bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Short-Term Treatment with an H+,K+-ATPase Inhibitor (B8301-078) on Enterochromaffin-Like (ECL) Cells in Rat Fundic Mucosa
Authors: Rohr Insa , Tuch Klaus
Published: September 2009

In the present study, female Sprague-Dawley rats were treated orally over 2, 14, and 29 days with 50 mg/kg/day of the H+,K+-ATPase inhibitor B8301–078, a substituted benzimidazole. The endocrine cells in the fundic mucosa were quantified by light microscopy with the aid of Grimelius silver staining and examined by electron microscopy. After 2 days of treatment, the number of argyrophilic Grimelius-positive cells (GPC) was clearly reduced compared to the controls, whereas after 14 and 29 days, hyperplasia was observed. Electron microscopy showed that there was only an apparent decrease in GPC density after 2 treatments. This reduction was due to the massive degranulation of the enterochromaffin-like (ECL) cells and the resultant decrease in stainability with silver. After 14 and 29 days the granular depletion was less pronounced. The cells were, therefore, detectable again by light microscopy.
Cephaloridine-Induced Renal Pathological and Biochemical Changes in Female Rabbits and Isolated Proximal Tubules in Suspension
Authors: Rush Glenn F. , Heim R. Alan , Ponsler G. Douglas , Engelhardt Jeffery
Published: September 2009

Cephaloridine (Cld) is a nephrotoxic cephalosporin antibiotic. The intracellular biochemical changes that occur leading to Cld-induced nephrotoxicity may involve lipid peroxidation and/or mitochondrial injury. The purpose of this report was to examine and correlate the biochemical changes induced by Cld in vivo and in vitro with the observed pathological changes in an attempt to understand better the mechanisms of βT-lactam-induced nephrotoxicity. Cld treatment (500 mg/kg sc) caused elevations in blood urea nitrogen and decreases in the accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices. Histopathological alterations, characterized by individual cell necrosis of tubular epithelial cells, were first seen 6 hr after treatment in the pars recta of the outer stripe of the medulla. Ultrastructural alterations involved the straight (S2and S3) segments of the proximal tubules. Mitochondrial morphology was, for the most part, unaffected by Cld exposure. Cld did not cause any significant changes in tissue malondialdehyde (MDA) content in vivo at any of the time points examined, but it did cause a depletion of GSH to approximately 40% of control by 1 hr after dosing that recovered toward control by 6 hr. Significant changes were observed in renal ATP content beginning at 6 hr after treatment; however, this change mirrored the onset of histological evidence of necrosis. In isolated tubules in vitro, the onset of glutathione (GSH) depletion and MDA formation clearly preceded lactate dehydrogenase (LDH) leakage, whereas ATP depletion was a mirror image of cell death. These data demonstrate that isolated proximal tubules in vitro are a reasonable model for Cld nephrotoxicity in vivo. Cld-induced mitochondrial alterations leading to ATP depletion and cell injury were not observed in this study.
Ultrastructural Alterations in Liver of Medaka (Oryzias latipes) Exposed to Diethylnitrosamine
Authors: Braunbeck Thomas A. , Teh Swee J. , Lester Susan M. , Hinton David E.
Published: September 2009

Liver cytotoxic alterations of adult medaka ( Oryzias latipes) following short-term bath exposure (48 hr) to 500 mg/L diethylnitrosamine (DEN) were studied (days 3–21) by electron microscopy and cytochemistry. Control medaka displayed hepatic sexual dimorphism as described for other sexually active fish. Following DEN exposure, decreased glycogen stores with loss of cellular compartmentation obscured sexual dimorphism. A spectrum of organelle alterations, previously not reported in livers of fish, was seen. Early changes in hepatocytes included: nuclear lipid inclusions, nucleolar changes, decreased amounts of granular endoplasmic reticulum (GER), increased fractionation and steatosis of GER, proliferation of smooth ER and lysosomes, reduction in number and content of particulate lipoproteins and vitellogenin in Golgi vesicles, and reduction in number and staining intensity of perioxisomes. At day 14 and/or 21, partial to complete reversal of the above alterations indicated hepatic recovery, and fewer necrotic cells were seen at day 21 versus day 14. Lesions that did not resolve during this study were altered mitochondria and areas of spongiosis hepatis that developed at day 8 and continued to increase throughout the study. Infiltration of lymphocytes, granulocytes, and large numbers of macrophages were late changes. The description, timing, and duration of lesions are of value for consideration as biomarkers of exposure and effect in aquatic toxicology.
Low Susceptibility of Nude Mice to Induction of Invasive Urinary Bladder Cancers by N-Ethyl-N-(4-hydroxybutyl)nitrosamine
Authors: Tamano Seiko , Shirai Tomoyuki , Kawabe Mayumi , Ni-I Hiroaki , Mori Yukio , Okada Masashi , Fukushima Shoji
Published: September 2009

A time-and dose-dependent study of N-ethyl- N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in nude mice maintained on tap water containing 0.025% EHBN for 4, 12, and 20 weeks ad libitum. A total of 13 invasive tumors, comprising 11 transitional cell carcinomas (TCCs) (84.6%) and 2 squamous cell carcinomas (SCCs) (15.4%), were found. Compared with previous results for B6C3F1 mice exposed to the same EHBN insult, the numbers of invasive carcinomas induced in nude mice, and especially of SCCs, were low. In order to ascertain whether this difference in cancer incidence between nude and B6C3F1 mice was due to variation in urinary excretion, the metabolism of EHBN was also investigated and compared with that of N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN). Respective total urinary excretions over 48 hr of N-ethyl- N-(3-carboxypropyl)nitrosamine (ECPN) or N-butyl- N-(3-carboxypropyl)nitrosamine (BCPN), the ultimate carcinogenic species of EHBN or BBN, were 822.4 ± 41.4 μg and 530.4 ± 81.0 μ g, respectively, in nude mice, and 800.6 ± 83.7 μg and 407.8 ± 69.7 μg, respectively, in B6C3F1 mice. In conclusion, although it is apparent that nude mice have a low susceptibility to EHBN induction of urinary bladder cancer, this does not appear to be dependent on reduced metabolism to the active form.
Renal Lesions Induced by Ochratoxin A Exposure in the F344 Rat
Authors: Boorman Gary A. , Mcdonald Margarita R. , Imoto Seiichi , Persing Ronald
Published: September 2009

Groups of 80 male and female F344 rats were exposed by gavage to ochratoxin A, a naturally occurring mycotoxin, at levels of 21, 70, and 210 μg/kg body weight for up to 2 years. Ochratoxin A induced nonneoplastic renal tubular epithelial changes consisting of cytoplasmic alteration, karyomegaly, degeneration, and cysts. Exposure-related renal tubular proliferative lesions included focal hyperplasia, tubular cell adenoma, and tubular cell carcinoma. Renal tubular cell adenoma occurred as early as 9 months in 1 high-dose male rat, and both adenomas and carcinomas were seen in males by 15 months. At the terminal sacrifice, renal tubular cell tumors were found in both male and female rats, but the response was more pronounced in the males. The incidence of renal tumors in the high-dose rats was the highest of any National Toxicology Program (NTP) study completed to date. In the high-dose males approximately one-third of the renal carcinomas developed metastases. This study demonstrates that ochratoxin A is a potent renal carcinogen in the F344 rat and suggests that contamination of feedstuff by this mycotoxin may pose a potential hazard to domestic animals and man.
Morphologic and Biochemical Changes in Articular Cartilages of Immature Beagle Dogs Dosed with Difloxacin
Authors: Burkhardt John E. , Hill Michael A. , Carlton William W.
Published: September 2009

Quinolones are efficacious antibacterial compounds, but they have been associated with arthralgia in human patients; experimentally, they have caused lesions in articular cartilages of immature animals. The earliest morphologic and biochemical changes induced in articular-epiphyseal cartilage complexes by difloxacin, a fluoroquinolone, were investigated in 27 3-month-old Beagle dogs that were dosed orally with the drug at 300 mg/kg body weight per day. Paraffin-embedded sections of humeral and femoral heads that were stained with either hematoxylin and eosin or toluidine blue and fast green were evaluated histologically, and lesions were scored according to established criteria. Although morphologic changes were not observed in cartilages of the control dogs or of the treated dogs in the 24-hr group, the severity of lesions, as represented by mean scores for lesions, increased during the 36–48 hr after dosing. The initial morphologic change, observed in cartilages from the treated dogs of the 36-and the 48-hr groups, was necrosis of chondrocytes that was rapidly followed by disruption of extracellular matrix and formation of fissures. Although glycosaminoglycan was aggregated along the margins of fissures, its concentration was not reduced in cartilages of any group of treated dogs. Collagen, however, was depleted from the cartilages of the dogs that were euthanized 36 or 48 hr after the first dose of difloxacin. Because degenerative changes were observed ultrastructurally in chondrocytes by 24 hr in a previous study, it was concluded that collagen was lost from affected cartilages as an early sequel to the degeneration of chondrocytes.
The Pathology of Chronic Bovine Fluorosis: A Review
Authors: Shupe James L. , Bruner Richard H. , Seymour Jon L. , Alden Carl L.
Published: September 2009

Clinical, pathologic, and analytical records from 200 cattle were reviewed to determine if long-term exposures to elevated fluorides resulted in previously unrecognized or unreported pathologic changes, especially skeletal neoplasia. Animals were part of comprehensive field and laboratory investigations of bovine fluorosis conducted by the Utah State University Agricultural Experiment Station over a 25-year period. Records indicated that over 170 cattle included in this review were exposed to dietary fluorides levels in excess of 25 ppm (dry wt), for most of their life span, and these animals exhibited bone fluoride concentrations ranging between 2,000 and 12,500 ppm (dry wt). Although dental and/or skeletal changes were present in most animals, significant soft tissue damage or neoplasia was not observed in any organ system. Renal degeneration and mineralization were slightly more prevalent in range cattleingesting high fluoride levels, but these changes were not recognized in animals that received high experimental fluoride doses. The absence of significant soft tissue damage or neoplasia in these cattle combined with results of an extensive literature review suggests that environmental fluorides are not significant factors in mammalian carcinogenesis.
Hepatocellular Proliferation in Ibuprofen-Treated Mice
Authors: Bendele Alison M. , Hulman James F. , White Sandy , Brodhecker Cheryl , Bendele Raymond A.
Published: September 2009

Female B6C3F1 mice were treated with ibuprofen for 2 wk or 90 days to monitor effects on hepatocellular proliferation during acute and subchronic exposure. Proliferation was assessed by bromodeoxyuridine labeling. Mice treated with 100, 200, or 400 mg/kg ibuprofen for 2 wk had significantly increased liver weights. A dose-related increase in the number of labeled hepatocytes per 1,000 hepatocytes suggested that the weight increases were in part a result of hepatocellular proliferation. Hepatocellular hypertrophy also contributed to the increased liver size as indicated by decreases in the number of hepatocytes per high power field. Ultrastructural evaluation indicated that hepatocyte peroxisome size increased significantly in treated mice. Mice treated with 100 or 200 mg/kg ibuprofen for 90 days and given bromodeoxyuridine during the last 2 wk of ibuprofen exposure had statistically significant increases in relative liver weights. However, the number of labeled hepatocytes per 1,000 hepatocytes was not increased, and there was no evidence of hepatocellular hypertrophy. Mice given 200 mg/kg ibuprofen for 90 days had significantly decreased serum triglycerides. These findings indicate that ibuprofen treatment of mice results in hepatomegaly characterized by hepatocellular hypertrophy and hyperplasia. Peroxisomal changes may be contributory to the pathogenesis of this lesion.
Retinal Degeneration Induced by N-Methyl-N-Nitrosourea and Detection of 7-Methyldeoxyguanosine in the Rat Retina
Authors: Ogino Hiroshi , Ito Mitsuya , Matsumoto Kazuyuki , Yagyu Sigeru , Tsuda Hiroyuki , Hirono Iwao , Wild Christopher P. , Montesano Ruggero
Published: September 2009

Retinal degeneration induced by a single parenteral dose (40 mg) of N-methyl- N-nitrosourea (MNU) was studied in rats and rabbits. Sequential observations showed that severe pathological changes, that is, complete or widespread destruction of the photoreceptor layer and the outer nuclear layer of the retina, occurred in both animals by 72 hr after the administration of MNU. At week 5, at the end stage of the retinal degeneration induced by MNU, thin remnants remained with the inner nuclear layer in direct contact with the pigment epithelium. An additional immunohistochemistry study using antibodies against 7-methyldeoxyguanosine (7-mdGua), revealed the presence of high levels of 7-mdGua DNA adducts in the nuclei of the outer nuclear layer cells. This finding suggests that the alkylation of the outer nuclear layer by MNU was the direct cause of the retinal degeneration seen in these animals.
Angiofollicular Lymphoid Hyperplasia (Castleman's Disease) in Two Mice Treated with Polyoma Virus or Urethane
Authors: Williams A. Olufemi , Banks Peter M. , Liebelt Annabel G. , Stewart Harold L. , Saffiotti Umberto
Published: September 2009

Localized angiofollicular hyperplasia, otherwise known as Castleman's disease, is described in the lymph nodes of 2 mice of different strains, one inoculated with polyoma virus at birth and the other given urethane within 24 hr of birth. A plasma cell component in the lesion, suggestive of bone marrow stem cell involvement, was present in the mouse treated with polyoma virus but absent in the mouse given intraperitoneal urethane. Dysregulated interleukin 6 has recently been reported to produce the systemic variety of angiofollicular hyperplasia in mice, but the role of this cytokine in the localized variety described in this report is not known. This lesion appears to be rare in mice, but when present it could easily be missed or overlooked because the typical layering of follicle cells and the relatively large germinal centers seen in humans do not appear prominent in mice. Although there is, obviously, no proof of a causal relationship between the lesion and polyoma virus or urethane, it is suggested that this lesion be searched for in order to estimate its frequency and possible etiologic associations.
Clinical Pathologic Alterations Associated with Subcutaneous Administration of Recombinant Human Interleukin-4 to Cynomolgus Monkeys
Authors: Gossett Kent A. , Barbolt Thomas A. , Cornacoff Joel B. , Zelinger David J. , Dean Jack H.
Published: September 2009

Recombinant human interleukin 4 (rhuIL-4) is a candidate for the treatment of refractory cancer based on its potential to enhance immune function. Recombinant human IL-4 was administered subcutaneously at 0, 1, 5, or 25 μg/kg/day for 28 days with a 14-day recovery to male and female cynomolgus monkeys as part of the preclinical safety evaluation. Clinical pathologic changes related to treatment with rhuIL-4 were evidence of consumptive coagulopathy, erythrocyte fragmentation, lymphocytosis, and lymphocyte morphologic changes indicative of marked antigenic or mitogenic stimulation, mild eosinophilia and neutrophilia, hypoalbuminemia, hypocholesterolemia, and hypertriglyceridemia. Based on data obtained after the 14-day recovery period, the clinical pathologic changes associated with rhuIL-4 administration were considered to be reversible.
Spontaneous Histiocytic Sarcoma with Possible Origin from the Bone Marrow and Lymph Node in Donryu and F-344 Rats
Authors: Ogasawara Hiroyuki , Mitsumori Kunitoshi , Onodera Hiroshi , Imazawa Takayoshi , Shibutani Makoto , Takahashi Michihito , Ward Jerrold M. , Maekawa Akihiko
Published: September 2009

Ninety-five male and 96 female Donryu rats reared up to 120 wk of age and 244 male and 243 female F-344 rats used as untreated controls in 5 carcinogenicity studies were examined histopathologically to clarify the primary site of histiocytic sarcoma. Histiocytic sarcoma in Donryu rats was observed in 5 of 95 (5.3%) males and 4 of 96 (4.2%) females. In F-344 rats, 4 of 244 (1.6%) males and 3 of 243 (1.2%) females had the neoplasms. Histologically, sarcomas consisting of large pleomorphic histiocytic cells were seen in the bone marrow, liver, lymph node, spleen, and lung. Among 16 sarcomas observed, 15 had neoplastic lesions in the bone marrow, and 1 F-344 rat had the lesions only in the lymph nodes. Eleven (6 F-344 rats and 5 Donryu rats) of the 15 cases had the lesions in the liver, and 4 Donryu rats had no lesions in the liver but lesions in the lymph node and/or spleen, except for 1 case where the sarcoma occurred only in the bone marrow. Among the 11 cases with the lesions both in the liver and bone marrow, neoplastic lesions were found also in the lymph node, spleen, and/or lung, but the severity of neoplastic proliferation of these organs was not so marked as that in the bone marrow except for 2 cases. Although histiocytic sarcomas in rats are considered to originate from the liver, peritoneum, or subcutis, the present results strongly suggest that some histiocytic sarcomas in Donryu and F-344 rats may also originate from the bone marrow and lymph nodes.
The Phenotypic and Functional Changes of Rat Kupffer Cells Cultured with Interleukin-2
Authors: Inoue Satoshi , Yamashita Akira
Published: September 2009

We examined the direct effects of human recombinant interleukin 2 (hrIL-2) in vitro on the phenotypic and the functional changes of rat Kupffer cells (KCs) isolated by collagenase perfusion and differential centrifugation. When KCs were cultured with high concentrations of hrIL-2, marked changes were dose-dependently observed in phenotypic expression, phagocytic activity, and accessory cell function compared to untreated KCs. In the phenotypic changes, approximately 70% of KCs expressed class 2 antigen after 48-hr culture. Moreover, rapid expression of iC3b receptor on KCs was observed after 6 hr culture. KC phagocytic activity of both 0.81-and 2- μm latex particles was increased by incubating with hrIL-2 (104 U/ml) as compared to those of untreated KCs. Complement-mediated phagocytosis was more dominant than that of Fc receptor-mediated phagocytosis without hrIL-2 and augmented by increasing concentrations of hrIL-2. Accessory cell function of KCs was greatly augmented by preincubation with hrIL-2 (104 U/ml) for 24 hr. In the presence of 10−6 M of indomethacin or prostaglandin E2, accessory cell function was at a lower level than without. This suppressive effect of indomethacin or prostaglandin E2 was reduced at lower concentrations. These results suggest that the potential ability of hrIL-2-activated KCs is closely associated with the ongoing pathophysiological process in the liver during IL-2 immunotherapy.
Pituitary Carcinoma of Pars Distalis as a Common Neoplasm in Fischer-344 Rats
Authors: Hosokawa Satoru , Fukuta Taneo , Imai Toshio , Sonoda Jiro , Aoki Toyohiko , Hayakawa Kazuhiro , Motooka Satoru , Nakanowatari Junichi
Published: September 2009

The incidence of invasive spontaneous pituitary carcinomas in Fischer-344 rats were studied. The pituitaries were examined histopathologically together with surrounding tissues including sphenoid bone. The incidence of carcinoma was higher than that previously reported in Fischer-344 rats. All the carcinomas observed in this study showed evidence of local invasion either ventrally into bone and bone marrow or laterally into peripheral nerves and blood vessels. No dorsal infiltration into the brain was recognized. Pituitary carcinoma with local invasion is a relatively common neoplasm when examined histopathologically together with the surrounding tissues.
Testicular Degeneration and Spermatid Retention in Young Male Rats
Authors: Lee Ki-Poong , Frame Steven R. , Sykes Greg P. , Valentine Rudolph
Published: September 2009

The incidence of spontaneous testicular atrophy and its morphological changes in relation to stage-specific spermatogenesis were investigated in young Crl:CDr/BR male rats at 10–12 wk of age used as controls for toxicity screening during 1983–1990. The incidence of testicular degeneration was 2.5% (5/197) in control rats used for oral toxicity studies and 9.4% (31/327) in rats used for inhalation studies. The epididymal tubules of rats with testicular degeneration had exfoliated germ cells and low sperm density. The high incidence of testicular degeneration observed in the control rats used in inhalation studies may be related to the stress associated with immobilization in the restrainer during nose-only exposure conditions. The severity of testicular degeneration in the inhalation studies was mostly minimal. In these minimally affected testes, mature spermatids (step 19) were retained within normal-appearing germinal epithelium at spermatogenic stages IX-XIV. Also, eosinophilic globular bodies (EGBs) were formed with elongated or mature spermatids throughout all spermatogenic stages, but the general architecture of germinal epithelium was normal in appearance. By electron microscopy, EGBs were sequestered necrotic spermatids, and the germ cell degeneration was associated with cytoplasmic vacuolation of Sertoli cells. In moderate testicular degeneration, markedly decreased maturing spermatids (steps 15–19) and a slight depletion of round spermatids were observed in stages I-VIII. In severe testicular degeneration, seminiferous tubules were lined with 1–2 layers of round spermatids and spermatocytes with giant cell formation. The round spermatids served as a marker to identify spermatogenic stages (I-VIII) of the atrophic tubules. Also, in severe testicular degeneration, tubules in spermatogenic stages X-XIV had no elongated spermatids, and spermatocytes were exfoliated with occasional giant cell formation. Many seminiferous tubules were lined with only 1–2 layers of spermatocytes, and specific germ cell markers were not present.
Influence of Dietary Protein Concentration on Severity of Nephropathy in Fischer-344 (F-344/N) Rats
Authors: Rao Ghanta N. , Edmondson Jennifer , Elwell Michael R.
Published: September 2009

Nephropathy is an age-related spontaneous disease of most rat strains, and protein content of diet may affect the severity. The purpose of this study was to determine the effect of a 15% protein nonpurified diet on body weight and severity of nephropathy in comparison to a 23% protein NIH-07 diet. Groups of 25 male and 25 female Fischer-344 (F-344) rats, 6 wk of age, were fed the 23 or 15% protein diet ad libitum for 2 yr. Rats were weighed at 1–4-wk intervals, and mean body weights were determined. Water consumption measurements and urinalysis were done at approximately 3-mo intervals during the second year of the study. At the end of the 2-yr study, kidneys from all rats, including those that died or were euthanatized after the eightieth week of the study, were examined by light microscopy and graded for severity of nephropathy as grades 1–4 (minimal, mild, moderate, marked). Growth patterns and the maximum body weights attained by each sex fed the 23 or 15% protein diet were not significantly different. The severity of nephropathy in male rats was significantly higher when fed the 23% protein diet (2.8 moderate to marked) compared to the 15% protein diet (1.3 minimal to mild). The severity of nephropathy in female rats increased slightly when fed the 23% protein diet (1.5 minimal to mild) compared to the 15% protein diet (1.0 minimal). When the 23% protein diet group was compared to the 15% protein diet group, the 24-hr urine volume, proteinuria, and water consumption values were increased, especially during the last 3 mo of the study. Reduction of protein concentration in the diet from 23 to 15% decreased the protein consumption by30% and markedly decreased the severity of nephropathy, especially in male F-344 rats, without substantial changes in growth patterns and body weight gains.
Effect of Alternate-Day Hydrocortisone Therapy on the Immunologically Immature Rat. I: Effect on Blood Cell Count, Immunoglobulin Concentrations, and Body and Organ Weights
Authors: El Fouhil Ahmed F. I. , Turkall Rita M.
Published: September 2009

The effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19, was studied in the immunologically immature rat, a steroid-sensitive species. Animals, sacrificed 2 days following the completion of treatment, suffered from an underweight thymus and spleen, leucocytosis, and peripheral lymphocytopenia, probably not due to redistribution of lymphocytes from blood to tissues. In addition, a significant decrease in serum IgM concentration, reflecting a deficit in primary immune response, was evidenced. Although the percentage of lymphocytes returned to normal in rats sacrificed 23 days after treatment, an overweight thymus and spleen and persistent leucocytosis may reflect a compensatory overactivity of the developing immune system. In contrast, serum IgM concentration increased, but to a value less than normal. An indirect effect of hydrocortisone on lymphocytes through its action on thymus, as well as a direct effect on B cells, is suggested. Unlike humans, alternate-day steroid therapy delayed the normal growth pattern of rat, with a defective rate of growth only during the treatment period.
Survival, Body Weight, and Spontaneous Neoplasms in Ad Libitum- Fed and Food-Restricted Fischer-344 Rats
Authors: Thurman J. Dale , Bucci Thomas J. , Hart Ronald W. , Turturro Angelo
Published: September 2009

Ad libitum- fed (AL) and food-restricted (FR) Fischer-344 male and female rats were monitored for survival, body weight, and spontaneous neoplasms. Mean and maximal lifespans for each group were inversely related to mean body weights. AL males were the shortest lived (mean lifespan 101 wk) followed by AL females (118 wk), FR males (125 wk), and FR females (132 wk). Gross and microscopic examinations were performed on 851 rats from cross-sectional and longevity components of the study. In FR groups, the incidence of mammary gland fibroadenomas, testicular interstitial cell tumors, and pituitary neoplasms was decreased while the latency of these neoplasms was increased. In longevity components, most FR groups had a higher incidence of leukemia than AL cohorts, but all FR groups had a higher mean age at death for the rats with leukemia. Higher leukemia rate in the FR groups was thought to be a result of their extended mean lifespan.
Effects of a Six-Week Exposure to Excess Iodide on Thyroid Glands of Growing and Nongrowing Male Fischer-344 Rats
Authors: Kanno Jun , Nemoto Tetsuo , Kasuga Tsutomu , Hayashi Yuzo
Published: September 2009

A 6-wk exposure to excess iodide intake (EII) via drinking water (260 mg potassium iodide/L) demonstrated different effects on growing (4-wk old) and nongrowing (45-wk old) male Fischer-344 rats. In growing rats, EII induced a significant increase in thyroid weight, pituitary weight, serum thyroid-stimulating hormone (TSH), and thyroxine (T4). The labeling index (LI) of thyroid follicular cells was slightly increased, although not statistically significant. Histologically, an increase in follicular cell height, an increase in colloid accumulation, and evidence of colloid absorption were noted. The effect of bovine TSH (bTSH) and protirelin tartrate (TRH-t) on LI was significantly augmented by EII. In nongrowing rats, EII induced a significant increase in thyroid weight and serum T4 but no increase in pituitary weight, serum TSH, and the LI of follicular cells. Histologically, an increase in colloid accumulation was found in small follicles. EII did not augment the effect of bTSH and TRH-t on the LI of follicular cells. This study suggests that growing rats are still susceptible to acute hypothyroidism even after 6 wk of continuous exposure to excess iodide, whereas nongrowing rats are refractory within an equivalent treatment period.
Renal Toxicity of a Nondopaminergic Antipsychotic Agent, Trimethyl Imidazopyrazolopyrimidine, in Rats
Authors: Macallum Grace E. , Albassam Mudher A.
Published: September 2009

A nondopaminergic antipsychotic agent, 5-ethyl-1,3,8-trimethyl-1 H -imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine (TIPP; PD 112488), has been tested for potential toxicity in rats. As part of a preclinical safety evaluation, 10 Wistar rats per sex were administered TIPP as a dietary admixture, receiving doses of 0, 5, 10, 20, 25, 50, 100, and 200 mg/kg for 2 wk. In addition, 3 groups of 6 male Wistar rats were administered TIPP (PD 114877 and PD 117498, acid hydrolysis products of TIPP) at 100 mg/kg by gavage for 5 days. All animals given 200 mg/kg were euthanatized in moribund condition or found dead after 1 wk of treatment. Clinical evidence of renal toxicity was noted and included emaciation, hematuria, urinary incontinence, and enlarged kidneys at doses of 10 mg/kg and higher. Plasma urea levels were higher than those of controls in all TIPP-treated groups. Significant pathologic changes of the urothelium were evident at all doses and were characterized by necrotizing pyelitis and cystitis. Necrosis and inflammation of the urothelium resulted in secondary hydronephrosis. No renal toxicity was noted with the acid hydrolysis products. The urothelial changes with oral administration of TIPP in rats is species-specific, and the specificity may be related to the metabolism and excretion of the drug.
Age-Related Pancreatic Islet Changes in Sprague-Dawley Rats
Authors: Dillberger John E.
Published: September 2009

To characterize the clinical pathologic and morphologic features of spontaneous age-related changes in pancreatic islets observed in Crl:CDR(SD)BR rats, I reviewed data from rats used as controls in 10 toxicity studies from 1987 to 1992. Rats were 3.5–26 mo old at necropsy. At necropsy, rats were weighed, and serum, urine, and pancreas samples were collected. Serum was analyzed for glucose, triglyceride, and cholesterol concentrations; urine was analyzed for glucose and ketones; and samples of pancreas were stained with hematoxylin and eosin, Masson's trichrome stain, or for insulin by an immunoperoxidase method with a Masson's trichrome counterstain and examined microscopically. Male rats gained weight more rapidly than females and were visibly obese by 5 mo. Weight gain was accompanied by increased fasting triglyceride and cholesterol concentrations. Triglyceride increased more than cholesterol: from 3.5 to 17 mo of age, triglyceride concentrations increased 3.4-fold in males and 3.1-fold in females. By 14 mo of age, rats generally had fasting triglyceride concentrations >200 mg/dl (2.2 μM). Fasting glucose concentrations generally were slightly (<30%) greater in males than females. More males than females had glucose >200 mg/dl (11 mM); several males had glucose >300 mg/dl (16.5 mM). Glucosuria was not detected in any rat. Ketonuria was much more common in males than in females, but its incidence did not parallel that of obesity and hypertriglyceridemia; instead, ketonuria was most common in young males and decreased with age. Morphologic islet changes were observed in rats as young as 3.5 mo old, and their incidence increased with age. They were much more common in males than in females at all ages. Islet changes began as β-cell hyperplasia causing enlarged islets. With time, fibrosis gradually dissected islets into discreet nests of cells separated by bands of collagenous tissue so that they resembled cirrhotic liver. As the process continued, the ratio of fibrous tissue to islet cells increased until some islets were reduced to scattered β cells imbedded in a mass of scar tissue. By the time rats were 26 mo old, enlarged islets were rare; instead, remaining islets generally were small. Islet cell neoplasia did not occur in rats 17 mo of age or younger. In 26-mo-old rats, neoplasms were more common in males than in females (incidence of 20% vs 10%, respectively). The pathogenesis of these abnormalities is unclear, but they suggest that male Sprague-Dawley rats fed ad libitum are a less than ideal system in which to conduct long-term toxicity/safety assessment studies or any other research studies that could be influenced by altered metabolism. These results also reveal that male and female Sprague-Dawley rats differ metabolically and that the differences may predispose males to islet cell neoplasms.
Evaluation of 4′-Iodo-4′-Deoxydoxorubicin-Induced Cardiotoxicity in Two Experimental Rat Models
Authors: Podestà Arturo , Torre Paola Della , Pinciroli Giovanni , Iatropoulos Michael J. , Brughera Marco , Mazué Guy
Published: September 2009

In the present study, 1 single-dose and 1 multiple-dose models were applied in studying 4′-iodo-4′-deoxydoxorubicin (I-DX) cardiotoxicity. Anthracycline cardiotoxicity has been reproduced in several animals including mice, rats, hamsters, rabbits, dogs, and monkeys. Of these species, the rat can be considered the most suitable species for the study of anthracycline-induced cardiomyopathy. The cardiotoxicity induced by I-DX in male Sprague-Dawley rats was compared to that of doxorubicin (DX), used as standard positive control. Groups of 36–42 rats were given single or repeated doses of the compounds, injected intravenously in a volume of 5.0 ml/kg. Animals were observed for up to 35 wk to follow the progression of the lesions. Cardiomyopathy was evaluated through well-established qualitative/quantitative morphological grading. The new DX derivative proved to be clearly less cardiotoxic than DX with both treatment schedules. Although both models can be considered useful for evaluating and comparing the cardiotoxicity of new anthracycline derivatives and mimicking the transvenous endomyocardial biopsies in humans, the chronic test seems to be more suitable for compounds like I-DX, which possess a low cardiotoxic potential and which could go undetected in the single-dose test.
Enhancement of Acute Myocardial Lesions by Asthma Drugs in Rats
Authors: Whitehurst Virgil E. , Joseph Xavier , Alleva Frederic R. , Vick James A. , Whittaker Paul , Zhang Jun , Fry Bert E. , Balazs Tibor
Published: September 2009

Asthma morbidity and mortality have risen significantly in the last 10 years. The reasons for the increase are multifactorial. One proposed explanation is possible myocardial toxicity arising from the use of β-agonists alone or in combination with methylxanthines. Previous studies have shown that β-agonists given alone and β-agonist/methylxanthine combinations given at higher than recommended clinical doses induced dose-related cardiotoxicity and sudden death in rats. The objective of the present study was to determine whether or not β-agonists given alone and in combination with methylxanthines at recommended clinical doses also induce cardiotoxicity and sudden death in rats. The β-agonists, isoproterenol hydrochloride (15 μg/kg), fenoterol hydrobromide (40 μg/kg), and terbutaline hemisulfate (0.4 mg/kg) were given in single sc doses separately and concurrently with the methylxanthines aminophylline hydrate (20 mg/kg) and caffeine (40 mg/kg), which were given ip to a susceptible animal model, the heavy Sprague-Dawley rat. β-agonist-induced myocardial toxicity (necrosis) was observed. The toxicity was enhanced by aminophylline resulting in the sudden death (most likely due to ventricular fibrillation) of some animals. A decrease in serum iron levels was observed in rats of all β-agonist and/or methylxanthine-treated groups.
Safety Assessment Programs for U.S. Regulatory Agencies: A Perspective of Requirements and Compliance
Authors: Bendele Raymond A.
Published: September 2009

Regulatory agencies and components within agencies in the United States have been established at different times but with the same basic charge: to protect the health and welfare of the citizenry by regulating the manufacture and use of chemicals and devices that might constitute a threat to the environment or a health hazard for individuals, groups of individuals, or the population as a whole. The character of each agency differs because of the political climate in which it has evolved, the personalities of the leadership, and the internal philosophies concerning how the agency's charge under the letter of the law should be accomplished in keeping with the congressional intent for establishment of the agency. The current safety assessment program requirements/guidelines and some aspects of their interpretation and application are discussed for the Environmental Protection Agency and for components of the Food and Drug Administration, including the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, and the Center for Veterinary Medicine.
Rodent Carcinogenicity Bioassay: Past, Present, and Future
Authors: Boorman Gary A. , Maronpot Robert R. , Eustis Scot L.
Published: September 2009

Toxicity/carcinogenicity studies in rodents have played a pivotal role in identifying chemicals that are potentially hazardous to humans. In fact, nearly all of the known human carcinogens are also carcinogenic in 1 or more rodent species. During the past 20 yr the quality and consistency of rodent studies has improved considerably, and much has been learned about mechanisms whereby chemicals initiate or promote the carcinogenic process in rats and mice. The process of identifying chemicals that cause toxicity or carcinogenicity in rodents is quite well established, but the procedures for extrapolating this data for risk management decisions in the protection of human health have lagged far behind. While many would accept the assumptions that genotoxic chemicals that cause cancer in animals pose a cancer risk to humans and that genotoxic chemicals causing cancer at high doses pose a risk at lower doses, there is much less certainty with respect to nongenotoxic chemicals. The confusion about risk extrapolation for nongenotoxic chemicals has often lead to criticism of the hazard identification process for chemicals in general. There is increasing awareness of the complexity of the carcinogenic process that has made species extrapolation and dose extrapolation from rodent studies to humans more complex. Although newer molecular biological techniques and cell kinetic measurements offer exciting possibilities for better risk assessment, it is the combination of well- designed rodent studies with appropriate mechanistic studies that offers the best hope for regulatory decisions based on sound scientific principles.
Integrating Safety Data: The Expert Report
Authors: Dayan Anthony D.
Published: September 2009

Complete evaluation of the toxicity of a new chemical entity requires critical analysis of the pattern of positive and negative findings in all types of toxicity tests, pharmacokinetics and metabolism in the species examined, and correlation of the effects with information about its pharmacodynamic and pharmacological properties. The goal is to obtain sufficient understanding of the mechanisms underlying the therapeutic and toxic effects of the compound to permit a well-supported extrapolation from the test to the target species. The Expert Report system in the European Community is based on comprehensive 25-page reviews of information about a compound arranged under 3 headings: Chemistry and Pharmacy, Pharmacology and Toxicology, and Clinical Studies. Each section requires a searching review of the experimental work and the relevant literature, integration of the findings, and then careful correlation among these 3 main areas of knowledge to indicate the circumstances of safe and effective use of the drug.
Pleural Lesions in Syrian Golden Hamsters and Fischer-344 Rats Following Intrapleural Instillation of Man-made Ceramic or Glass Fibers
Authors: Everitt Jeffrey I. , Bermudez Edilberto , Mangum James B. , Wong Brian , Moss Owen R. , Janszen Derek , Alphons A. A. , Rutten J. J. L.
Published: September 2009

The mesothelium is a target of the toxic and carcinogenic effects of certain natural mineral and man-made fibers. Long-term inhalation of a ceramic fiber (RCF-1) results in a high incidence of pleural mesotheliomas in Syrian golden hamsters but not in identically exposed Fischer-344 rats. The present study compared the histopathology of the early pleural response in rats and hamsters instilled with artificial fibers. Groups of Syrian golden hamsters and Fischer-344 rats were instilled with ceramic (RCF-1) or glass (MMVF-10) fibers directly into the pleural space. Each species received approximately equal numbers of long, thin fibers per g body weight. Fiber-induced lesions were compared 7 and 28 days postinstillation. Both hamsters and rats developed qualitatively similar dose-dependent inflammatory lesions that were not fiber-type specific. Both species developed fibrosis in conjunction with inflammation in the visceral pleura, but a striking interspecies difference was noted in the pattern of mesothelial cell response. Hamsters developed greater surface mesothelial cell proliferation and had focal aggregates of mesothelial cells embedded deep within regions of visceral pleural fibrosis. It is hypothesized from the present study that the marked fiber-induced proliferative mesothelial cell response of the hamster visceral pleura may explain the high number of pleural mesotheliomas found in long-term fiber studies in this species.
Sequential Observation of Spontaneous Endometrial Adenocarcinoma Development in Donryu Rats
Authors: Nagaoka Takaharu , Takeuchi Masaki , Onodera Hiroshi , Matsushima Yuko , Ando-Lu Jin , Maekawa Akihiko
Published: September 2009

Sequential observation of spontaneous endometrial adenocarcinoma development revealed a clear, hormone-dependent, histogenetic pathway in Donryu rats. The first histological changes of the uterine endometrium appeared in both the lining epithelium and uterine gland of the endometrium at 6 mo of age, along with the beginning of persistent estrus. These changes included areas of tall columnar epithelium and gland formation in the lining epithelium as well as metaplastic change in the uterine gland. At 8 mo of age, endometrial hyperplasias were found, with subsequent increase in both incidence and degree. At 8–10 mo of age, hyperplasias were all within the limit of grade ++. After 12 mo of age, however, severe hyperplasias (grade + + +) began to increase markedly, and adenocarcinomas developed at 15 mo of age. The findings thus suggest that uterine endometrial adenocarcinomas arise from hyperplastic lesions, which should therefore be regarded as preneoplastic, as in the human case. Sequential analysis of plasma gonad steroids also ascertained a link between the appearance of these lesions and an increased estrogen: progesterone ratio, suggesting that estrogen may play an important role in development of both hyperplastic and neoplastic lesions. In Fischer-344 rats used for comparative assessment of strain differences, neither advanced histological changes nor hormonal changes were evident.
Metal Accumulation and Nephron Heterogeneity in Mercuric Chloride-Induced Acute Renal Failure
Authors: Wilks Martin F. , Gregg Neill J. , Bach Peter H.
Published: September 2009

The present study was designed to assess the effects of mercury on glomerular integrity during the early phase of acute renal failure. The silver amplification method showed distribution of mercury in midcortical and juxtamedullary glomeruli and on the brush border of the S2 segment of the proximal tubule 15 min after treatment. At 30 min, there was a decrease in glomerular staining and increased mercury in the proximal tubule. After 3 hr, mercury was no longer detectable in glomeruli but was widespread in the lumen of the proximal tubule. By 24 hr, mercury was prominent in all proximal tubular segments throughout the cortex. The presence of mercury in glomeruli was not related to hemodynamic changes, as there was no evidence for blood redistribution toward juxtamedullary glomeruli as assessed by the filling of the microvascular system with Monastral Blue B. The reduced activity of horseradish peroxidase (administered iv 90 sec and 10 min before sacrifice) in juxtamedullary glomeruli 30 min after mercury administration suggests a decreased uptake of horseradish peroxidase or an increased glomerular protein filtration. These data support glomerular filtration as the predominant excretory route for mercury, highlight the marked nephron heterogeneity in the distribution of this metal, and show that impairment of glomerular integrity occurs before necrosis of the proximal tubules and acute renal failure.
The Rat as a Model to Evaluate the Gastric Irritation Potential of Alkaline Products
Authors: Sauers Leonard J. , Maurer James K. , Reer Paul J.
Published: September 2009

Animal models historically used to assess the acute gastric irritation potential of accidental ingestion of consumer products include the dog, pig, rabbit, and cat. In looking at alternative methods that are of shorter duration and more cost-effective, the rat is being evaluated as a potential model. Acute gastric irritation is known to increase as the reserve alkalinity of the formulation increases. In initial experiments to assess the rat as a potential model, animals were dosed via oral gavage with 1 of 4 formulations ranging in reserve alkalinity from 4.0 to 10.8. Necropsies were performed at 15 and 60 min after dosing. Macroscopic and microscopic evaluations of the stomach revealed morphological differences in the various treatment groups that distinguish granular formulations having either a low (R.A. = 4.0), moderate (R.A. = 7.1), or higher (R.A. = 10.8) reserve alkalinity. Additionally, it was observed that the acute gastric changes in rats dosed with a liquid formulation having a low (R.A. = 4.2) reserve alkalinity were similar to those in rats dosed with a granular formulation having a moderate reserve alkalinity (R.A. = 7.1). This suggests that other factors such as types of ingredients, pH, and physical form influence the extent of acute gastric irritation and demonstrates that an evaluation of only reserve alkalinity is not sufficient to ensure the safety of these products. This preliminary work supports the rat as a potential model to assess the acute gastric irritation potential of alkaline formulations or substances.