Assessment of the morphology and significance of the lymph nodal and hepatic lesions produced in rats by the feeding of certain mineral oils and waxes. Proceedings of a pathology workshop held at the Fraunhofer Institute of Toxicology and Aerosol Research Hannover, Germany, May 7-9, 2001.

A Panel of medical and veterinary pathologists reviewed published and unpublished reports dealing with studies of various white mineral oils and waxes in F344 and Sprague-Dawley rats. They also had available and studied histologic slides from both subchronic and chronic studies of certain mineral hydrocarbons (90-day oral study of low melting point wax (LMPW) in female Fischer 344 and Sprague-Dawley rats; 90-day studies of P15H* and P70H white oil and high melting point wax (HMPW) in male and female F344 rats and 24 month study of P70H white oil in male and female F344 rats. The Panel also reviewed mineral oil-induced alterations in tissues of human patients (liver, hepatic lymph node and spleen). The Panel agreed that certain of the mineral hydrocarbons produced lesions in the mesenteric lymph nodes and liver of the F344 rat and these lesions were best described as microgranulomas/granulomas. The lesions were fundamentally similar in both organs, although varying in severity with dose and type of mineral hydrocarbons. The Panel agreed that hepatic lesions with inflammatory cell infiltration, necrosis, and fibrosis were produced only by feeding of LMPW and the lesions were confined to F344 rats and not found in Sprague-Dawley rats. The most severe granulomatous lesions in the mesenteric lymph nodes were found in high dose LMPW-fed F344 rats. The microgranulomas were similar in subchronic and chronic studies. Also, little difference existed between controls and treated F344 rats in the incidence and severity of the lesions after 2 years of feeding P70H white oil. The Panel agreed that some slight reversibility existed for these lesions, but also agreed that complete resolution was unlikely as regression of the lesions in the rat would likely be slow. The Panel agreed that a minimal severity infiltrate of mononuclear inflammatory cells occurred in the base of the mitral valve in a slightly increased incidence in F344 rats fed LMPW. The Panel concluded that these mitral valve alterations had little if any toxicologic significance as the focal infiltrate was minimal in severity, occurred in controls, occurred in association with murine cardiomyopathy, and were unlike the responses in the liver and mesenteric lymph nodes. The Panel agreed that the lesions observed in the liver and mesenteric lymph nodes of F344 rats exposed to MHCs, especially the LMPW, were different morphologically from changes observed in lymph node, liver, and spleen of humans that were mineral oil-users. These changes in humans are usually found incidentally in tissues taken at biopsy or autopsy. The MHC-induced lesions can be considered incidental and inconsequential in humans.

Dose responses from inhaled monodisperse aerosols of 244Cm2O3 in the lung, liver and skeleton of F344 rats and comparison with 239PuO2.

The purpose of this study was to obtain information on the alpha-particle dose-response relationship of 244Cm in rats. Rats were exposed briefly by inhalation to graded levels of monodisperse aerosols of 244Cm2O3 heat-treated at 1150 degrees C. The initial lung burden (ILB) of each animal was determined by the use of the gamma-ray-emitting radionuclide 243Cm in the aerosols. Seven groups of 84-day-old F344/Crl rats (a total of 637 males and 645 females) were exposed once to 244Cm2O3 or sham-exposed to filtered ambient air. Mean ILBs of all rats per group ranged from 0.51 +/- 0.17 (+/-SD) to 240 +/- 82 kBq kg-1 body weight. Mean lifetime alpha-particle doses to the lungs per group ranged from 0.20 +/- 0.069 (+/-SD) to 36 +/- 6.5 Gy. After death, each rat was radiographed and necropsied. Dose-related increases occurred in incidences of benign and malignant lung neoplasms, except for the groups of rats with higher mean ILBs that were examined histologically (98 +/- 18 and 240 +/- 77 kBq kg-1 body weight) in which survival was markedly decreased. Also, average alpha-particle doses of 0.0014 +/- 0.00058 (+/-SD) to 0.17 +/- 0.091 Gy and 0.18 +/- 0.007 to 1.6 +/- 1.1 Gy were also absorbed by the liver and skeleton, respectively, in the rats in the different exposure groups. Primary liver neoplasms occurred in several rats. However, the incidence of these lesions was not related to dose. Increased incidences of bone neoplasms occurred only in rats receiving higher doses to the skeleton. Excess numbers of rats with lung neoplasms per 10(4) Gy to the lung per group ranged from 760 +/- 430 (+/- SE) at a mean dose of 0.48 Gy to 84 +/- 16 at a mean dose of 37 Gy. Risk factors for the lowest and highest ILB kg-1 body weight groups were not considered reliable because of large errors associated with these calculations and the life-span shortening in the highest ILB kg-1 group. Inhaled 244Cm2O3 appeared to be about 50% less effective as a lung carcinogen in rats compared to 239PuO2 at similar doses.

Biological effects of 137CsCl injected in beagle dogs of different ages.

The toxicity of 137Cs in the beagle dog was investigated at the Inhalation Toxicology Research Institute (ITRI) and Argonne National Laboratory (ANL) as part of programs to evaluate the biological effects of both radionuclides in atomic bomb fallout and internally deposited fission-product radionuclides. In the ITRI study, young adult dogs were exposed once by intravenous injection to a range of 137Cs concentrations; the results have recently been published (Nikula et al., Radiat. Res. 142, 347-361, 1995). The purpose of the present report is to summarize the ANL study and to compare the results of the two studies. At ANL, 63 dogs in three age groups (15 juveniles, 142-151 days old; 38 young adults, 388-427 days old; and 10 middle-aged dogs, 1387-2060 days old) were given 137Cs intravenously at levels (61-162 MBq/kg) near those expected to be lethal within 30 days after injection. There were 17 control dogs from the same colony. Twenty-three of the dogs injected with 137Cs, including all middle-aged dogs, died within 52 days after injection due to hematopoietic cell damage resulting in severe pancytopenia that led to fatal hemorrhage and/or septicemia. The other significant early effect was damage to the germinal epithelium of the seminiferous tubules of all male dogs. These early effects are the same as those reported for the dogs injected with 137Cs at ITRI. In addition, the design of the ANL study revealed an age- and gender-related differential radiosensitivity for early effects: The middle-aged dogs died significantly earlier due to complications of hematological dyscrasia compared to the juvenile and young adult dogs, and the middle-aged females died significantly earlier than the middle-aged males. The most significant non-neoplastic late effects in the 137Cs-injected dogs from ANL and ITRI were atrophy of the germinal epithelium of seminiferous tubules with azoospermia, and a significant dose-dependent decrease in survival. However, the survival of the ANL dogs was decreased more than that of the ITRI dogs at similar radiation doses from 137Cs. Numerous neoplasms occurred at many different sites in the dogs injected with 137Cs at ANL and ITRI. Two differences in the findings of the two studies were that (1) there was an increased risk for malignant thyroid neoplasms in the ANL male dogs injected with 137Cs, but not the ITRI dogs of either gender, and (2) there was an increased relative risk for benign neoplasms excluding mammary neoplasms in the ITRI dogs injected with 137Cs, but not the ANL dogs. In both groups, there were dose-related increased incidences of malignant neoplasms, malignant neoplasms excluding mammary neoplasms, all sarcomas considered as a group, all non-mammary carcinomas considered as a group and malignant liver neoplasms. In summary, the similarity of the findings between the two studies and the dose-response relationships for survival and for large groupings of neoplasms suggests that these results are consistent findings in 137Cs-injected dogs and might be dose-related late effects in humans exposed to sufficient amounts of internally deposited 137Cs.

Classification of cystic keratinizing squamous lesions of the rat lung: report of a workshop.

An international workshop of toxicologic pathologists reviewed cystic keratinizing squamous lesions of the rat lung. These lesions develop in response to the chronic inhalation of diverse particulate materials. Controversy exists over the biological significance of these changes and their relevance to humans. For the first time, in one place, a group of pathologists analyzed slides from all available studies. The workshop reached a consensus as to classification of these unique pulmonary tissue responses and offers diagnostic criteria for application. Although additional research is needed, this working classification scheme should serve as a practical interim approach for pathologists and regulatory agencies.

The effect of 6-aminonicotinamide on testicular development in the rat.

6-Aminonicotinamide (6-AN), a niacin antagonist, was administered sc to pregnant female (1.0, 3.0, or 6.0 mg 6-AN/kg body weight) and neonatal male (1.5, 3.0, 6.0 or 12.0 mg 6-AN/kg body weight) Sprague-Dawley rats on the 15th, 17th and 19th days of gestation or the 5th, 7th and 9th days of life, respectively, to determine the effects of the antimetabolite on testicular morphology and development. In prenatal males, microscopic alterations were present in testes of fetuses from females treated with 6.0 mg 6-AN/kg and consisted of necrosis and loss of gonocytes, and vacuolation of interstitial cells. Histologic changes in testes of neonatal rats treated with 3.0, 6.0 or 12.0 mg 6-AN/kg were qualitatively similar with necrosis and loss of spermatogonia and supporting cells, and increased cross-sectional areas of affected tubules. Quantitation of the number of nuclei/cm2 of seminiferous tubule indicated 6-AN caused a significant reduction in the numbers of supporting cells and spermatogonia/tubular cross-section.

Early ultrastructural lesions of diphenylamine-induced renal papillary necrosis in Syrian hamsters.

The ultrastructural lesions of diphenylamine-induced renal papillary necrosis in Syrian hamsters were characterized by transmission electron microscopy. Twenty-four male Syrian hamsters were orally administered 600 mg diphenylamine/kg body weight as a single dose. At 30 minutes and at 1, 2, 4, 8, 16 and 24 hours after administration of diphenylamine, three hamsters were anesthetized with pentobarbital, perfused via the left ventricle with half-strength KARNOVSKY's fixative, and the renal papilla and outer medulla collected. Three hamsters administered 0.5 ml peanut oil/kg body weight (vehicle controls) were anesthetized at 24 hours, perfused, and the renal papilla and outer medulla collected. Initial ultrastructural lesions were observed in the endothelial cells of the ascending vasa recta in the proximal portion of the renal papilla at 1 hour after diphenylamine administration. The endothelial cell basal plasma membrane was elevated from the basal lamina, forming large subendothelial vacuoles. Alterations in inner medullary interstitial cells, endothelial cells of the descending vasa recta, and the epithelial cells of the thin limbs of Henle and the medullary collecting tubules were observed subsequent to the lesion in the ascending vasa recta. It was concluded that the endothelial cell of the ascending vasa recta is the target cell in diphenylamine-induced renal papillary necrosis in Syrian hamsters.

Pathologic features of naturally occurring juvenile polyarteritis in beagle dogs.

Eighteen young Beagle dogs (eight males and 10 females), ages 6-40 months, with canine juvenile polyarteritis syndrome (CJPS), a naturally occurring vasculitis and perivasculitis of unknown etiology, were necropsied, and their tissues were examined by histopathologic and histochemical methods. The condition is characterized by recurring episodes of an acute onset of fever (> 40 C) and neck pain that persist for 3-7 days. The major histopathologic alterations were a systemic vasculitis and perivasculitis. During the febrile, painful period of CJPS, the vascular lesions ranged from a histiocytic-lymphocytic periarterial infiltration to transmural arterial inflammation with concomitant fibrinoid necrosis and vascular thrombosis. Massive periarterial accumulations of inflammatory cells were common and often extended into adjacent tissues. The small- to medium-sized muscular arteries of the heart, cranial mediastinum, and cervical spinal meninges were consistently involved. Vasculitis occasionally occurred in other organ systems. The vascular lesions in dogs examined during clinically normal periods consisted of intimal and medial fibrosis, ruptured elastic laminae, and mild perivasculitis; these lesions were probably related to previous episodes of vasculitis. Eight dogs that had experienced repeated acute episodes also developed splenic, hepatic, and renal amyloidosis. The clinical signs, laboratory abnormalities, and the vascular lesions suggest that the condition may be immune-system mediated. CJPS may serve as a naturally occurring animal model of human immune-system-mediated vasculitides such as polyarteritis nodosa, infantile polyarteritis, and Kawasaki disease.

Immunoreactivity of canine epithelial and nonepithelial neoplasms with monoclonal antibody B72.3.

Monoclonal antibody (MAb) B72.3, which binds to a human tumor-associated glycoprotein termed TAG-72, was applied to a wide range of epithelial and nonepithelial neoplasms from dogs. Immunoreactivity was detected by the use of an avidin-biotin complex (ABC) immunoperoxidase method. A variety of epithelial neoplasms, but none of the nonepithelial neoplasms, were positive (> or = 5% staining) for MAb B72.3. MAb B72.3 stained 100% (4/4) of gastric, 100% (6/6) of intestinal, 50% (2/4) of pancreatic, and 80% (4/5) of rectal adenocarcinomas but only 20% (1/5) of squamous cell carcinomas and 20% (1/5) of complex tubular mammary gland adenocarcinomas. None of the hepatocellular carcinomas and perianal and sebaceous gland adenocarcinomas stained. Most types of benign epithelial neoplasms did not stain, except for 75% (6/8) of rectal adenomas and 25% (1/4) of squamous cell papillomas. Normal gastrointestinal mucosa adjacent to and entrapped in neoplasms did stain with MAb B72.3. None of the benign and malignant nonepithelial neoplasms of mesenchymal, neuroendocrine, or lymphohematopoietic tissue origin stained. The results of this study demonstrate that MAb B72.3 has selective immunoreactivity for adenocarcinomas, especially those arising from the digestive tract; however, limited immunoreactivity was observed for other types of carcinomas and benign epithelial neoplasms and for normal gastrointestinal mucosa in the dog.

Immunoreactivity of canine transitional cell carcinoma of the urinary bladder with monoclonal antibodies to tumor-associated glycoprotein 72.

Tumor-associated glycoprotein 72 (TAG-72) is a large, high molecular weight, mucinlike antigen that is expressed in a wide variety of human carcinomas. Three different TAG-72 monoclonal antibodies (MAbs), designated B72.3, CC49, and CC83, were applied to the following archived samples from the dog: 1) 51 transitional cell carcinomas of the urinary bladder, 2) 15 hyperplastic/inflamed urinary bladders, and 3) eight normal urinary bladders. Immunoreactivity was detected with an avidin-biotin complex immunoperoxidase method. Fifty-three percent (27/51) of transitional cell carcinomas were positive (> or = 5% staining) for MAb B72.3. MAb B72.3 staining of these transitional cell carcinomas did not statistically correlate with any of the examined features of malignancy, including histologic grade, clinical stage, DNA ploidy, or presence of vascular/lymphatic invasion. In regard to the staining of transitional cell carcinoma by the other two TAG-72 antibodies, 53% (27/51) of the samples were positive for MAb CC83 and 63% (32/51) were positive for MAb CC49. The finding that similar populations of neoplastic urothelial cells in serial sections from the same neoplasm stained with all three TAG-72 antibodies supports the hypothesis that an antigen similar to TAG-72 was expressed in canine transitional cell carcinoma. None of the normal urinary bladders nor any of the hyperplastic/inflamed urinary bladders stained with any of the three TAG-72 antibodies tested. The results of these studies demonstrated that the staining of canine transitional cell carcinoma with all three TAG-72 antibodies was specific for neoplastic urothelial cells and that an antigen similar to TAG-72 was expressed.

"Proliferative keratin cyst," a lesion in the lungs of rats following chronic exposure to para-aramid fibrils.

Cystic and keratinizing squamous lesions have been observed in rats exposed chronically to a number of particulates. A variety of diagnostic terms have been applied to these pulmonary lesions but no consensus exists as to their most proper morphological classification. In an attempt to obtain a consensus for cystic keratinizing pulmonary lesions produced in rats by Kevlar para-aramid fibrils and TiO2 powder, a panel of medical and veterinary pathologists was invited to participate in a workshop addressing the morphology of the lesions and to reach a consensus on a suitable descriptive diagnostic term. All participants agreed that the cystic keratinizing lesions were not malignant neoplasms. The majority was of the opinion that the lesions were not neoplasms. A minority (3/13) considered the lesions to be benign tumors. The panel considered that the most appropriate morphologic diagnosis for the lesions was "proliferative keratin cyst" (PKC). In addition, the panel agreed on the following descriptive text: "The lesions are cysts lined by a well-differentiated stratified squamous epithelium with a central keratin mass. Growth appears to have occurred by keratin accumulation and by peripheral extension of the metaplastic change into the adjacent alveolar spaces. The lesions are sharply demarcated except in those areas in which there has been extension of metaplasia into adjacent alveoli. The squamous epithelium has few mitotic figures and dysplasia is absent."

Plutonium-induced proliferative lesions and pulmonary epithelial neoplasms in the rat: immunohistochemical and ultrastructural evidence for their origin from type II pneumocytes.

Immunohistochemistry and transmission electron microscopy were used to clarify the cellular origin for plutonium-239-induced pulmonary proliferative (preneoplastic) epithelial lesions and epithelial neoplasms in F344 rats. Examples of each histologic type of proliferative lesion and neoplasm were stained by the avidin-biotin complex immunoperoxidase method using antibodies to rat surfactant apoprotein and Clara cell antigen. Rat surfactant apoprotein immunostaining was detected in type II pneumocytes in sections of normal lung, in the cells of the proliferative lesions classified histologically as alveolar epithelial hyperplasia (51) and mixed foci (alveolar epithelial hyperplasia with fibrosis) (30), and in adenomas (2), adenocarcinomas (3), and adenosquamous carcinomas (2). With the exception of one adenosquamous carcinoma, Clara cell antigen immunostaining was not detected in any of the pulmonary lesions but was detected in nonciliated cuboidal epithelial (Clara) cells in normal bronchioles. The epithelial cells of the proliferative lesions and neoplasms had ultrastructural features consistent with type II pneumocytes, i.e., the presence of cytoplasmic lamellar and multivesicular bodies. The results of these studies indicate that the majority of plutonium-induced proliferative epithelial lesions and neoplasms in the rat originate from alveolar type II pneumocytes.

Flow cytometric DNA ploidy analysis in canine transitional cell carcinoma of urinary bladders.

Flow cytometric analysis of DNA ploidy was performed on 51 formalin-fixed, paraffin-embedded samples of canine transitional cell carcinoma of the urinary bladder. The DNA ploidy data obtained were compared to several clinicopathologic features. In addition, the DNA ploidy of 15 hyperplastic/inflamed and 8 normal canine urinary bladders was measured. Forty-three of the 51 neoplastic samples had interpretable DNA histograms. DNA aneuploidy was found in 34/43 (79%) of the transitional cell carcinoma samples. Of the 34 aneuploid neoplasms, 16 (47%) were hyperdiploid, 17 (50%) were tetraploid, and 1 (3%) was hypertetraploid. No significant correlation was found between the presence of DNA aneuploidy and the growth pattern, histologic grade, clinical stage, or individual morphologic features of this neoplasm. Additionally, the DNA ploidy was not related to the sex, age, or survival time of dogs with transitional cell carcinoma. All of the normal and all but one of the hyperplastic/inflamed urinary bladders were diploid. The results from this study demonstrated that DNA ploidy can be measured from paraffin-embedded canine samples by flow cytometry, a majority of the canine transitional cell carcinomas were aneuploid, and a significant correlation did not exist between the DNA ploidy and specific clinicopathologic features of this neoplasm.

Naturally occurring atriocaval mesotheliomas in rats.

Atriocaval mesotheliomas were observed in two control Sprague-Dawley rats out of a total of 2889 rats examined. Both neoplasms were located at the base of the interventricular septum. Microscopically, the neoplasms consisted of varying proportions of glandular structures and a fibrous tissue stroma. Glandular structures were lined by a single layer of cuboidal to low columnar epithelium with cells containing a moderate amount of eosinophilic fibrillar to granular cytoplasm and a pleomorphic vesicular round nucleus with coarsely clumped chromatin and often a single eccentric prominent nucleolus. Epithelial cells were stained with antibodies raised against both vimentin and cytokeratin. Electron microscopical features included the presence of microvilli, terminal bars composed of modified tight junctions and desmosomes at the lateral and apical borders, and numerous tonofilaments associated with desmosomes.

Sequential analysis of the pathogenesis of plutonium-induced pulmonary neoplasms in the rat: morphology, morphometry, and cytokinetics.

Light microscopy, morphometry, and cytokinetic techniques were used to examine the dynamics of plutonium-induced pulmonary proliferative lesions and neoplasms in rats at several intervals to 450 days after inhalation exposure to aerosols of 239PuO2. Maximal increases in alveolar and bronchiolar epithelial cell labeling were seen at 30 days; decreasing subsequently, the levels remained elevated above control indices. Focal proliferative epithelial lesions developed in the lung by 180 days and before the onset of pulmonary neoplasms. Pulmonary neoplasms, predominantly adenocarcinomas and squamous cell carcinomas, were initially observed at 308 days. The proliferative lesions progressed through a succession of morphological changes leading to the development of neoplasms. The volume density (fraction) and epithelial surface area of foci of alveolar epithelial hyperplasia increased progressively between 180 and 450 days after exposure, in contrast to the other proliferative lesions. We conclude that plutonium-induced pulmonary neoplasms develop through a succession of focal proliferative lesions that represent developmental preneoplastic lesions. Progressive increases in volume and epithelial surface area of the alveolar epithelial hyperplasias suggest that they may be more at risk for neoplastic transformation than the other histological types of proliferative foci.

Effects of difloxacin on the metabolism of glycosaminoglycans and collagen in organ cultures of articular cartilage.

Fluoroquinolones, including difloxacin, are potent antibacterial compounds which, as a side effect, cause lesions in articular-epiphyseal cartilage complexes (AECC) of growing animals. To evaluate the effects of difloxacin on the structure of AECC and the metabolism of sulfated glycosaminoglycans (GAG) and collagen, explants of AECC were obtained from 18 healthy, 3-month-old Beagle dogs and cultured in medium which either had no difloxacin or had the drug at one of three concentrations (40, 80, or 160 micrograms/ml). Rates of synthesis of GAG and collagen were reduced by concentrations of difloxacin that were at or above 80 micrograms/ml. The rate of synthesis of total protein, however, was reduced only at the highest dose level. Catabolism of GAG and collagen was unaffected by the treatment. The principal ultrastructural changes in affected chondrocytes were distension of rough endoplasmic reticulum with electron-dense material that was probably protein, and vacuolation of cytoplasm. Structural changes were not observed in the extracellular matrix. It, therefore, appeared plausible that difloxacin affected chondrocytes by interfering with secretion of the matrix components, GAG and collagen.

Early sequential ultrastructural renal alterations induced by 2-bromoethylamine hydrobromide in the Swiss ICR mouse.

Thirty-two male Swiss ICR mice were injected intraperitoneally with 300 mg 2-bromoethylamine hydrobromide/kg body weight, anesthetized, and perfused with glutaraldehyde-paraformaldehyde solution at 5, 15, 30, 60, 90, 120, 150, and 180 minutes after treatment. Eight control mice were injected intraperitoneally with sterile diluent, and one was perfused at each of the same time periods as the treated mice. Proximal tubule epithelial alterations progressed over time from increased secondary lysosome and myeloid body formation to cellular and mitochondrial swelling and eventually cell necrosis. The glomerular, peritubular, and vasa recta capillaries had endothelial cell swelling and desquamation and platelet aggregation. Bromoethylamine nephrotoxicosis in the male Swiss ICR mouse is an ischemic necrosis of the proximal tubules and papilla initiated by endothelial cell damage and makes an excellent model of chemically induced damage to endothelial cells and tubular necrosis.

Incidence, histopathologic and electron microscopic features of spontaneous nephroblastomas in rats.

Primary renal neoplasms in the rats are uncommon. Nephroblastoma is the only renal embryonal tumor of the rat; all other tumors are reported in older rats. The occurrence of spontaneous nephroblastoma in rats has been reported. However, metastasis from the nephroblastoma in rat is extremely rare. Data from 2669 Sprague-Dawley control rats and 1060 Fischer-344 rats were reviewed and evaluated to determine the incidence and pathology of nephroblastoma. This tumor was observed in three Sprague-Dawley rats. Metastasis was observed in the lungs and renal lymph nodes in two different rats. No case of nephroblastoma was observed in Fischer-344 rats. Detailed histopathological and electron microscopic features of these neoplasms are described and discussed.

Ultrastructural changes in articular cartilages of immature beagle dogs dosed with difloxacin, a fluoroquinolone.

The ultrastructural features of quinolone-induced arthropathy were studied in the humeral and femoral heads of nine skeletally immature Beagle dogs (3 months old) that were dosed orally with difloxacin at 300 mg/kg body weight and euthanatized 24, 36, or 48 hours later in groups of three. Three age-matched dogs were given a placebo and euthanatized after 48 hours. Mitochondria in chondrocytes had significantly greater cross-sectional areas (P less than 0.05) in electron micrographs from dogs euthanatized after 48 hours of treatment than did those in other groups. There was also a significantly greater percentage of chondrocytes with swollen mitochondria in treated dogs than in the controls (P less than 0.05). These changes preceded the necrosis observed in some chondrocytes in the dogs of the 48-hour group. Disruption of extracellular matrix was first observed in the pericellular matrix of necrotic chondrocytes, indicating that this change was secondary to the changes in chondrocytes. Fissures within cartilages apparently resulted from the loss of the normal association of proteoglycans with collagen fibrils.

Experimental renal papillary necrosis in the Mongolian gerbil (Meriones unguiculatus).

Sequential light microscopic and ultrastructural examination of kidneys from male and light microscopic examination of female Mongolian gerbils given 250 mg 2-bromoethylamine hydrobromide (BEA)/kg body weight ip were performed. In addition, male Mongolian gerbils were treated with both BEA and ip injections of either water, dimethyl sulfoxide, piperonyl butoxide, or reserpine. Light microscopic renal lesions in male Mongolian gerbils progressed from congestion of the vasa recta of the proximal inner medulla at 6 hr post-treatment to total renal papillary necrosis (RPN) at 24 hr post-treatment. There was no sex difference in sensitivity to BEA. Ultrastructural alterations in male gerbils were restricted to the vasa recta. Vascular lesions of endothelial swelling and pericapillary edema in the vasa recta of the proximal inner medulla was observed 2 hr post-treatment and progressed to occlusion by platelets adherent to exposed basement membranes at 6 hr post-treatment. Diuresis induced by injections of saline and injections of dimethyl sulfoxide or piperonyl butoxide did not affect the development of BEA-induced RPN. Reserpine slowed the development of BEA-induced RPN by its vasodilatory effect on the renal vasculature, not by blocking the endothelial toxicity of BEA. RPN induced by BEA in the Mongolian gerbil is apparently an ischemic necrosis of the inner medulla that develops secondary to endothelial damage of the vasa recta.