Ocular toxicity animals

Ocular damaging and irritant agents can be identified and evaluated by the Draize rabbit test [114]. However, more recently this test has been criticized on the basis of ethical considerations and unreliable prognosis of human response. Alternative methods such as the evaluation of toxicity on ocular cell cultures have been recommended and are being indicated as promising prognostic tools [115-120]. Direct confocal microscopic analysis [121], hydration level of isolated corneas [122], and various other tests on isolated corneas or animal eyes have also been proposed for evaluation of ocular toxic effects. 

Eye Irritation. Because of the prospect of permanent blindness, ocular toxicity has long been a subject of both interest and concern. Although all regions of the eye are subject to systemic toxicity, usually chronic but sometimes acute, the tests of concern in this section are tests for irritancy of compounds applied topically to the eye. The tests used are all variations of the Draize test, and the preferred experimental animal is the albino rabbit. 

The eye irritation test is probably the most criticized by advocates of animal rights and animal welfare, primarily because it is inhumane. It has also been criticized on narrower scientific grounds in that both concentration and volumes used are unrealistically high, and that the results, because of high variability and the greater sensitivity of the rabbit eye, may not be applicable to humans. It is clear, however, that because of great significance of visual impairment, tests for ocular toxicity will continue. 

Although dermal exposure is potentially important as a route of exposure around hazardous waste sites, the limited data on dermal/ocular toxicity do not permit a complete evaluation of the toxic potential of the tin compounds by this route. Skin and eye irritation and dermatitis have been observed in both humans and animals after acute and intermediate exposure to inorganic tin or organotin compounds. None of the compounds appear to cause dermal sensitization in humans or animals. 

White Phosphorus. There is limited information on the ocular toxicity of white phosphoms. Ocular effects were not reported in humans or animals following inhalation exposure. Very few human studies reported ocular effects following acute ingestion of white phosphoms. 

PURPOSE AND RATIONALE This test uses an ex vivo model of corneal organ culture, preferentially porcine, to obtain information of the possible ocular toxicity of various chemicals. This test is used as an alternative to the Draize Test to minimize or replace the use of live animal testing of ocular irritancy (Symposium, Proceeding 1996). The test allows for determination of reversibility of corneal injury following exposure to chemicals, drugs or cosmetics (Xu etal. 2004). 

This test uses the eyes of a live animal, preferentially rabbits, to obtain information of the possible ocular toxicity of various chemicals. This test is most closely related to the human situation where these chemicals will later be used as ocular drugs or cosmetics or where the human eye might be exposed accidentally to these substances. This is a classical test developed about 60 years ago (Draize et al. 1944). 

The eyes of the rabbit differ in certain aspects from the eyes of humans. They are more sensitive, have a lower tear production and blink frequency and posses a nictitating membrane. Nevertheless, the Draize test predicts human ocular toxicity correctly in 85 % cases but overestimates in 10% and underestimates in 5 % (Gad and Chengelis 1991). In addition, ethical concerns have been raised in the use of animals and benefit vs risk of these tests for the protection of the human eye must be carefully evaluated. 

Research should be conducted in experimental animals to determine the lowest concentration that causes serious effects, such as severe eye irritation or damage. Data are limited on the exposure that result in eye irritation, particularly for the concentrations, conditions, and durations associated with the transition from irritation to irreversible eye damage. More data quantifying the effects of other chemicals in lowering the threshold for ocular toxicity also are needed. Research should also be conducted to elucidate the dose-response curve for cytochrome oxidase inhibition with increasing hydrogen sulfide concentrations (i.e., 15 ppm and above). 

Today, the overwhelming majority of animal ocular toxicity studies are performed in the rabbit model, and the study of SM is no exception. New Zealand white rabbits have been used extensively with both liquid SM and vapor exposures (Amir et al, 2000, 2003 Bossone et al, 2002 Vidan et al, 2002 Babin et al, 2004). Other animal models have been employed, including those using bovine and rat corneas. Many articles appear on these in the Bulletin of Johns Hopkins Hospital, Vol. 82, 1948. Individual articles from this volume are cited in the mechanism of action section. 

The administration of DMSO is accompanied by few problems and is relatively safe. However, concentrations higher than 10% administered i.v. may cause intravascular hemolysis, diarrhea, muscle tremors and colic. Ocular toxicity and teratogenicity have been reported in laboratory animals treated with DMSO. In addition, the cutaneous absorption of DMSO may cause sedation, dizziness, headache or nausea in certain individuals. Because of these potential adverse effects, users, especially pregnant women, should take care to avoid contact when applying DMSO. Another major concern is the ability of DMSO to translocate other chemicals (Brayton 1986). Despite this, the i.v. administration of DMSO does not increase the CSF concentrations of trimethoprim or sulfamethoxazole (Green et al 1990). 

Considerable inference has been made from melanin binding to ocular toxicity. Analysis of the data by Leblanc et al. (1998) indicates that in aU cases, there are no direct consequences of drug-melanin binding. Any drug-related toxicity of the retina in humans and animals was described... 

The routine ophthalmic examination is an efficient and effective technique to identify ocular toxicity (Munger and Collins, 2013 Wilkie, 2014). Long a required evaluation in Good Laboratory Practice (GLP) safety studies, these examinations can be readily applied to any mammalian in vivo study in which ocular effects are anticipated or observed. Minimal pharmacologic intervention is required to examine the eye, and most typical laboratory animal species require only manual restraint. The examinations are not invasive, and the same animal or cohort of animals can be examined... 

Munger RJ, Collins MA (2013) Assessment of ocular toxicity potential basic theory and techniques. In Assessing Ocular Toxicity in Laboratory Animals (AB, W. and Colhns M, eds), pp. 23-52 New York Springer. 

In vitro methods will continue to mature and, little by little, replace animal tests. However, a great deal of work first remains to be done on in vivo toxicological mechanisms. Therefore in vitro methods are already being used both to reduce animal testing (screening) and to study the mechanisms involved in ocular toxicity (research). 

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