposed to off-gas emissions to determine their response. To simulate the emission of vapors at the workplace, part of the workplace floor was broken into pieces and placed in the chamber. Ambient air and floor vapor exposures were performed at temperatures of 21° and 25°C. Samples from the chamber were collected and analyzed. Benzyl alcohol, an irritant present in the flooring material, was used as a marker for liberation of vapors. Symptoms were reported by the subjects, and an otorhinolaryngologist examined the participants before and after each exposur...

The results of 11 ocular irritation studies in rabbits, dogs, and monkeys treated with 2,3, or 4% dorzolamide hydrochloride (DZ), a new topical ocular carbonic anhydrase inhibitor, are presented. Additional interaction studies were conducted with other ophthalmic products and the irritancy of degradates was evaluated. Hydroxyethyl-cellulose-based solutions were used in the rabbits and dogs three times daily (t.i.d.) and a GELRITE ® (gellan gum) formulation was used in monkeys twice daily (b.i.d.). A general survey of the eye, scoring (Draize) of ocular reactions, ophthalmoscopic and slit lamp examination, and corneal thickness measurement (rabbits only), and gross and microscopic examination of the eyes, ocular adnexae, and optic nerves were routine. All DZ formulations and vehicles caused minor increases in blinking and lacrimation compared to saline controls. As the concentration of DZ increased, the number of blinks increased; however, the Draize scores were null or very low (0-2) even at the h...

Lower eyelid blepharoplasty surgery has undergone a dramatic evolution over the last decade. As more patients have requested cosmetic lower eyelid surgery, this has been accompanied by a greater number of surgeons performing the surgery and a greater number of patients with complications of a varied nature. Ophthalmologists, the surgeons most familiar with the anatomy of the eyelids, orbit, ocular structures, and adjacent face, have been called on more and more regularly to evaluate patients before their having cosmetic surgery, performed by other specialists, and then to manage complications ranging from minor ocular irritation to severe visually threatening ocular and periocular problems after surgery. In addition, more ophthalmologists are performing cosmetic eyelid surgery today than ever. Lower eyelid surgery has always instilled fear in the hearts of cosmetic surgeons because of the unacceptably high frequency of lower eyelid malpositions after surgery and the difficulty of correcting these problems...

Manufacturing intermediates and formulation components constitute the bulk of compounds evaluated in ocular irritation protocols. A cost-effective in vitro screen for predicting severe ocular reactions, which reduces the chance of exposing animals to caustic chemicals, was a logical first step in a tiered approach to the reduction, refinement, and eventual replacement of animals in ocular irritation test protocols. Our laboratory has validated the agar diffusion cytolysis method, which employs a monolayered SIRC cell culture as an initial biological ocular screen. Twenty-four hours after plating 100-mm dishes, the culture medium was replaced with a 0.01% neutral red/1% agar overlay and incubated for a minimum of 16 h. Solid or liquid compounds were applied atop the agar diffusion matrix in glass cylinders or on paper discs, respectively, at doses of 2, 5, 10, and 25 mg or μ1 and incubated at 37°C for 24 h. Clear zones resulting from the loss of the neutral red dye following compound-induced cytolysis were...

The Clean Air Act of 1990 mandates that those areas of the country that do not attain the health-based National Ambient Air Quality Standard for CO must add oxygenates (2.7% by weight) to auto fuels (oxyfuels). In the fall of 1992, the addition of methyl tertiary butyl ether (MTBE) to automotive fuels coincided with complaints of illness in some parts of the country. In Alaska, the reported symptoms included headache, nasal, throat, or ocular irritation, nausea or vomiting, dizziness, and sensations of “spaciness” or disorientation. We conducted a chamber exposure experiment to determine if exposure to pure MTBE would elicit similar responses to those reported to be related to MTBE exposure. Nineteen male and 18 female subjects were exposed in a repeated-measures design to clean air (CA) and 1.39 ppm (5.0 mg/m3) MTBE for 1 h. This level was selected to approximate a typical exposure experienced during refueling. Exposures were separated by at least I wk. Symptom questionnaires were completed befor...

Given the number of components scored in the Draize test and the diverse mechanisms leading to distinct clinical signs (opacity, inflammation, necrosis, etc.), no single-endpoint in vitro test is likely to suffice to predict ocular irritation potential. We have sought to develop a test battery to measure these clinical signs to evaluate chemicals for worker safety. The bovine corneal opacity-permeability assay, which measures two endpoints, corneal opacity and loss of integrity of the epithelial cell barrier, has proven to be quite useful. With this combination of endpoints, we find better than an 80% correlation with in vivo ocular irritation data. Cytotoxicity assays, on the other hand, have been of limited use. We have evaluated neutral red uptake, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye reduction, and [3H]leucine incorporation and have found that these endpoints show good correlation with in vivo scores only when rankings are made within a single chemical class. In many appli...

Eight raw materials (seven nonionic surfactants and one anionic surfactant) were evaluated in Skin2 model ZK1200 to determine their in vitro ocular irritation potential. In vivo ocular irritation scores for these surfactants ranged from nonirritating to severely irritating. Cytotoxicity values, obtained via MTT reduction, were used to rank order the test materials as well as classify and group them according to their ocular irritation potential. The human skin model and protocol used in this research appear to be promising in vitro tools for categorizing surfactants and offer a high degree of correlation with published in vivo results.

The enucleated eye test (EET) for screening eye irritants was first described in 1981. In order to validate this method, an interlaboratory trial was established. Substances of varying degrees of ocular irritation were tested using both a 10 and a 60 s exposure period. The 10 s exposure time allowed the most irritant of substances to be identified by the EET. For the majority of substances tested, the 60 s exposure generated greater responses than the 10 s exposure. By assessing the in vitro response, each substance could be graded into one of four irritancy ratings. Despite the three laboratories adopting different in vitro grading systems, consistency amongst the laboratories was good, with 22 of the 27 substances tested being rated within one in vitro category. In comparison with existing in vivo data, the in vitro responses from a 10 s exposure correlated better than the reactions from a 60 s exposure protocol. The effects of liquid test substances were more successfully predicted in vitro than the ef...

The Living Dermal Equivalent (LDE), composed of human dermal fibroblasts in a collagen-containing matrix, was used as a model system for examining toxic responses to a broad range of test chemicals and final product formulations. The thiazolyl blue (MTT) assay for mitochondrial function and the release of proinflammatory eicosanoids (prostaglandin E2 and prostacyclin) were used as end points to rank order the relative irritancy of test samples. In these studies a total of 65 test samples including liquids, creams, emulsions, and solids were applied topically to the air-exposed surface of the LDE. Protocols were designed to maximize the discrimination between samples with known ocular irritation potentials. For a given set of samples, altering the experimental conditions, including the dosage and time of exposure, is shown to influence the degree to which responses of the LDE agree with in vivo data. Strategies for using the LDE as an in vitro ocular irritation model are presented and recommendatio...

In a previous report we queried certain of the claims made by the manufacturer of Polyclens (Opti-clean). This paper further investigates these queries and attempts to assess the clinical value and limitations of the product.

Methyl fluorosulfonate (Magic Methyl®), an active met hy la ting agent used by research chemists, was studied for acute oral toxicity, acute inhalation toxicity, ocular irritation, and dermal irritation. This compound is very hazardous and may have been responsible for at least one human death. The results of these studies confirmed that Magic Methyl is markedly toxic by all routes studied and particularly by the inhalation route since the LC50 value for rats was found to be between 5 and 6 ppm.

Human experience can be used in combination with animal test data to determine the safety of consumer products. Results of rabbit low-volume eye irritation testing and human experience were evaluated to determine the ocular safety of shampoos. These data were reviewed for four marketed shampoos and show that the shampoos have a low eye irritation potential. This review supports the use of the rabbit low-volume eye irritation test in determining human ocular irritation potential of new shampoo formulations and the use of consumer accidental exposure information in product safety assessment.

Because of the continued popularity of contact lenses in the United States, ocular inflammatory diseases are being encountered with increasing frequency by both ophthalmologists and primary care physicians. Distinction between minor noninfectious inflammation and serious, sight-threatening infection is crucial to the proper management of these patients. Symptoms of infectious keratitis are pain and loss of vision. Signs include infiltration or loss of clarity of the cornea, eyelid swelling, and purulent discharge. If an infectious process is suspected, the patient should be referred to an ophthalmologist immediately. If this is not possible, the contact lens should be removed and a culture performed, if possible. Aminoglycoside antibiotic drops should be applied frequently until ophthalmologic consultation is obtained. Patients should be reminded of the need for strict adherence to disinfection techniques and avoidance of homemade saline preparations. They should also be told to discontinue use of contact lenses at the first sign of ocular irritation or inflammation and to report to their physician if inflammation persists.

The protozoan Tetrahymena thermophila was evaluated as an indicator organism that might substitute for chemical irritancy testing in rabbit eyes. Using normal motion of the cell as an endpoint of a cytotoxicity assay, it was found that either inbred or outbred cells reacted equally. The temperature, surface area, or age of the culture did not affect test results. When 21 chemicals were compared in vitro to the in vivo Draize eye irritation test, in 86% of the comparisons T. thermophila indicated equal or greater “irritancy” than in vivo testing. It is suggested that the T. thermophila test may be useful as part of a battery of in vitro tests to evaluate the potential irritancy of chemicals to the rabbit eye.

A few issues pertaining to the validation of in vitro alternative tests (IVATs) to the Draize eye irritation test are presented as a foundation for examining the validation process being presented by the Soap and Detergent Association.

A case of superficial punctate keratitis caused by exposure to chlorinated swimming pool water is described. Although pool water tonicity, pH and a variety of chlorine species present in pool water may be implicated in such reactions, a review of the relevant literature revealed that very little is known about the true nature of these reactions. The wearing of swimming goggles as a preventative measure is the only recommendation which can be made based on current knowledge.

An in vitro ocular irritation test, the corneal epithelial plasminogen activator (CEPA) test, is proposed as an alternative to the in vivo Draize eye irritan-cy test. The scientific rationale and basis, the test protocol, and the score system of this test are described. The results of two correlation studies in which 15 chemicals and products were evaluated are summarized. The advantages, disadvantages, and areas for refinement of the CEPA test are discussed.

A new, modified surfactant has been produced by Alcon/B.P. which claims to be a significant improvement over other surfactant cleaners and to be suitable for all types of contact lens material. Short term Canadian clinical trials would appear to support the manufacturer's claims although long term trials are still awaited and particularly the claim that the need for periodic cleaners is reduced. The cleaner has some disadvantages including a requirement for greater care with subsequent rinsing of the cleaner from the lens; ocular irritation if adequate rinsing is not carried out; and possibly a slightly greater potential for surface abrasion in softer lens materials.

Due to the number of soft contact lens wearers who cannot tolerate the ocular irritating side effects of conventional chemical disinfecting systems, there has been a noticeable shift towards the us...

Studies have been made with humans to determine the influence of one and sixty micron aerosols of o-chlorobenzylidene malononitrile on respiratory and ocular irritating effects. Small particles rapidly produce respiratory and ocular irritation. Only 3 of 17 individuals could tolerate small particles for as long as 60 seconds. Large particles predominately produce ocular irritation. Of 18 subjects exposed, 15 were able to tolerate the cloud for at least 60 seconds. Large particles increase recovery time from ocular irritation.

The ocular irritation caused by the installation of solutions of varying pH and buffering capacity was investigated. The range of comfort for varying environmental pH is a function of the relative buffering capacity of the solution.