General considerations in ocular toxicity risk assessment from the toxicologists’ viewpoints

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...

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Bibliographic Details
Published in:Journal of toxicological sciences 2015/06/01, Vol.40(3), pp.295-307
Main Authors: Onodera, Hiroshi, Sasaki, Shoji, Otake, Seiji, Tomohiro, Masayuki, Shibuya, Kazumoto, Nomura, Mamoru
Format: Article
Language:English
Subjects:
Animals
Dogs
Drug Approval
Drug-Related Side Effects and Adverse Reactions
Eye - drug effects
Eye examinations
Humans
Mice
Ocular histopathology
Ocular toxicity
Quality of vision
Rabbits
Rats
Risk Assessment
Sight-threatening
Toxicology
Vision, Ocular - drug effects
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Summary: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 ocula
ISSN:0388-1350
1880-3989
DOI:10.2131/jts.40.295