Chronic effects of flutamide in male beagle dogs.

Flutamide, a potent nonsteroidal antiandrogen, was administered orally to male beagle dogs for 2, 3, or 4 years at doses of 10, 20, or 40 mg/kg/day. At each study interval, the results of clinical pathology examinations, organ weight determinations, necropsy, and histopathologic examinations generally were similar and included atrophy of the prostate gland, testicular interstitial cell hyperplasia, and seminiferous tubular atrophy and degeneration. After 3 years of drug exposure, there were 3 dogs with testicular interstitial cell adenomas and a few dogs with 1 or more enlarged mammary gland nipples. Based upon the pharmacologic activity of flutamide, these findings were expected and considered the consequence of long-term blocking of testosterone receptors and an exaggerated compensatory response to increased secretion of luteinizing hormone. The findings of this study were consistent with other examples of dysregulated hormone stimulation of target tissues noted during the nonclinical safety assessment of flutamide. In consideration of the clinical indication of flutamide for advanced prostatic carcinoma and based upon reports of minimal flutamide-related adverse clinical responses, the findings of this study pose no concern for human risk assessment.

Vacuolation in renal tubular epithelium of Cd-1 mice: an incidental finding.

Prominent cytoplasmic vacuoles were observed in renal tubular epithelial cells of the outer medulla in several kidneys from test article-dosed mice (Crl:CD-1 (ICR)BR VAF/PLUS) during routine light microscopic (LM) examination. Because the vacuolar change was detected infrequently and was not found in any control mice from that study, it was not clear whether the vacuolation represented a drug-induced change. To address this question, kidney sections from mice from multiple unrelated studies were examined by LM for similar vacuolar changes. Vacuolation was seen by LM in 2.3% of the control and 2.8% of the test article-dosed mice. Transmission electron microscopy (TEM) was also performed on kidneys with prominent light microscopic vacuoles in 5 control mice and 2 test article-dosed mice to further characterize the vacuoles. Ultrastructurally, the vacuoles contained fibrillar and finely stipled granular material or membranous whorls. Kidneys from control mice lacking light microscopic evidence of vacuolation had smaller vacuoles containing similar material when examined by TEM. Because vacuoles were present in both control mice and test article-dosed mice, it was concluded that the vacuoles were incidental and unrelated to compound administration. These studies also demonstrated that vacuoles can be expected to be observed by LM examination in 2-3% of Crl:CD-1 (ICR)BR VAF/PLUS, mice.

Submucosal mesenchymal tumors of the mouse urinary bladder.

A unique morphologic change has been described in the submucosa of the urinary bladder of mice since the 1950s. These lesions, variously referred to as vegetative changes, reactive lesions, submucosal granulomas, leiomyosarcomas, atypical hemangiosarcomas, or submucosal mesenchymal tumors have been considered rare and of questionable etiology. Although the morphologic criteria are fairly well defined, the pathobiology of the lesion is not well characterized and the previously listed nomenclature reflects this uncertainty. The lesion may not be limited to the urinary bladder, the cell of origin is controversial, the biology is unknown, and whether the lesion is granulomatous, hypertrophy, hyperplasia, metaplasia, or a benign or malignant neoplasm is not well defined. Data compiled from multiple sources are discussed to review the strain of mouse most often affected, sex, age at diagnosis, anatomic location, incidence, descriptive morphology, immunohistochemical staining results, and other features of the submucosal mesenchymal tumor of the mouse urinary bladder. Presented are suggested terminology for the lesion, submucosal mesenchymal tumor of the mouse urinary bladder; the relevance of the tumor for human risk assessment; and discussion of the possible histogenesis of this lesion from primitive mesenchymal cells of the submucosa (lamina propria) of the urinary bladder of mice.

Cationic amphiphilic drug-induced phospholipidosis.

Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung. In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans.

An idiopathic febrile necrotizing arteritis syndrome in the dog: beagle pain syndrome.

The clinical, laboratory, and pathologic features of a syndrome in dogs characterized by intermittent pain, fever, neutrophilia, and necrotizing arteritis are described to alert others involved in toxicity testing to the existence of this disorder. It is considered that this idiopathic syndrome is a latent condition, the expression of which can be precipitated in predisposed dogs by experimental treatment, and thus, its occurrence could complicate interpretation of toxicity studies. We have observed the disorder in 14 beagle dogs. The syndrome is rare and most cases for study were supplied by the breeder. Typical clinical signs observed included evidence of pain when the mouth was opened, grunting when lifted, and standing with an arched back and lowered head. Appetite was usually reduced. Body temperature was elevated (e.g., 104-106 degrees F). There was progressive, bilateral atrophy of temporal and cervical musculature. Such signs have been observed to persist unremittingly or, more commonly, with periods of expression and remission. Neutrophilic leukocytosis and thrombocytosis were present. Hemoglobin and hematocrit were usually slightly decreased. Serum total protein was usually normal but albumin was reduced and alpha-2 globulins were markedly increased. Rheumatoid factor was elevated in several dogs. Arteritis was observed histologically and was characterized by necrosis, intimal proliferation, neutrophil and mononuclear cell infiltration in the media and periarterial tissues, and hemorrhage. Amyloidosis was observed in several dogs. The cause of this disorder is unknown. Knowledge of the distinct features of this syndrome should obviate complication of interpretation of results in toxicity studies and hopefully will lead to studies of this syndrome to provide an understanding of its etiopathogenesis.

Radiation-induced pulmonary fibrosis resolves spontaneously if dense scars are not formed.

The relation of static compliance of excised lungs to collagen accumulation and histologic fibrosis was examined in Syrian hamsters inhaling sufficient 238PuO2 particles to achieve initial lung burdens of 50 or 100 nCi. Control animals were exposed to nonradioactive aerosols. Irradiated lungs from hamsters at both dose levels had compliance reduced to the same extent at point of maximal reduction. However, collagen accumulation was more closely related to 238Pu exposure level than the compliance measurements. Histologic examination revealed both diffuse alveolar thickening and some dense fibrous scars, the former predominating at lower dose levels. Hamsters exposed to 50 nCi 238PuO2 showed normal collagen content and static lung compliance with minimal histologic fibrosis 288 days after exposure. In contrast, hamsters exposed to 100 nCi had significant pulmonary fibrosis at that time and the highest incidence of dense scars at any time period. Such findings are consistent with a stiffening of lung parenchyma. They suggest that the diffuse interstitial fibrosis developed by this injury resolves spontaneously; dense fibrous scars, however, do not.

Red cell fragmentation in the dog: an editorial review.

Red blood cell fragments in blood smears from dogs are described morphologically and pathogenetically. Categories include microangiopathic fragmentation, spherocytic fragmentation. Heinz body fragmentation, metabolic fragmentation associated with systemic disease, and artifactual fragmentation. Microangiopathic fragmentation is associated with direct physical damage to normal circulating red blood cells as they pass through abnormal capillary beds. Spherocytic fragmentation is a common feature of immune-mediated hemolytic anemia and results from the removal of portions of antibody-coated erythrocyte plasma membranes by phagocytes of the reticuloendothelial system. Heinz body fragmentation occurs when rigid particles of oxidized hemoglobin are torn from affected red cells as they circulate through the spleen. Metabolic fragmentation is an ill-defined syndrome most commonly associated with cholesterol loading of red cell membranes caused by lipid metabolism abnormalities. Resulting spiculated red cells are more susceptible to traumatic disruption. All the types of red cell fragmentation described in dogs have been observed and documented in man.

Microangiopathic hemolytic anemia associated with radiation-induced hemangiosarcomas.

A retrospective study of red blood cell parameters in 53 dogs with experimental radiation-induced hemangiosarcoma showed 24 had anemia. Morphologic alterations in red blood cells in peripheral blood films from anemic dogs included signs of regeneration (anisocytosis and polychromasia), hypochromasia, red cell fragmentation and acanthocytosis. The degree and type of red cell changes varied from dog to dog and generally correlated with the principal site of tumor involvement. Blood from dogs with tumors principally involving liver had red cell regeneration, fragmentation and acanthocytosis. Blood from dogs with tumors primarily involving the heart had only red cell fragmentation. Blood films from dogs with skeletal and pulmonary hemangiosarcomas were similar to blood films from dogs with hepatic hemangiosarcoma except that red cell alterations generally were less severe. Scanning and transmission electron micrographic evaluation of neoplastic tissue showed large amounts of fibrin within neoplastic vascular sinuses and disruption and distortion of red blood cells traversing these abnormal vascular beds. The red blood cell fragmentation syndrome associated with radiation-induced hemangiosarcomas therefore was considered to be a microangiopathic hemolytic anemia of localized origin.

Cardiopulmonary function and morphologic changes in beagle dogs after multiple lung lavages.

This study evaluated the long-term biomedical risks risks of multiple, massive saline lung lavage using dogs. Risks were assessed using clinical examinations of cardiopulmonary function, thoracic radiographs, auscultation of the chest, body temperature, and hematologic values. Thirty-six dogs given 10 lavages over a 49-day period had no gross lesions at time of necropsy 7 days after the last lavage. Six dogs, followed with clinical examinations after each of 10 lung lavages, had no detectable effects from the lavage except for elevated body temperature and bronchial breathing at 24 hr after some procedures. No gross lesions were found at sacrifice 28 days after the last lavage. The only histologic lesions found were those also found in unlavaged control dogs. Six dogs that were lavaged 10 or more times had normal pulmonary function values for 4 yr after the last lung lavage. No chronic sequelae were found in healthy beagle dogs given 10 or more lung lavages suggesting a minimal long-term risk associated with these procedures.

Mucosal morphologic alterations in Thiry-Vella fistulas.

Three Thiry-Vella fistulas were surgically placed in each of 9 dogs to study the effects of x-irradiation on isolated loops of small intestine. Mucosal biopsy samples were removed from the fistulas for 5 days at 24-hour intervals after surgical operation to assess the morphologic alterations that occurred in the fistula mucosa following surgical isolation. There was a reduction of villus height during the 1st day, reduction of crypt depth on days 2 and 3, and stabilization of villus height and crypt depth during days 3 to 5 after surgical operation. The surgical technique and morphologic alterations observed in the mucosa of the fistulas during the 5 days after surgery are described.

Anomalous portosystemic anastomoses associated with chronic hepatic insufficiency in six young dogs.

Chronic hepatic insufficiency due to anomalies of the portal venous system was diagnosed in 6 young dogs. The disorder was characterized by a variety of abnormal central nervous system signs or ascites, or both. Laboratory findings were characteristic of chronic, generalized hepatic dysfunction. The diagnosis was established by angiographic studies of the portal venous system. Of the 6 dogs, 3 died, 1 was euthanatized, and 2 are still alive and require medical management for ascites.