Search

Three Mycoplasma spp. were isolated from five colony bred laboratory dogs (Canis familiaris) obtained from a single vendor. Four of these animals were Beagles and one was a mongrel. Three displayed clinical signs of respiratory disease including dyspnea, chronic coughing and moist rales, while the other two dogs were observed during thoracic surgery to have macroscopic lesions suggestive of pneumonia. All five dogs were submitted for diagnostic necropsy during which they were cultured for bacteria and mycoplasma. Mycoplasma spp. having three distinct colonial forms were isolated from the lungs of each of the animals. These three isolates were sent to the National Cancer Institute Diagnostic Microbiology Laboratory and to the National Institutes of Health, NIAID, Mycoplasmology Laboratory. Neither laboratory could serotype these isolates against antisera to 73 Mycoplasma spp., including the common canine mycoplasmas, and nine Acholeplasma spp. Histologically, the bronchopneumonia was characterized by bronchiectasis, purulent bronchiolitis, bronchial and bronchiolar epithelial hyperplasia, chronic non-suppurative peribronchiolitis and perivasculitis, bronchiolitis obliterans, and acute to subacute purulent pneumonia. The similarity between the pathologic findings in these animals and those observed in respiratory mycoplasmosis of other species, e.g. the rat, suggests a causal relationship between the isolated mycoplasmas and the pulmonary disease observed in these dogs.

The light microscopic features of a spontaneous neoplasm of adipose tissue from a rat were suggestive of a mixed liposarcoma with a myxoid matrix. However, ultrastructurally, the cell characteristics were those of a hibernoma. These characteristics included cells containing lipid droplets of variable size, numberous pleomorphic mitochondria and close apposition to blood vessels. Lipofuscin granules and subplasmalemmal condensations were not observed ultrastructurally.

Three mixtures of benzo(alpha)(a)pyrene (BP) and ferric oxide with different physical properties were given intratracheally to Syrian golden hamsters for an examination of their neoplastic potential. Hamsters treated with a preparation containing large aggregates of BP and ferric oxide resulting from nucleation of BP on the particles showed an earlier onset and higher incidence of respiratory tract tumors than animals given a mixture containing smaller aggregates prepared by hand-grinding. The greatest number of tumors were present in the trachea and the predominant type was the squamous carcinoma. A third preparation in which the carcinogen was not attached to the ferric oxide showed a low tumor incidence similar to that present after intratracheal intubation of BP in gelatin without a carrier particle. For this model system of respiratory carcinogenesis, the physical attachment of BP and the carrier dust is necessary for a high tumor yield.

Pulmonary prostacyclin (PGI2) production, arterial perfusion, and ultrastructure were correlated in rats sacrificed from 1 day to 6 months after a single exposure of 25 Gy of gamma rays to the right hemithorax. PGI2 production by the irradiated lung decreased to approximately half the normal value 1 day after irradiation (P less than 0.05), then increased steadily throughout the study. By 6 months postirradiation, the right lung produced two to three times as much PGI2 as did either shielded left lung or sham-irradiated lungs (P less than 0.05). Perfusion scans revealed hyperemia of the right lung from 1 to 14 days after irradiation. From its peak at 14 days postirradiation, however, perfusion of the irradiated lung decreased steadily, then reached a plateau from 3 to 6 months at less than half that in the shielded left lung. Electron micrographs of the right lung revealed perivascular edema from 1 to 30 days after irradiation. The right lung then exhibited changes typical of radiation pneumonitis followed by progressive interstitial fibrosis. Platelet aggregates were not observed at any time. Thus, decreased PGI2 production is an immediate but transient response of the lung to radiation injury. Then from 2 to 6 months after irradiation, the fibrotic, hypoperfused lung produces increasing amounts of the potent vasodilator and antithrombotic agent, PGI2. Pulmonary PGI2 production and arterial perfusion are inversely correlated for at least 6 months after hemithoracic irradiation.

Toxicity of single-dose spirogermanium was evaluated after iv and im administration to CDF1 mice and beagle dogs. The im LD50 in mice was approximately threefold greater than the iv LD50. The lethal dose in dogs was the same for both routes of administration, but death was delayed after im injection. Convulsive seizures occurred only after the im doses that were lethal, but they were observed after administration of iv doses that were nonlethal. Microscopic evidence of drug toxicity (necrosis and degeneration) was found in mitotically active tissues: intestinal tract, lymphoid tissue, and bone marrow. Necrosis, hemorrhage, edema, and granulation tissue were observed in the muscle injection site.

The carcinogenic potential of misoprostol, a synthetic prostaglandin E1 analogue with anti-ulcer potential, was evaluated in CD Sprague-Dawley rats. The compound was given daily by gavage at 24, 240, and 2,400 micrograms/kg, up to 150 times the daily human dose for 2 years. Necropsies were done on all animals and the incidences of non-neoplastic and neoplastic changes analyzed for significance by life table methods. The only statistically significant non-neoplastic finding was epithelial hyperplasia and hyperkeratosis of the gastric mucosa. These changes, which are characteristic of some prostaglandins, were expected. Other non-neoplastic findings were typical of known spontaneous conditions in this strain of rats. The most frequent neoplasm was the pituitary adenoma, followed by the mammary fibroadenoma, mammary adenoma, mammary adenocarcinoma, and thyroid C-cell adenoma. A rare neoplasm, squamous cell carcinoma of the ovary was found in two rats. There was no evidence that misoprostol is carcinogenic for CD Sprague-Dawley rats.

A 225-day-old male fourth generation rat from a developing recombinant inbred line (Lewis x Brown Norway) had a bilaterally symmetrical enlargement of the scrotum. Palpation indicated the presence of a firm lobulated mass extending from the tip of the scrotum to the abdominal wall. Bilateral nodular masses totally occupied the scrotal sacs, surrounded the testicles, and extended along the spermatic cords into the abdominal cavity. Tumor nodules also were present in the intestinal mesentery, omentum, mesenteric lymph nodes, pancreas, and lung. Histologically, the neoplasm presented a spectrum of characteristics varying from that of a granuloma with giant cells to a diffuse proliferation of spindle-shaped mononuclear cells.

Single oral dose toxicities of six hexamethylmelamine samples with different particle size distributions were evaluated in Osborne-Mendel rats. The calculated LD50 values for the 6 samples were 1706 to 2150 mg/kg )10,236 to 12,900 mg/m2). The two samples with median particle size less than 40 micron were more toxic than the other 4 samples. Among the latter samples, severity of toxic effects was not correlated with particle size. Leukocytes, lymphocytes, platelets and body weight showed dose-related decreases for all samples. Particle size appeared to have a minimal effect on these variables. The drug produced toxic effects on rapidly proliferating tissues: lymphoid, hematopoietic and germinal epithelium. At lethal doses, microscopic lesions were lymphoid tissue hypoplasia, bone marrow hypoplasia with elevated myeloid:erythroid ratios and spermatogenic arrest. The major target organs at nonlethal doses were bone marrow and germ cells, with germinal epithelium showing the most severe lesions.

Mongolian gerbils fed diets containing lead acetate maintained body weight comparable to gerbils fed the same diet without added lead. Intranuclear lead inclusion bodies in epithelial cells of the proximal convoluted tubules of the kidney were first observed at 4 weeks, and increased in number to about 50 per high power field at 12 weeks. At this time, a corticomedullary area of empty-appearing tubules was prominent. Transmission electron microscopy confirmed the increase in number and size of nuclear lead inclusion over the 12-week period. Cytoplasmic changes observed in proximal tubule cells containing lead inclusions were considered indicative of acute lethal injury. Distinct cytoplasmic fibrillar structures, first apparent at 8 weeks, were present in some proximal tubular lining cells and strongly resembled newly formed intranuclear lead inclusions. After 12 weeks, the total amount of lead present in the gerbil kidney was four to six times greater than that in rat kidney as determined by atomic absorption spectrophotometry. A hypothesis has been formulated that relates the more efficient nephron of the gerbil kidney to the rapid and extensive development of intranuclear inclusion bodies and the greater accumulation of total lead.

Two New Zealand white rabbits which were used in a teratology experiment had a unilateral corneal opacity. The affected eye had a raised opaque membrane that extended from the limbus toward the center of the cornea to form a ring at the corneal margin. Sections of cornea showed local areas of thickened, elevated epithelium interspersed with areas of abnormally thin epithelium. A diagnosis of corneal epithelial dystrophy was made.

Bromovinyldeoxyuridine (BVDU), a substituted pyrimidine analog with antiviral activity, was given orally to beagle dogs (6/sex/dosage) at dosages of 0, 5, 12, and 30 mg/kg/day for 52 weeks. Complete physical examinations, including ECG recordings and rectal temperature measurements, and clinical laboratory determinations were performed every 13 weeks. At the end of the dosing period, 4 dogs/sex/dosage were sacrificed and complete gross and microscopic examinations performed. The remaining 2 dogs/sex/dosage were sacrificed following a 13-week recovery period. BVDU had no effect on feed consumption, respiration, body temperature, or heart rate. At 30 mg/kg, males gained less weight than controls. At 12 mg/kg (males) and 30 mg/kg (both sexes) there were slight, but statistically significant decreases in mean corpuscular volume, but no changes in red blood cell (RBC) count, hematocrit, or hemoglobin, and no evidence of reticulocytosis. In males dosed at 30 mg/kg, during the last 6 months of dosing, partial thromboplastin times, serum alanine aminotransferase, and alkaline phosphatase increased, and cholesterol decreased. Histologically, bile ductule hyperplasia and gall bladder epithelial hyperplasia were present at 12 and 30 mg/kg in both sexes at the end of both the dosing and recovery periods. At 30 mg/kg, bone marrow hypocellularity and testicular germ cell atrophy were also present in males. Thus, the liver and gall bladder are the major target organs of chronically administered BVDU in dogs. BVDU causes degenerative and proliferative hepatobiliary damage, and secondarily causes changes in clinical chemical parameters. At higher dosages, there are hypoplastic and degenerative changes in the bone marrow and testes.

Normal lung architecture of the rat, mouse, hamster, horse, and human was compared to that of emphysematous lungs from the same species by utilizing a light microscope and a scanning electron microscope (SEM). The results obtained by SEM examination of normal and emphysematous lungs corresponded to those obtained with the light microscope. However, the SEM provided a view of alveoli and airway morphology not obtainable with the light microscope. Because of the variability in pore size and number of pores per alveolus, a pore-to-alveolus ratio was determined with the SEM on the normal lungs of the above species plus the rabbit, dog, guinea pig, and rhesus monkey. Depending on the extent of other pathways for collateral ventilation, differences in number of pores per alveolus may affect a species' susceptibility to a given mechanism in the genesis of spontaneous or induced emphysema. The small number of pores per alveolus in the rat, mouse, rabbit, and hamster suggests that they would not be responsible for emphysematous changes. Pores do appear to be involved in human and horse emphysema.

We have utilized the 6-day air-pouch model in rats to study the local tissue response to interleukin-1 exposure. Injection of either recombinant human interleukin 1 alpha (rIL-1 alpha) or interleukin 1 beta (rIL-1 beta) directly into preformed air pouches caused a 10- to 100-fold increase in the number of white blood cells present within the pouch. On a weight basis, rIL-1 beta was more active than rIL-1 alpha. Polymorphonuclear neutrophils (PMN) represented the majority of cells entering the pouch following either a single injection or repeated daily injections of rIL-1 alpha or rIL-1 beta. Significant increases in the number of mononuclear cells present were observed only following repeated injections. Repeated injections of rIL-1 beta, but not rIL-1 alpha, also caused the accumulation of large amounts of fluid within preformed pouches and a grossly apparent thickening of the connective-tissue lining of the pouch. Microscopic examination of stained sections of pouch lining tissue indicated a proliferation of the connective-tissue elements of the lining and deposition of large quantities of extracellular collagen within the pouch wall. These findings are entirely consistent with a role for interleukin 1 in the development and perpetuation of inflammatory reactions.

Male mice (CDF1) in a single-treatment schedule, male and female dogs in a single-treatment and in three multiple-treatment schedules, and male and female monkeys in one multiple-treatment schedule were used to evaluate the toxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide. Vehicle controls receiving anhydrous N,N-dimethylacetamide plus lactic acid were included in the dog and monkey studies. The liver was the major target organ of toxicity in mice. Lymphoid depletion and generalized bone marrow suppression were the most sensitive indicators of toxicity in dogs and monkeys. At high toxic doses, CNS and intestinal toxic effects were present. Hepatotoxic effects were most prominent in dogs after single iv injections. Multiple-dose regimens were more toxic than single-dose regimens in dogs, but inclusion of rest periods between multiple-treatment periods or reduction of the dose attenuated the toxic effects. The monkey was more resistant to drug toxicity than the dog. Local tissue reaction studies in guinea pigs and rabbits suggested that local irritation responses observed may have been due to the acidity of the drug and vehicle solutions.

Single-treatment schedules in mice and dogs and multiple-treatment schedules in dogs and monkeys were used to evaluate the toxicity of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole. The LD50 of the iv single dose in male and female mice collectively was 993 mg/kg (2980 mg/m2). The major target organs in mice, dogs, and monkeys were the bone marrow, lymphoid tissue, and gastrointestinal tract. Clinical signs at lethal and high toxic doses were weight loss, diarrhea, hematochezia, emesis, anorexia, mydriasis, dyspnea, lethargy, and stupor. The immediate toxic effect on blood cells was a depression of rbcs with suppression of lymphoid elements occurring later. In dogs, the most toxic schedule was single bolus injections. Attenuation of toxic responses occurred if rest periods were introduced between single or repeated daily dose schedules. The monkeys were more sensitive than the dogs to the high toxic dose on a milligram per meter squared basis, with similar sensitivity to the low toxic dose in the repeated daily injections.

Single- and multiple-treatment schedule in dogs were used to evaluate the toxicity of ICRF-187. The major target organs were the bone marrow, lymphoid tissue, gastrointestinal tract, liver, and kidney. Liver, kidney, and intestinal toxic effects were most severe at lethal doses. Toxic effects on the kidney and intestinal tract were reduced or absent at lower doses. Hepatotoxicity was most severe after single doses and was only slowly reversible at high doses. Repeated dosage regimens had the greatest effect on circulating blood cells, and anemia and neutropenia were most prominent after three series of five daily doses with rest periods between series. ICRF-187 was more toxic to dogs in terms of total dose received when administered in five daily doses than in single doses. A rest period between series of five daily doses allowed a larger total dose to be administered.

To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of 60Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90-150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.

Misoprostol, a synthetic prostaglandin E1 methyl ester analogue with anti-ulcer potential, was evaluated for its carcinogenic potential in CD-1 strain mice. The compound was given daily by gavage at 160, 1,600, and 16,000 micrograms/kg for 21 months. Necropsies were done on all animals and the incidences of non-neoplastic and neoplastic changes analyzed for significance by life table methods. The only statistically significant non-neoplastic compound-related findings were epithelial hyperplasia and hyperkeratosis of the gastric mucosa and hyperostosis of bone in the marrow cavity of sternebrae and femurs. The changes in the gastric epithelium are characteristic of some prostaglandins and were expected. The bone hyperostosis was associated with misoprostol in high dosages, and was considered unique to the mouse. Other non-neoplastic findings were typical of known spontaneous conditions in mice. The most frequent neoplasm was the hepatocellular adenoma followed by lymphosarcoma, lung alveolar carcinoma, and Harderian gland adenoma. Several proliferative lesions of the duodenum were considered to be spontaneous. These were focal avillous hyperplasia, focal atypical hyperplasia, and junctional polyp. There was no evidence that misoprostol is carcinogenic for CD-1 mice.

Single intravenous doses of CDF1 mice, and single and five daily intravenous treatment schedules in beagle dogs and rhesus monkeys were used to evaluate the toxicity of Streptozotocin (SZN). The major target organs in the three species were liver, kidney, lymphoid tissue and pancreatic islet beta cells. Moderate bone marrow depression and gastrointestinal toxicity were observed in the large animal species after lethal doses. Monkeys were less sensitive than the dog to the hepatotoxic effects of SZN and clinical signs of liver dysfunction were more severe in dogs after multiple doses. Microscopic lesions in the renal proximal convoluted tubules were present in the three species; these lesions appeared to be irreversible for dogs. The toxic effect on the endocrine pancreas was manifest by hyperglycemia, glucosuria, islet atrophy and beta cell degranulation. Multiple dose regimens were less toxic than single doses in dogs and monkeys in terms of the total dose received.

To study the role of endothelial damage in the pathogenesis of lung injury induced by the pyrrolizidine alkaloid monocrotaline, three functions (angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) production) associated with the pulmonary endothelium were examined, and were correlated with pulmonary arterial perfusion and ultrastructure in rats receiving monocrotaline in their drinking water (20 mg/liter) for 1-12 weeks. Lung ACE activity increased after 1 week of monocrotaline, then decreased steadily from 1 to 6 weeks, before plateauing at approximately 55% of normal. PLA activity in monocrotaline-treated lungs did not change significantly for the first 2 weeks, then decreased to 59 and 79% of the control value after 6 and 12 weeks, respectively. In contrast, PGI2 production increased progressively, reaching 140 and 270% of the control level after 6 and 12 weeks of monocrotaline treatment, respectively. These endothelial functional changes were not accompanied by significant changes in pulmonary arterial perfusion as visualized by 99mTc lung scans. Electron microscopy of monocrotaline-treated lungs revealed endothelial damage (perivascular and subendothelial edema, degeneration) starting at 1 week, and inflammatory and hemorrhagic reactions starting at 2 weeks. At 6 and 12 weeks, monocrotaline-treated rats also exhibited increased pulmonary arterial wall thickness, right heart enlargement, and cardio- and hepatomegaly. Thus, monocrotaline-induced pulmonary injury is accompanied, and in some cases preceded, by structural and functional abnormalities in the pulmonary endothelium.

The mechanism of reduced fibrinolysis in lungs of rats whose right hemithorax had been exposed to a single dose of 25 Gy of 60Co gamma rays was determined, and fibrinolytic changes were correlated with perfusion and morphologic alterations. Reduced fibrinolytic activity in the irradiated lung was evident after 1 month, and decreased further at 2 months. From 2 to 6 months postirradiation, right lung fibrinolytic activity reached a plateau at about half of the activity in the shielded left lung or in sham-irradiated control lungs. The reduced fibrinolytic activity was largely due to decreased plasminogen activator activity, rather than to increased inhibitor activity. Changes in fibrinolytic activity of the irradiated lung closely paralleled changes in arterial perfusion. Mild ultrastructural changes in the irradiated lung (endothelial blebbing and interstitial edema) preceded fibrinolytic and perfusion defects. In contrast, marked changes such as fibrin deposition in the alveolar space and interstitial hypercellularity and fibrosis occurred after pulmonary fibrinolytic activity and perfusion were reduced.

Dogs and cats killed by intravenous injection of either 0.3 ml/kg body weight T-61 or 100 mg/kg body weight pentoarbital and necropsied at less than 5 minutes or at 15 minutes after injection did not have gross or microscopic pathological changes. However, dogs and cats killed with T-61 at a dose of 1.0--1.5 ml/kg body weight and necropsied at 15 minutes after injection had significant gross and microscopic pathological lesions. Grossly, the lungs were severely edematous, did not collapse, and were deep red. Microscopically, the lungs had severe pulmonary edema and endothelial necrosis. Endothelial swelling of glomerular tuft vessels was also present. These lung and kidney lesions are classified as an euthanasia artefact.

Cis-diamminedichloroplatinum [cis-DDP; NSC-119875] and four analogs (NSC-241240, NSC-271674, NSC-263158, and NSC-268252) were evaluated for their acute nephrotoxic potential in male F344 rats following iv administration. Indices of nephrotoxicity included blood urea nitrogen, serum creatinine, kidney weights, and microscopic examination. Results indicated that renal function, organ weights, and histology are important criteria for assessing the nephrotoxic potential of cis-DDP analogs, although alterations in these parameters may have been influenced by severe body weight loss. cis-DDP appeared to be the most nephrotoxic compound studied, and NSC-241240 demonstrated minimal renal damage. Ranking of compounds in order of their nephrotoxic potential (most to least) was cis-DDP, NSC-263158, NSC-268252, NSC-271674, and NSC-241240.

The effects of an anesthetic agent on lung tumor induction in noninbred Syrian golden hamsters were investigated after intratracheal instillation of a benzo[a]pyrene-ferric oxide mixture. Inhalation anesthesia with ether or methoxyflurane was accomplished with a closed recirculatory system that allowed a short induction time for anesthesia and a good control over the concentration of anesthetic. This type of anesthetic induction was compared with systemic induction by Brevital. Survival rates during the 10 weekly instillations were least for the Brevital-treated group and greatest for the methoxyflurane-treated group. Body weight gain was lower in both the ether- and Brevital-treated groups as compared to the group anesthetized with methoxyflurane. The animals anesthetized with Brevital had the shortest tumor latency, but the tumor incidence during the weeks of the experiment was similar in the group treated with this agent and the group treated with ether. Exposure to methoxyflurane and the carcinogen produced a slow onset of deaths from tumors and lower tumor incidence. These results are discussed in relation to retention of the dose of carcinogen in the respiratory tract and effect of inhalation anesthia on consequent lung tissue pathology.

Male rats received 25 Gy (2,500 rad) of gamma rays to the right hemithorax and were killed three or six months later. Microscopic pulmonary abnormalities developed sooner and progressed more rapidly in animals given control feed than in those given the collagen antagonist D-penicillamine (10 mg/day, p.o.). Three and four months after irradiation, hypoperfusion and radiographic hyperlucency of the right lung were observed in both the treated and control animals.

Misoprostol, a synthetic prostaglandin E1, was administered to CD-1 mice daily by gavage for 21 months in a safety study. Hyperostosis of the marrow cavity in the sternum and femur was found predominantly in female mice of the medium (1,600 mcg/kg/day) and high dosage (16,000 mcg/kg/day) groups. Many of the mice with hyperostosis also had cystic ovaries and cystic endometrial hyperplasia indicative of hyperestrinism. It is postulated that the hyperostosis was the result not only of the effects of misoprostol but also of endogenous estrogen. Since misoprostol did not cause hyperostosis in either rats or dogs, it is probable that this effect in mice is unique.