Spontaneous Pathology and Routine Clinical Pathology Parameters in Aging Beagle Dogs

Abstract

AstraZeneca ran a bespoke study to generate age-matched clinical pathology and histopathology data from a cohort of Beagle dogs aged between 25 and 37 months to support the use of these older animals in routine preclinical toxicology studies. As the upper age range of Beagle dogs routinely used in toxicology studies does not normally exceed 24 months, there is an absence of appropriate age-matched historical control data. The generation of such data was crucial to understand whether age-related differences in spontaneous findings might confound the interpretation of toxicology study data. While the majority of the histopathology findings in all the older dogs occurred at a similar prevalence as those expected in young adult dogs (<24 months), a number of differences were observed in the thymus (involution), bone marrow (increased adiposity), testes (degenerative changes), and lung (fibrosis, pigment and alveolar hyperplasia) that could be misinterpreted as a test article effect. Minor differences in some clinical pathology values (hemoglobin, alkaline phosphatase, absolute reticulocytes) were of a small magnitude and considered unlikely to affect the interpretation of study data.Keywords aging, background lesions, beagle, dog, clinical pathology, incidental findings, histopathology, toxicology studies While Beagle dogs were originally developed for hunting, they have been extensively used as a species for the toxicity testing of agrochemicals and pharmaceuticals. 2,4,22 Olson 21 provided data that supported the use of nonrodents in safety testing by comparing human toxicities with those identified in animals. The results showed the true positive concordance rate of 71% for rodent and nonrodent species combined, with nonrodents alone being predictive for 63% of human toxicities.Chronic toxicity testing in dogs is normally confined to studies with a maximum duration of 1 year, with animals typically being 6 to 12 months old at study start. As a result, publications detailing the incidence of spontaneous pathology findings in Beagles are confined to animals no older than 2 years. 12,[16][17][18]28 While chronic lifetime studies in Beagle dogs have been undertaken at the Lovelace Respiratory Research Institute (LLRI), 19 published data from these studies does not include detailed observations of the spontaneous pathology noted in dogs aged between 2 and 5 years.AstraZeneca had a cohort of older beagle dogs available for use on routine toxicity studies, with the age of all animals exceeding the upper age limit of Beagles routinely used in toxicity testing (>24 months), raising concerns about a lack of suitable age-and strain-matched historical control data and potential impact on the interpretation of histopathology findings.AstraZeneca has a commitment to fully implement the principles of replacement, reduction, and refinement (3 Rs) for the use of animals in research; therefore, the aim of the study described here was to generate a complete ''guideline compliant'' set of hematology, clinical chemistry, and ...

Spontaneous and Dosing Route–related Lung Lesions in Beagle Dogs from Oral Gavage and Inhalation Toxicity Studies

“…However, in this study, neither of the 2 dogs with this lesion had nephropathy, and no other lesions suggestive of metastatic calcification were observed in these animals. This lesion has not been reported in young beagles (Hottendorf and Hirth 1974;Oghiso, Fukuda, and Iida 1982;Hahn and Dagle 2001;Barnes et al 2016). However, a high incidence of vascular mineralization has been reported in aging beagle dogs (Hahn and Dagle 2001), most likely this is related to the high incidence of chronic nephropathy reported in these aging dogs.…”

Canine Cognitive Dysfunction and Alzheimer’s Disease – Two Facets of the Same Disease?

“…Amyloid-β was found to be present in the form of insoluble plaques in the area of the cerebral cortex in humans and dogs, and cognitive impairment in elderly dogs was in some studies strongly associated with the accumulation of Aβ in the brain (Cummings et al, 1993; Cummings and Cotman, 1995; Pugliese et al, 2006; Rofina et al, 2006; Barnes et al, 2016). However, in two other studies there was no significant correlation between the amount of Aβ brain load and CCD symptoms (Chambers et al, 2011; Ozawa et al, 2016) so the clear connection between Aβ load in the brain and clinical signs of CCD has not been firmly established yet.…”

Why Animals Die

“…Of comparative interest, neoplasms are also common in many animal species, particularly in dogs, cats, and rodents. 1,3,4,8 –11,43,46,53…”

“…25,29,30,37,39 Renal pathology in aging dogs and cats is described in this issue. 3,5,12,16 Infectious diseases, including panleukopenia, lymphomas, and feline infectious peritonitis, may be common in certain cat populations.…”

“…Of comparative interest, neoplasms are also common in many animal species, particularly in dogs, cats, and rodents. 1,3,4,[8][9][10][11]43,46,53 Common cancer types differ between human and animal species probably due to genetics and etiologic factors, such as cigarette smoke, diet, and infectious agents. Chronic respiratory diseases in humans occur from cigarette smoking and other environmental exposures and do not usually occur in animals.…”