Spontaneous Lesions in Cynomolgus Monkeys Used in Toxicity Studies

Itō, Takayasu; Chatani, Fumio; Sasaki, Satoshi; Ando, Takao; Miyajima, Hiroaki

doi:10.1538/expanim1978.41.4_455

Cited by 37 publications

(30 citation statements)

References 24 publications

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“…This study extends and refines previously published observations of incidental findings in the thymus (Chamanza et al 2010;Ito et al 1992;Okazaki et al 1996;Kaspareit et al 2006;Spoor, Radi, and Dunstan 2008) by providing a detailed evaluation of the range of light microscopic observations correlated with thymus weight and maturity stage. We also conducted a review of selected immunomodulators to determine the relative sensitivity of thymus and spleen parameters.…”

Section: Introductionsupporting

confidence: 85%

Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis)

et al. 2016

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Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system.

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Section: Introductionsupporting

confidence: 85%

Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis)

et al. 2016

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“…There are very few reports of this kind in the literature (Drevon-Gaillot et al 2006;Ito et al 1992;Lowenstine 2003;Shimoi et al 1998). Most other published reports are based on studies in zoo or wild-caught primates or in older animals (Bennett et al 1998;Scott 1999), which predictably have a spectrum of pathological findings that is slightly different from that of laboratory-raised animals used in toxicological studies.…”

Section: Discussionmentioning

confidence: 99%

Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies

et al. 2010

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The authors performed a retrospective study to determine the incidences and range of spontaneous pathology findings in control cynomolgus monkeys. Data were collected from 570 monkeys (285 animals per sex), aged twelve to thirty-six months, from sixty regulatory studies evaluated at our laboratory between 2003 and 2009. The most common finding overall was lymphoplasmacytic infiltrates observed in the following incidence: liver (60.7%), kidneys (28.8%), heart (25.8%), salivary glands (21.2%), and stomach (12.1%). Inflammation also commonly occurred in the heart, kidneys, lungs, and stomach. The most common degenerative changes were localized fatty change in the liver, myocardial degeneration, and mineralization and pigment deposits in various tissues. Parathyroid, thyroid, and pituitary cysts; ectopic thymus in the parathyroid or thyroid gland; accessory spleen within the pancreas; and adrenohepatic fusion were among the most common congenital findings. Some incidental findings bearing similarities to drug-induced lesions were also encountered in various organs. It is hoped that the results presented here and elsewhere could form the groundwork for the creation of a reliable database of incidental pathology findings in laboratory nonhuman primates.

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“…As with the marmoset the appearance can vary dependent upon the diet given, with variations in glycogen and fat being the 2 most common confounders observed. A review of the more common spontaneous lesions, exceeding a 1% incidence, in wild caught Cynomolgus monkeys ( Figure 6) has shown that the liver has the highest incidence of spontaneous microscopic lesions of all of the tissues surveyed in both the male and female (Ito et al, 1992). Mononuclear cell infiltration was by far the most common spontaneous pathology observed, with lower incidences of hepatocyte vacuolation, parasitic granuloma, necrosis, and sinusoidal pigmentation ( Figure 7).…”

Section: Incidence Of Spontaneous Nonneoplastic Lesions In the Cynomomentioning

confidence: 99%

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Foster

2005

Toxicol Pathol

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This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.

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Spontaneous Lesions in Cynomolgus Monkeys Used in Toxicity Studies

Cited by 37 publications

References 24 publications

Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis)

Maturity-related Variability of the Thymus in Cynomolgus Monkeys (Macaca fascicularis)

Incidences and Range of Spontaneous Findings in Control Cynomolgus Monkeys (Macaca fascicularis) Used in Toxicity Studies

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

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