Corneal Mineralization in Wistar Hannover Rats

Hashimoto, Satomi; Doi, Takuya; Wako, Yumi; Sato, Junko; Wada, Sou; Tsuchitani, Minoru

doi:10.1293/tox.26.275

Cited by 11 publications

(9 citation statements)

References 8 publications

(21 reference statements)

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“…The multitude of general references and texts covering background histopathologic data pertaining to strains or sub-strains will not be reviewed in this manuscript nor included in the bibliography since they are too numerous, are updated or superseded rather frequently, may be included in other manuscripts in this publication, and can all be found easily online through the respective breeding companies, contract research organizations, or through literature searches using the strains and/or suppliers of interest. A few specific examples are provided to illustrate the variability in nonneoplastic (Table 1) and neoplastic (Figure 2) histopathologic end points between and within strains (Bellhorn, Korte, and Abrutyn 1988; Hashimoto et al 2013; King-Herbert and Thayer 2006). Chadwick and colleagues demonstrated nicely the effects of strain (including disease models) and diet on the background incidence of histopathological findings, and select changes are summarized in Table 2 for illustrative purposes (Chadwick et al 2014).…”

Section: Background Values and Datamentioning

confidence: 99%

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Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Colman

2016

Toxicol Pathol

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It has been long established that not only the species but also the strain and supplier of rodents used in preclinical safety studies can have a significant impact on the outcome of studies due to variability in their genetic background and thus spontaneous pathologic findings. In addition, local husbandry, housing, and other environmental conditions may have effects on the development and expression of comorbidities, particularly in longer-term or chronic studies. More recently, similar effects related to the source, including genetic and environmental variability, have been recognized in cynomolgus macaques ( Macaca fascicularis). The increased use of cynomolgus macaques from various sources of captive-bred animals (including nonnative, U.S./European Union-based breeding facilities or colonies) can affect study design and study results and outcome. It is important to acknowledge and understand the impact of this variability on the results and interpretation of research studies. This review includes recent examples where variability of preclinical animal models (rats and monkeys) affected the postmortem observations highlighting its relevance to study design or interpretation in safety studies.

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Section: Background Values and Datamentioning

confidence: 99%

“… a Adapted from Bellhorn, Korte, and Abrutyn (1988). b Adapted from Hashimoto et al (2013). c Internal Novartis review (2011). …”

Section: Background Values and Datamentioning

confidence: 99%

Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Colman

2016

Toxicol Pathol

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“…Ophthalmological examination (Week 13) identified two incidences of corneal opacity in the control (one per sex) and three in high-dose males, in addition four incidences of persistent pupillary membrane in the control (one male, three females) and the high-dose treatment group (three males, one female) were observed. Both optical abnormalities have been reported to occur spontaneously and in high frequencies in Wistar and Han rats [35,36]. Ocular examination results were not statistically significant for either sex during the pre-test and at the end of the treatment period; thus the isolated incidences were not attributed to L-5-MTHF-Ca administration.…”

Section: Resultsmentioning

confidence: 86%

Safety evaluation of calcium L-methylfolate

Niederberger¹,

Dahms

Broschard

et al. 2019

Toxicology Reports

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“…3) are also often observed in albino rats (Inagaki and Kuno 2001;Taradach et al, 1981;Shibuya et al, 2001aShibuya et al, , 2001b. Especially, in Wistar rats, severe corneal opacities are in very high incidence (Hashimoto et al, 2013;Okamura et al, 2011). Incidence of these spontaneous findings in rats varies by ages, product lots or housing environments.…”

Section: Ophthalmological Examinations In Nonclinical Toxicity Studiesmentioning

confidence: 99%

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

et al. 2015

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-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...

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Corneal Mineralization in Wistar Hannover Rats

Cited by 11 publications

References 8 publications

Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Impact of the Genetics and Source of Preclinical Safety Animal Models on Study Design, Results, and Interpretation

Safety evaluation of calcium L-methylfolate

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

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