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Histopathology of Incidental Findings in Beagles Used in Toxicity Studies

The purpose of our publication is to widely communicate the pictures of spontaneous findings occurring in beagles. Spontaneous arteritis occurs commonly in beagles. Frequent sites of arteritis are the heart, spleen, pancreas, epididymis and spinal cord. Morphological similarities between spontaneous and drug-induced arterial lesions may cause confusion when evaluating vascular toxicity of chemicals such as vasodilating agents. Focal and minimal inflammatory lesions are occasionally seen in the lung and may be associated with aspiration of food particles or of unknown causes. A cystic change with copious mucin production occurs occasionally in the mucosal epithelium of the gall bladder. Nesidioblastosis is seen rarely in the pancreas of beagles. C-cell complex and lymphocytic thyroiditis are common thyroid lesions. Spontaneous focal hypospermatogenesis and lobular Sertoli-cell-only seminiferous tubules occurring frequently in beagles must be distinguished from drug-induced damage of the seminiferous tubules in toxicity studies. The morphological differences of the female genital system in each cycle need to be understood; therefore, we present the normal features of the cyclic changes of the female genital organs. Further, we provide more information on spontaneous findings in beagles for exact diagnoses in toxicity studies.


Introduction
To achieve an accurate pathological evaluation in toxicity studies, it is particularly important to know the background histopathology, that is, to be familiar with pictures of incidental findings. As abundant studies using rats are common in laboratories, toxicological pathologists know the background data of spontaneous lesion in rats and can visualize these histological figures easily. However, most pathologists do not have much experience with studies of beagles. Therefore, toxicological pathologists cannot help but depend on the literature or textbooks when performing pathological evaluations in dog studies. In veterinary pathol-ogy, many textbooks have been published, and information concerning disease pathology in dogs is readily available [1][2][3][4][5][6][7][8] . However, the descriptions of background lesions in beagles are insufficient in veterinary pathology textbooks due to the lack of understanding of the importance of publishing incidental findings, which are pathologically insignificant spontaneous lesions with no sign of disease. The papers that have reported background data did not aim to show histological pictures exhaustively 9-12 . Therefore, in this report, we provide pictures of spontaneous lesions in beagles that were detected in background data collection studies and ordinary toxicity studies in our laboratory. The figures are grouped and arranged according to the cardiovascular, lymphoid, respiratory, alimentary, urinary, reproductive, endocrine, nervous and integumentary systems.

Materials and Methods
A total of 1188 beagles (605 males and 583 females) were subjected to background data collection studies and ordinary toxicity studies conducted in our laboratory from 1995 to 2011. The age range was 6 to 23 months. They were purchased from Ridglan Farms, Inc. (146 males and 142 females), Kitayama Labes Co., Ltd. (former known as TOYO Beagle, 169 males and 152 females), Covance Research Products Inc. (former known as Hazelton Research Animals, Inc., 268 males and 267 females), Marshall Bio-Resources (6 males and 6 females), Beijing Marshall Biotechnology Co., Ltd. (4 males and 4 females), NRD Beagle (5 males and 5 females), CSK Research Park Inc. (5 males and 5 females) and the Institute for Animal Reproduction (2 males and 2 females). The animals were housed individually in metal cages (700 × 800 × 700 mm, 780 × 880 × 780 mm or 900 × 1106 × 808 mm) in conventional air-conditioned rooms at 19 °C to 25 °C with 35% to 75% relative humidity and a 12-hour light/12-hour dark cycle. They were provided every day with 300 g or 250 g (for Marshall beagles) of commercially available food (DS, DS-5 or DS-A, Oriental Yeast Co., Ltd.) and were also allowed free access to drinking water. The animals were cared for according to the principles outlined in the guides for the care and use of laboratory animals prepared by the Japanese Association for Laboratory Animal Science and our institution.
Organs fixed in 10% neutral phosphate-buffered formalin were embedded in paraffin, and sections were made and stained with hematoxylin and eosin (HE) for microscopic examination.

Result
We chose 155 typical findings or rare lesions from the background data of the beagles, and they are shown as follows. Detailed explanations for these findings are shown in the figure legends.

Discussion
In veterinary pathology, many textbooks have been published, and information concerning disease pathology in dogs is readily available [1][2][3][4][5][6][7][8] . Furthermore, there are some reports referring to spontaneous lesions of beagles in veterinary and toxicologic journals [9][10][11][12] . However, few publications showing pictures of spontaneous lesions exhaustively are available as a histopathology atlas. Therefore, we provided many pictures of spontaneous lesions in beagles that were detected in background data collection studies and ordinary toxicity studies in our laboratory.
The morphogenesis of blood cysts in the atrioventricular valve ( Fig. 1) was reported by Takeda et al., who showed that the endothelium surrounding the blood cysts revealed focal positive staining for the factor VIII-related antigen 13 .
The figures showing proliferation of the epicardial mesothelium ( Fig. 4) were previously reported by Mesfin and referred to as epicardial fibrous fronds. There was no difference in the incidence of the lesion between male and female dogs or the right and left atria 14 .
Arteritis in beagles always causes confusion. Morphological similarities between spontaneous and drug-induced arterial lesions may make it difficult to evaluate a lesion in the toxicity studies of chemicals such as vasodilating agents. At an early stage, however, drug-induced arterial lesions are composed of medial necrosis and medial and adventitial hemorrhage with very few or no inflammatory cells; these may be the differential points from spontaneous arteritis 15 .
Cystic mucinous hyperplasia of the mucosal epithelium of the gall bladder ( Fig. 70) occurs spontaneously, but the change is also induced by long-term dosing of certain some steroids 16 .
Spontaneous testicular findings of beagles were detailed by Rehm and Goedken et al 17,18 . Placenta-like hyperplasia was detailed by Koguchi et al 19 .
Furthermore, we picked up the previous reports concerning spontaneous lesions in dogs, especially beagles, such as mineralization in the gastric lamina propria ( Indeed, not all lesions have been comprehended in various textbooks and journals. Therefore, we have to keep collecting background data continuously. These background lesions may not have an effect on the results of toxicity studies but should be taken into account along with their potential to influence safety assessment in drug administration.     The change is thought to be a reactive response to physical irritation.

Fig. 5.
Heart: Hemorrhage in the endocardium. Slight focal hemorrhage in the endocardium and subendocardium occurs occasionally and is mainly considered an agonal change. It is necessary to distinguish this agonal change from druginduced hemorrhage by certain drugs such as minoxidil, theobromine and other vasodilating drugs.

Arteritis (Figs. 8-12)
The term of arteritis refers to various inflammatory changes of the arterial wall. Endarteritis, periarteritis and panarteritis are used to describe the affected part, and polyarteritis is used for multiple lesions. Various adjectives are added to describe the morphological characteristics such as acute arteritis, necrotizing arteritis, polyarteritis nodosa or granulomatous arteritis. Multiple terms have been used to describe the same changes. Immunologic disorders or other latent infections are suggested to be the causes in beagles; however, the detailed pathogenesis has not yet been clarified. Frequent sites of arteritis are the heart, spleen, pancreas, epididymis and spinal cord.           Vaccination is considered to be attributable to the change, so attention must be paid to the immunologic failure or overresponse if the follicle formation is severe.              Squamous metaplasia of the mucosal epithelium leading from a hyperplastic lesion occurs occasionally in the region near the bifurcation. The tracheal bifurcation is predisposed to hyperplasia ( Fig. 35) and squamous metaplasia because this region is most likely to receive the physiological irritant effects.                                    Fig. 70, neither copious mucin production nor cystic change is found.