Histopathology of the eye is an essential part of ocular toxicity evaluation. There are structural variations of the eye among several laboratory animals commonly used in toxicity studies, and many cases of ocular lesions in these animals are related to anatomical and physiological characteristics of the eye. Since albino rats have no melanin in the eye, findings of the fundus can be observed clearly by ophthalmoscopy. Retinal atrophy is observed as a hyper-reflective lesion in the fundus and is usually observed as degeneration of the retina in histopathology. Albino rats are sensitive to light, and light-induced retinal degeneration is commonly observed because there is no melanin in the eye. Therefore, it is important to differentiate the causes of retinal degeneration because the lesion occurs spontaneously and is induced by several drugs or by lighting. In dogs, the tapetum lucidum, a multilayered reflective tissue of the choroid, is one of unique structures of the eye. Since tapetal cells contain reflecting crystals in which a high level of zinc has been demonstrated chemically, drug-induced tapetum degeneration is possibly related to zinc chelation. The eye of the monkey has a macula similar to that of humans. The macula consists only of cones with a high density, and light falls directly on the macula that plays an important role in visual acuity. Macular degeneration occurring in monkeys resembles histopathologically that of humans. Hence, the eye of the monkey is a suitable model to investigate macular degeneration and to assess drug-induced macular lesions.

-Humans commonly obtain approximately 80% of external information from vision. Since loss of vision markedly decreases quality of life, risk assessments for visual toxicity of new drugs are extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only indicates a brief instruction for ophthalmologic examinations, and submitted data for drug approval according only to this guideline are not always considered sufficient in light of ocular toxicity risk assessments. The eye is an assembly of many specialized sub-organs which have specific functions, and its integral maintenance of homeostasis plays an important role of visual function. When only a part of integrity of functions is lost, overall function of the eye might be commonly disturbed. Therefore, understanding of anatomy and physiology of these sub-organs may help know mechanisms of observed ocular changes. In ophthalmologic examinations in nonclinical toxicity studies, it is vital to understand the principles and features of each examination. Comparisons of findings between pre and post drug treatment as well as considerations of species differences, strain differences, age differences, and location/degree of abnormalities are essential. In addition, many kinds of spontaneous ocular findings are well known in experimental animals. To differentiate treatment-related changes from spontaneous findings, mastering basic skills for ophthalmologic examinations and taking advantage of collection of background data are necessary. For ocular toxicity risk assessments, while an evaluation of "sight-threatening" effects is most critical matter, "quality of vision" related findings also should be considered. To extrapolate animal data to human, clinical significances of ocular toxicity findings should be evaluated based on considerations for "species differences", "safety margins", "reversibility", and "risk-benefit balance". In addition, a detailed recording of features of lesions is also important for an appropriate judgment of clinical significance of ocular findings. For preparation of histopathological specimens, careful sampling of organs and suitable selection of fixatives are important. To accurately orient ocular lesions in the specimen for histopathological examinations, securing close communications prior to necropsy among ophthalmologists, gross necropsy pathologists and histopathology technicians should be effective and helpful. It is impossible to detect all ocular changes in histopathological examinations; that is, there is a limitation in histopathological examinations. Therefore, for ocular toxicity risk assessments, comprehensive evaluation with pathological findings as well as other results of various examinations in toxicity studies should be considered. In conclusion, for ocular toxicity risk assessments, integrated judgments from all examination data in nonclinical toxicity studies are required. To achieve appropriate risk assessments which can be extrapolated to human, close communications and sharing...