Ocular Toxicity Study Research Articles

Influence of dietary melatonin on photoreceptor survival in the rat retina: An ocular toxicity study

Previous studies have shown that melatonin treatment increases the susceptibility of retinal photoreceptors to light-induced cell death. The purpose of this study was to evaluate under various conditions the potential toxicity of dietary melatonin on retinal photoreceptors. Male and female Fischer 344 (non-pigmented) and Long–Evans (pigmented) rats were treated with daily single doses of melatonin by gavage for a period of 14days early in the light period or early in the dark period. In another group, rats were treated 3 times per week with melatonin early in the light period, and then exposed to high intensity illumination (1000–1500lx; HII) for 2h, and then returned to the normal cyclic lighting regime. At the end of the treatment periods, morphometric measurements of outer nuclear layer thickness (ONL; the layer containing the photoreceptor cell nuclei) were made at specific loci throughout the retinas. In male and female non-pigmented Fischer rats, melatonin administration increased the degree of photoreceptor cell death when administered during the nighttime and during the day when followed by exposure to HII. There were some modest effects of melatonin on photoreceptor cell death when administered to Fischer rats during the day or night without exposure to HII. Melatonin treatment caused increases in the degree of photoreceptor cell death when administered in the night to male pigmented Long–Evans rats, but melatonin administration during the day, either with or without exposure to HII, had little if any effect on photoreceptor cell survival. In pigmented female Long–Evans rats, melatonin administration did not appear to have significant effects on photoreceptor cell death in any treatment group. The results of this study confirm and extend previous reports that melatonin increases the susceptibility of photoreceptors to light-induced cell death in non-pigmented rats. It further suggests that during the dark period, melatonin administration alone (i.e., no HII exposure) to pigmented male rats may have a toxic effect on retinal cells. These results suggest that dietary melatonin, in combination with a brief exposure to high intensity illumination, induces cellular disruption in a small number of photoreceptors. Chronic exposure to natural or artificial light and simultaneous intake of melatonin may potentially contribute to a significant loss of photoreceptor cells in the aging retina.

A Pharmacokinetic and Safety Evaluation of an Episcleral Cyclosporine Implant for Potential Use in High-Risk Keratoplasty Rejection

To determine the short and long-term pharmacokinetics and assess the toxicity of a cyclosporine (CsA) episcleral implant for the prevention of high-risk keratoplasty rejection. CsA episcleral implants were made with a high (implant A) or low (implant B) release rate, and in vitro release rates were performed. Short-term pharmacokinetics were performed in rabbits using implant B, and the spatial and temporal spread of drug was observed by sampling from multiple corneal and conjunctival sites at 3 and 72 hours. Implant A was used in long-term pharmacokinetic studies in dogs aged more than 1 year. An ocular toxicity study was performed in dogs older than 1 year. A high release rate was observed with both implants over the initial 5 months followed by a steady state release. The cumulative release over the 400-day assay period from implants A and B was 3.8 +/- 0.3 and 2.3 +/- 0.3 mg, respectively. In the short-term pharmacokinetic studies, the cornea had CsA concentrations of 0.15 +/- 0.06, 0.07 +/- 0.02, and 0.05 +/- 0.02 microg/mg at sites centered 8, 13, and 18 mm away from the implant site, respectively. In the long-term pharmacokinetic studies, corneal CsA levels ranged from 0.18 +/- 0.06 to 0.009 +/- 0.004 microg/mg during the 1-year study. There were no signs of ocular toxicity at 1 year. Episcleral implants are safe and effective at delivering therapeutic CsA levels to the cornea to potentially prevent corneal allograft rejection. The implant can be surgically inserted at the time of penetrating keratoplasties, since the implant achieves therapeutic levels as early as 3 hours.

Development of a base set of toxicity tests using ultrafine TiO 2 particles as a component of nanoparticle risk management

The development of a risk management system for nanoscale or ultrafine particle-types requires a base set of hazard data. Assessing risk is a function of hazard and exposure data. Previously, we have suggested “parallel tracks” as a strategy for conducting nanoparticle research. On the one hand, mechanistic studies on “representative” nanoparticles could be supported by governmental agencies. Alternatively, with regard to commercial nanoparticles, the environmental, health and safety (EHS) framework would include a minimum base set of toxicity studies which should be supported by the companies that are developing nano-based products. The minimum base set could include the following criteria: substantial particle characterization, pulmonary toxicity studies, acute dermal toxicity and sensitization studies, acute oral and ocular toxicity studies, along with screening type genotoxicity, and aquatic toxicity studies. We report here the toxicity results of a base set of hazard tests on a set of newly developed, well-characterized, ultrafine TiO 2 (uf-TiO 2) particle-types. In vivo pulmonary toxicity studies in rats demonstrated low inflammatory potential and lung tissue toxicity. Acute dermal irritation studies in rabbits and local lymph node assay results in mice indicated that uf-TiO 2 was not a skin irritant or dermal sensitizer. Acute oral toxicity studies demonstrated very low toxicity and uf-TiO 2 produced short-term and reversible ocular conjunctival redness in rabbits. Genotoxicity tests demonstrated that uf-TiO 2 was negative in both the bacterial reverse mutation test and in an in vitro mammalian chromosome aberration test with Chinese hamster ovary cells. The results of aquatic toxicity screening studies demonstrated that uf-TiO 2 exhibited low concern for aquatic hazard in unaerated, 48 h, static acute tests using the water flea, Daphnia magna; exhibited low concern for aquatic hazard in unaerated, 96 h, static acute tests using the rainbow trout, Oncorhynchus mykiss; and exhibited medium concern in a 72 h acute test using the green algae Pseudokirchneriella subcapitata. To summarize the findings, the results of most of the studies demonstrated low hazard potential in mammals or aquatic species following acute exposures to the ultrafine TiO 2 particle-types tested in this program.

Ocular toxicity study of trypan blue injected into the vitreous cavity of rabbit eyes.

To evaluate the ocular toxicity of trypan blue (TB) injected into the vitreous cavity of rabbit eyes. TB is a dye that could be useful for staining epiretinal membranes during vitrectomy surgery. Ten New Zealand White (NZW) rabbits underwent gas-compression vitrectomy. Rabbits were divided into three groups to receive injections of 0.1 ml basic salt solution, 0.1 ml of a 0.06% TB solution or 0.1 ml of a 0.2% TB solution. Ocular toxicity was assessed by slit-lamp biomicroscopy, ophthalmoscopy, electroretinography and histology. Transient posterior capsule opacification was noted in all animals. No significant reductions in a-wave or b-wave amplitudes were found in any of the animals. Light and electron microscopic examination of the inferior retina in the 0.2% TB-treated eyes showed damaged photoreceptors and marked disorganization. Immunohistochemical staining for rhodopsin was strongly reduced in those sections and staining for proliferation with Ki-67 was positive. No histological abnormalities were found in the upper retina of the 0.2% TB-treated eyes or in any part of the retina of the 0.06% TB-treated or control eyes. No histological abnormalities were found in any of the anterior chamber angle specimens. Although no signs of toxicity were found after the prolonged presence of TB at a concentration of 0.06% in the vitreous cavity of rabbit eyes, marked damage occurred in the lower retina of 0.2% TB-treated eyes. The short-term presence of TB at a concentration of 0.06% in the vitreous cavity is harmless to the rabbit eye but a higher concentration of TB could be unsafe.

Final report on the safety assessment of Octyidodecyl Stearoyl Stearate.

Octyldodecyl Stearoyl Stearate functions as an occlusive skin-conditioning agent and as a nonaqueous viscosity-increasing agent in many cosmetic formulations. Current concentrations of use are between 0.7% and 23%, although historically higher concentrations were used. The chemical is formed by a high-temperature, acid-catalyzed esterification reaction of long-chain alcohols (primarily C-20) and a mixture of primarily C-18 fatty acids. Levels of stearic acid, octyldodecanol, and octylydocecyl hydroxystearate in the final product are 5% or less--no other residual compounds are reported. Only limited safety test data were available on Octyldodecyl Stearoyl Stearate, but previous safety assessments of long-chain alcohols and fatty acids found these precursors to be safe for use in cosmetic formulations. Octyldodecyl Stearoyl Stearate produced no adverse effects in acute exposures in rats. The chemical was mostly nonirritating to animal skin at concentrations ranging from 7.5% to 10%; one study did find moderate irritation in rabbit skin at a concentration of 7.5%. Clinical tests at a concentration of 10.4% confirmed the absence of significant irritation in humans. An ocular toxicity study in rabbits found no toxicity. No evidence of genotoxicity was found in either a mammalian test system or in the Ames test system, with or without metabolic activation. The available data on Octyldodecyl Stearoyl Stearate and the previously considered data on long-chain alcohols and fatty acids, however, did not provide a sufficient basis to make a determination of safety. Additional data needs include (1) chemical properties, including the octanol/water partition coefficient; and (2) if there is significant dermal absorption or if significant quantities of the ingredient may contact mucous membranes or be ingested, then reproductive and developmental toxicity data may be needed. Until such time as these data are received, the available data do not support the safety of Octyldodecyl Stearoyl Stearate as used in cosmetic formulations.

Ocular toxicity of experimental intravitreal itraconazole

We investigated itraconazole, a new triazole antifungal agent that poorly penetrates ocular tissues after oral administration. We injected itraconazole in doses from 10 to 100 micrograms dissolved in 100% dimethyl sulfoxide into the eyes of New Zealand rabbits. Ocular toxicity studies performed five weeks after administration showed no substantial retinal or histopathologic changes in eyes injected with either 100% dimethyl sulfoxide or 10 micrograms of itraconazole. Higher doses caused focal areas of retinal necrosis. Our results indicated that intravitreal doses of 10 micrograms or less of itraconazole may be beneficial in the treatment of fungal endophthalmitis.

Ocular toxicity studies with zinc pyridinethione

Ocular toxicity studies were conducted with orally administered zinc pyridinethione (ZPT) in random source domestic cats, standard beagle dogs, atapetal beagle dogs, and rhesus monkeys. The administration of ZPT to cats resulted in ocular lesions characterized by tapetal degeneration and atrophy. ZPT also caused ocular lesions in standard beagle dogs. The initial lesions consisted of a degeneration of tapetal cells, soon accompanied by intense tapetal inflammation which progressed to retinitis, intraretinal hemorrhage, and subretinal edema, resulting in retinal detachment and blindness. No gross or histopathological ocular lesions occurred in the atapetal beagle dogs or rhesus monkeys. The results of these studies provide strong evidence that the tapetum lucidum is the target tissue for the ocular toxicity of ZPT, since the eyes of animals lacking this choroidal structure are not perceptibly affected by oral administration of this compound. The tapetum lucidum is found in many animals but is not present in humans or most nonhuman primates.