bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary Histopathology of Rats Following Parenteral Injections of Nickel Chloride
Authors: Knight Joseph A. , Rezuke William N. , Gillies Concettina G. , Hopfer Sidney M. , Sunderman F. William
Published: September 2009

To elucidate the subacute toxic reactions to parenteral administration of Ni2+, male F-344 rats were given daily injections of NiCl2 (62.5 or 125 μmol/kg, sc) for 3 to 6 weeks. Nickel accumulation was greater in lung than in the other major organs, based upon tissue analyses by electrothermal atomic absorption spectrometry. After 5 or 6 weeks of NiCl2 treatment, severe pathological changes developed in the lungs, including a) prominent hydropic and degenerative changes of the endothelium of pulmonary arteries and veins; b) marked proliferation of alveolar lining cells, affecting Type II (granular) pneumocytes; c) thickening of alveolar walls, with proteinaceous alveolar exudate; d) hyperplasia of bronchial epithelium, with cellular atypia and mitoses; and e) focal bronchial pneumonia with intrabronchial exudates. These pulmonary responses to repeated daily injections of NiCl2 were substantially different from the pathological lesions seen 24 to 72 hours after a single sc injection of NiCl2 (500 or 750 μmol/kg), which included perivascular edema, karyorrhexis and pyknosis of mononuclear cells in focal perivascular infiltrates, and mild pulmonary congestion. This study shows that the lung is a primary site of toxicity in rats following parenteral administration of NiCl2; vascular endothelial cells, Type II pneumocytes, bronchial epithelial cells, and mononuclear cells constitute the principal cellular targets for pulmonary toxicity of Ni2+.
Variable Hepatocellular Vacuolization Associated with Glycogen in Rabbits
Authors: Wells Monique Y. , Weisbrode Steven E. , Maurer James K. , Capen Charles C. , Bruce Robert D.
Published: September 2009

Marked variation in hepatocellular vacuolization was present in New Zealand white rabbits used as controls in 28-day and 91-day percutaneous studies conducted at 5 different laboratories. Vacuoles in hepatocytes of alcohol-fixed and formalin-fixed livers contained periodic acid-Schiff (PAS)-positive material which was removed with diastase digestion, indicating the presence of glycogen. The magnitude of hepatocyte vacuolization was subjectively assessed by light microscopy using 5 histologic grades. Quantitative measurements of hepatocyte perimeter and lobule radius for representative liver sections of each histologic grade corroborated the different grades used. Factors associated significantly with the degree of vacuolization were sex (females were affected more severely than males), body weight, relative liver weight, and the laboratory conducting the study. Also apparent were variations in mean severity of hepatocyte vacuolization between studies conducted at the same laboratory, and variation in severity of vacuolization within individual studies. Duration of the study and season had no significant association with the degree of vacuolization. Marked variation of hepatocellular vacuolization due to glycogen accumulation must be recognized when evaluating results of toxicity testing in rabbits.
Morphologic Classification and Incidence of Hematopoietic Neoplasms in the Sprague-Dawley Rat
Authors: Frith Charles H.
Published: September 2009

Hematopoietic and related neoplasms were morphologically studied in a total of 1,765 male and 1,765 female Sprague-Dawley rats from 6 chronic toxicity studies conducted at a large toxicology testing laboratory. The most common types of lymphoid neoplasms seen included the lymphoblastic lymphoma (0.65%) and the large granular lymphocyte lymphoma (LGL, Fischer or mononuclear cell leukemia) (0.60%). The most common type of nonlymphoid neoplasm with morphologic features similar to lymphoid tumors was histiocytic sarcoma (1.1%). A small number of cases of myelogenous leukemia were also seen. Additional work is needed in the classification of hematopoietic neoplasms in rats including refined immunomorphological studies.
Pituitary Gland: Neuropeptides, Neurotransmitters and Growth Factors
Authors: Koenig James I.
Published: September 2009

The hypothalamus receives neuronal afferents from numerous sources including inputs from limbic structures, such as the amygdala and hippocampus, and from brainstem regions involved in the regulation of the cardiovascular system and other autonomic functions. These afferents using a vast array of neurotransmitters and neuropeptides influence the activity of the hypothalamic neurons which synthesize and secrete the hypothalamic releasing and release-inhibiting factors into the hypophyseal portal circulatory system. The afferents can modulate the activity of the hypothalamic neurons by forming synapses on the neuronal cell body, on the nerve terminals in the median eminence or both. The chemicals most frequently used as neurotransmitters are the biogenic amines, including the catecholamines (norepinephrine, dopamine and epinephrine), serotonin, acetylcholine and gamma-aminobutyric acid (GABA). The stimulatory influence of norepinephrine, serotonin, and acetylcholine on the secretion of corticotropin (ACTH) in rodents and man will be discussed, whereas GABA exerts an inhibitory effect on the secretion of ACTH in both man and rodents. These effects appear to be mediated by changes in the secretion of the corticotropin-releasing hormone (CRH) and vasopressin into the hypophyseal portal circulation. Numerous neuropeptides appear to alter the secretion of ACTH in the rat. We will discuss the stimulatory actions of neuropeptide Y (NPY), angiotensin II, and peptides of immune cell origin on the secretion of ACTH and CRH. The opioid peptides inhibit the secretion of CRH into the portal blood, however, they exert a potent stimulatory effect on prolactin secretion in the rat and man. We will discuss the receptor subtypes involved in mediating these effects and the interactions of the opioid peptides with the neurotransmitter-containing neurons which project to the hypothalamus. This discussion will focus on the factors which impinge on the releasing factor-containing neurons in the hypothalamus and how they can be studied under in vivo and in vitro conditions.
The Mechanisms of Action of Reproductive Toxicants
Authors: Mattison Donald R. , Thomford Peter J.
Published: September 2009

Successful human reproduction is a complex process which requires normal function of 2 individuals. Reproductive toxicants can impair reproduction by acting in the male, female or both. Reproductive toxicants can produce their adverse effects by several direct and indirect mechanisms. The mechanisms by which reproductive toxicants impair reproduction are reviewed.
Guidelines and Requirements for the Evaluation of Contraceptive Steroids
Authors: McKenzie Basil E.
Published: September 2009

Since their introduction in the early 1960s, the oral contraceptive (OCs) steroids have been subjected to preclinical and clinical investigations unprecedented in medical history. As a result of such extensive studies, it is now possible to make a comprehensive review of preclinical and clinical data on oral contraceptives. The OCs were introduced at a time when the Food and Drug Administration (FDA) was undergoing drastic changes as a result of the thalidomide tragedy, the introduction of the Kefauver-Harris Amendment, and, the desire for greater control over the pharmaceutical industry. The initial requirements for the safety evaluation of OCs were identical to those of other drugs. There were no explicit requirements for OCs although it was generally felt that the requirements should be more stringent because the OCs were being used in otherwise healthy women for long periods of time and with minimal medical supervision. In the 1960s when it became apparent from ongoing studies that there was an increased incidence of mammary tumors in dogs treated with some progestins, the FDA made the decision to terminate clinical studies and established the requirement for 7- and 10-yr studies in dogs and monkeys, respectively. The primary purpose of this paper is to present an historical perspective of the evolution of the preclinical requirements for the evaluation of the safety of OCs prior to their use in the various phases (I, II, III) of clinical trials. Some proposed changes in the requirements are discussed. This information will form the basis for other presentations dealing with the safety assessment of OCs in rats, dogs, and monkeys.
Comparative Aspects of Contraceptive Steroids: Effects Observed In Rats
Authors: McConnell Robert F.
Published: September 2009

Current regulatory guidelines for testing contraceptive drugs in long-term rodent studies have established dosages based on multiples of the proposed human usage level. These multiples in rodents are 1–2, 10, and 50. The estrogen/progestogen ratio for most human contraceptive drugs ranges from 1/5 to 1/80. One of the biological endpoints in arriving at the human estrogen/progestogen ratio is the development of an endometrial decidualization response. The ratio necessary to achieve a similar uterine response in the rat is 1:10,000 to 1:20,000. Thus, dosages in the rodent, when based only on a multiple of the proposed human usage level, result in a highly estrogenic combination with estrogen being completely dominant. Continuously elevated estrogen in the rat is toxic to dopaminergic neurons in the hypothalamus which secrete prolactin inhibiting factor (PIF). Hyperplasia of pituitary lactotrophs occurs from both the direct stimulatory effect of estrogen and the uninhibited secretory activity of lactotrophs related to depressed PIF secretions. Prolactinomas result. Increased levels of prolactin lead to mammary gland stimulation and tumor development. Dosage levels for future rodent studies of contraceptive drugs should be based on pharmacokinetics, endocrine profiles, and biological endpoints rather than on multiples of the human usage level.
Comparative Aspects of Contraceptive Steroids—Effects Observed in Beagle Dogs
Authors: Johnson A. Neill
Published: September 2009

The effects of oral contraceptives have been studied in the beagle bitch for periods up to 7 yr. High doses of these potent estrogen: progestogen (E:P) combinations have been shown to promote tumors in the mammary glands, smooth muscle of the tubular genitalia, and occasionally in the transitional epithelium of the neck/trigone area of the urinary bladder. The contraceptive formulations used in humans are balanced with an E:P ratio of about 1:5 to 1:80 to produce a desired decidual response in the uterus. The corresponding ratio for producing the decidual reaction in the dog is 1:1,000 to 1:3,000 with the result that the dog is grossly overdosed with estrogens when given the human formulation at the usual multiples of up to 25 times the human dose. Smooth muscle tumors of the tubular reproductive tract are common sequelae to estrogen overstimulation in the dog and are known to occur in other species, including the human. The dog also has major differences in hormonal control and sensitivity when compared to humans. Progestogens stimulate synthesis and release of growth hormone (GH) in dogs which in turn is the major stimulant (with progestogens) of mammary growth and tumors. Evidence is accumulating which indicates that most if not all progestogens can produce mammary tumors in the dog if given by the correct route and at high enough dosage. In contrast, GH in humans is not increased nor does it have any significant mammotrophic role. Mammary tumors in dogs related to oral contraceptives are now widely considered to be irrelevant as a model or predictor for human tumors. Transitional cell tumors in the urinary bladder seem to be a species specific phenomenon seen on occasion in the dog, but not in the rat, monkey, or human. The usual location in the neck/trigone area may be related to the embryologic origin of this portion of the bladder, which derives from tissues more closely related to the genital organs than does the rest of the bladder.
Oral Contraceptives: Significance of their Effects in Man and Relationship to Findings in Animal Models
Authors: Pasquale Samuel A.
Published: September 2009

Combination oral contraceptives have been available since 1960. They contain both an estrogen and a progestogen and have been studied extensively in both lower animals and humans and have been the subject of special regulatory requirements for toxicological and clinical studies. The initial oral contraceptives, by today's standards, contained very high levels of both hormones. There has been a continuous decrease in the dose of both the estrogen and the progestogen during the past quarter century, with continued maintenance of high degree of effectiveness. This decrease of dosage has been stimulated by findings from prospective clinical trials and retrospective case control trials. As additional information has been gained with oral contraceptives, new benefits beyond their effectiveness as contraceptives have been realized. Today's oral contraceptives provide a high degree of effectiveness, low incidence of nuisance side effects, and low incidence of major adverse effects.
Tumor Promoting Effect of Goitrogens on the Rat Thyroid
Authors: Kanno Jun , Matsuoka Chiaki , Furuta Kyoko , Onodera Hiroshi , miyajima Hiroaki , Maekawa Akihiko , Hayashi Yuzo
Published: September 2009

To evaluate the mechanism of the promoting effect of goitrogens on thyroid tumorigenesis, well-known goitrogens having different pharmacologic action, i.e., thiourea, phenobarbital sodium (PB), potassium thi-ocyanate (KSCN), and 3,4,5,6-tctrachloro-2',4',5',7'-tetraiodo-fluorescein sodium salt (Rose Bengal B, FD&C Red No. 105) (FR105) were administered to the DHPN-initiated and non-initiated F344 male rats in the drinking water for 25 weeks. Remington's iodine deficient diet (I-dcf) was fed as a positive control. These goitrogens showed significant tumor promoting effect or promoting tendency on the rat thyroids. According to the changes in thyroid morphology and thyroid-related hormone tilers observed in the present study, we proposed to classify goitrogens at least into 2 groups, i.e., iodine deficiency-type promoters and the iodine excess-type promoters. The former contains goitrogens inducing TSH-stimulated diffuse goiter composed of uniform follicles with activated tall follicular epithelial cells, such as thiourea, KSCN and PB, and the latter contains goitrogens inducing colloid goiter composed of a mixture of colloid-rich follicles with flat follicular cells and normal-looking follicles with cuboidal follicular cells, such as FR105. This classification may be useful for the risk assessment of goitrogens.
Acute Parenteral Neurotoxicity of Domoic Acid in Cynomolgus Monkeys (M. fascicularis)
Authors: Tryphonas Leander , Truelove John , Iverson Frank
Published: September 2009

To study the CNS effects of domoic acid (D.A.), 6 adult Cynomolgus monkeys (M. fascicularis) were dosed intraperitoneally (4 mg/kg) or intravenously (0.025-0.5 mg/kg) with D.A. obtained from cultured mussels contaminated with this neurotoxin. Clinical signs of neurotoxicity were preceded by a short presymptomatic period (2-3 min) and an even shorter prodromal period (0.5-1 min). The symptomatic period proper was characterized by persistent chewing with frothing, varying degrees of gagging, and vomit. Monkeys in the higher dose regimen exhibited additional signs including abnormal head and body positions, rigidity of movements and loss of balance, and tremors. The duration of the symptomatic period was dose dependent. Excitotoxic lesions consisting of vacuolation of the neuropil, astrocytic swelling, and neuronal shrinkage and hyperchromasia were detected in the area postrema, the hypothalamus, the hippocampus, and the inner layers of the retina in monkeys given D.A. at 0.5 mg/kg intravenously and 4 mg/kg intraperitoneally. It was concluded that D.A., administered intravenously, is neuroexcitatory and a powerful emetic at doses of 0.025 to 0.2 mg/kg. At higher doses (0.5 mg/kg intravenously and 4 mg/kg intraperitoneally), D.A. is strongly excitotoxic.
Passive Role of Articular Chondrocytes in Quinolone-Induced Arthropathy in Guinea Pigs
Authors: Bendele Alison M. , Hulman James F. , Harvey Anita K. , Hrubey Pamela S. , Chandrasekhar Srinivasan
Published: September 2009

The role of articular chondrocytes and matrix degrading enzymes such as collagenase and neutral protease in the pathogenesis of quinolone-induced cartilage degeneration was investigated in immature guinea pigs. Articular cartilage from nalidixic acid (NA) treated guinea pigs was examined for the presence of protease activity or the ex vivo synthesis of collagenase at various times post-treatment. Histologic evaluation of knee joints confirmed the presence of degenerative changes in the matrix, but increased collagenase synthesis or protease activity were not detected. A separate group of animals was used to determine the importance of articular chondrocytes in the lesion generation. These cells were killed by intra-articular injection of the glycolysis inhibitor iodoacetic acid (IA) prior to treatment of the animals with NA. Typical “blister-like” lesions developed in cartilage devoid of viable chondrocytes at the time of exposure to NA indicating that their presence was not required for lesion development. Cartilage exposed to IA only did not exhibit “blister-like” lesions indicating that chondrocyte death and proteoglycan loss in conjunction with frictional forces associated with load-bearing were not sufficient to induce major matrical disruptive changes during the period of this study. These results indicate that articular chondrocytes are not actively involved in inducing the degenerative changes and provide no evidence for involvement of collagenase or neutral protease in the pathogenesis of the lesion.
Hepatopathology of Diethylnitrosamine in the Medaka (Oryzias latipes) Following Short-Term Exposure
Authors: Bunton Tracie E.
Published: September 2009

The effect of short-term exposure (48 hr) of 14-day-old medaka (Oryzias latipes) to diethylnitrosamine (DEN) was tested on 4 groups of fish at 0, 100, 200, and 400 mg/L, with interim sacrifices of up to 6 months post exposure. Many of the lesions seen were similar to those seen in other fish DEN carcinogenicity studies using longer term, adult exposures, including a cytotoxic phase with cystic degeneration of the hepatic parenchyma, cellular vacuolation, globular acidophilic cytoplasmic inclusions, spongiosis hepatis, foci of cellular alteration, adenomas, and cholangiomas. There were also several proliferative lesions of uncertain origin which occurred throughout the study. There appeared to be a direct relationship between exposure level and the incidence and severity of the lesions seen, including aggressiveness and invasiveness of the neoplasms seen. However, there was a possible difference from other studies in the types of neoplasms seen with this protocol, which may be related to age at exposure, exposure level, duration of exposure, or a combination of these factors. Similarities in lesions seen in this study and in rodent and other fish studies is an indication of promise for the use of this model in carcinogenicity testing. Differences indicate the variety of ways the fish liver can respond to toxic injury, and lend flexibility to the model.
Intercellular Communication in Bronchial Epithelial Cells: Review of Evidence for a Possible Role in Lung Carcinogenesis
Authors: Albright Craig D. , Jones Raymond T. , Grimley Philip M. , Resau James H.
Published: September 2009

A challenging aspect of lung carcinogenesis is the elucidation of the mechanisms which permit initiated bronchial epithelial cells to attain a growth advantage over normal bronchial epithelial cells, and subsequently evolve into a malignant phenotype. In this review, the effects of interactions between normal and transformed cells, and the potential role of representative extrinsic factors on cell-cell communication are discussed. Evidence is presented to show how cell injury and the effects of serum and calcium may affect morphology and communication, and tumor development. A large number of autocrine-paracrine factors (e.g., TGFβ, TGFα) are released by bronchial epithelial cells. These factors may inhibit or promote the proliferation of normal and transformed bronchial epithelial cells, respectively. The ability of certain injurious and tumor promoting agents (e.g., formaldehyde, TPA) to select for the transformed phenotype may involve selective cell injury, the induction of terminal differentiation and an inhibition of gap junction communication among normal BE cells.
Tissue Reaction to an Implantable Identification Device in Mice
Authors: Rao Ghanta N. , Edmondson Jennifer
Published: September 2009

Long-term toxicity and carcinogenicity studies require positive identification of animals. Due to the unreliability of traditional methods, it was necessary to investigate more dependable identification methods that can be read directly or by electronic means. A two-year study to determine the stability of and tissue reaction to a microchip glass-sealed device implanted in subcutaneous tissue of mice was conducted. Seventy B6C3F1 mice of each sex were anesthetized and implanted with the microchip. The devices were read by an electronic detector and palpated at periodic intervals. Ten mice of each sex were necropsied at 3 months and at 15 months with the remaining animals necropsied at 24 months. Of the 140 devices implanted, 3 were lost and 4 failed during the 24-month study. Devices were palpable and appeared to be fixed at one location with no obvious swelling due to inflammation or palpable masses around the implants for 24 months. At the 3, 15, and 24 month necropsies, implants were encapsulated by connective tissue. Light microscopic evaluation indicated that the capsule around the implants was thin and composed of fibrocytes and mature collagen fibers, with minimal to mild inflammation and occasional granulomatous reaction. Neoplastic changes were not observed in the tissue around the glass-sealed devices with polypropylene cap for up to 24 months.
Spontaneous Malignant Mixed Müllerian Tumors and Rhabdomyosarcoma of the Uterus in Rats
Authors: Kaspareit-Rittinghausen Joachim , Deerberg Friederich
Published: September 2009

Five malignant mixed müllerian tumors and one rhabdomyosarcoma were observed in LEWIS rats. Heterologous miillerian neoplasms (cases 1-4) consisted of epithelial and mesenchymal elements including squamous epithelium, glandular epithelium and sarcomatous, rhabdomyosarcomatous, cartilaginous as well as osseous parts. All the heterologous tumors revealed undifferentiated areas with an anaplastic appearance. The homologous miillerian tumor (case 5) was composed of glandular epithelium embedded in sarcomatous tissue. The rhabdomyosarcoma (case 6) consisted of bundles of elongated strap-like cells mixed with cells resembling rhabdomyoblasts.
Acute Cardiovascular Toxicity Induced by an Adenosine Agonist-Antihypertensive in Beagles
Authors: Metz Alan L. , Dominick Mark A. , Suchanek Gwen , Gough Alec W.
Published: September 2009

An adenosine agonist, designated chemically as (R)-N-(2,3-dihydro-1H-inden-1-yl) adenosine, or CI-947, was administered to 3 male and 3 female beagles in oral doses of 5 mg/kg body weight. Multiple episodes of arrhythmia were recorded electrocardiographically with Holter monitors in 2 males and 2 females monitored up to 48 hr. One male and 1 female were necropsied at 24 hr and the remaining dogs were necropsied at 48 hr post-dosing. At 48 hr, multifocal perivascular epicardial and myocardial hemorrhage was noted grossly in 1 female. Microscopic coronary arterial alterations were present in all treated dogs irrespective of the occurrence of arrhythmias. At 24 hr, proteinic material and red cells were present in the media accompanied by minimal adventitial accumulation of neutrophils. At 48 hr, coronary arterial lesions progressed to media vacuolation, transmural necrosis, and perivascular accumulation of neutrophils. Ultrastructural alterations included: endothelial retraction, subendothelial accumulation of fibrin and platelets, necrosis of smooth muscle cells, and mural infiltration of granulocytes and monocytes. Coronary vascular injury may be due to altered hemodynamics associated with the coronary vasodilator properties of adenosine agonist compounds.
Endrin-Induced Histopathological Changes and Lipid Peroxidation in Livers and Kidneys of Rats, Mice, Guinea Pigs and Hamsters
Authors: Hassan Mohammad Q. , Numan Intisar T. , Al-Nasiri Nazar , Stohs Sidney J.
Published: September 2009

Endrin toxicity may be due to an oxidative stress associated with increased lipid peroxidation, decreased glutathione content, and inhibition of glutathione peroxidase activity. Extensive interspecies variability exists in sensitivity towards endrin. Therefore, histopathological changes and lipid peroxidation in the livers and kidneys of rats, mice, hamsters, and guinea pigs were examined 24 hr after the administration of 4 mg endrin/kg body weight orally in corn oil. Degeneration and necrotic changes with inflammatory cell infiltration were observed in livers and kidneys, and interspecies variability occurred. Fatty changes in the form of hepatic foam cells with cytoplasmic vacuolation were present. Lipofuscin pigments, associated with lipid peroxidation, were observed in hepatocytes and Kupffer cells. These histopathological conditions were prevented in rats which had been pretreated with butylated hydroxyanisole, vitamins E and C, or cysteine, antioxidants and free radical scavengers which have previously been shown to inhibit lipid peroxidation. The extent of endrin-induced lipid peroxidation correlated well with the degree of histopathological changes. Thus, histological changes consistent with the induction of an oxidative stress were observed following the administration of endrin to various animal species.
Spontaneously Occurring Leiomyosarcomas of the Mouse Urinary Bladder
Authors: Chandra Manik , Frith Charles H.
Published: September 2009

Spontaneous leiomyosarcomas of the mouse urinary bladder have not been reported. Data from 8 chronic toxicity/oncogenicity studies that included 400 male and 400 female mice were reviewed and evaluated to gather information on spontaneously occurring urinary bladder leiomyosarcomas. Three control mice from 3 different studies had leiomyosarcomas in the submucosa of the trigone area of the urinary bladder. These tumors were not connected to the surface epithelium; however, they were connected to and destroyed the smooth muscle layer of the urinary bladder. This communication describes the incidence and histopatho-logical features of these neoplasms.
Morphologic and Immunohistochemical Characterization of Leydig Cell Tumor Variants in Wistar Rats
Authors: Qureshi Shafqat R. , Perentes Elias , Ettlin Robert A. , Kolopp Maryelle , Prentice David E. , Frankfurter Anthony
Published: September 2009

During a routine long-term drug safety study, lasting approximately 2½ yr, male Wistar rats, treated with a prolactin-inhibiting compound, developed an excess of Leydig cell tumors (LCTs). Most tumors were typical for the rat but a small number showed an unusual variation and some appeared malignant. The variation consisted of glandular and/or tubular structures within the tumor mass which occasionally anastomosed and contained an eosinophilic periodic-acid Schiff (PAS) positive material. In a few of these variants, malignant features such as cellular atypia, capsular, and lymphatic invasion and necrosis were seen. No metastases were detected. Detailed morphological and immunohistochemical investigations were conducted in order to establish the cell of origin of these variants. Glandular/tubular structures were found to stain with varying intensity for vimentin and cytokeratin, but were always negative for β-tubulin. The results indicated that the cell of origin of these LCT variants was indeed the Leydig cell and that glandular and/or tubular structures within LCTs represented a form of Leydig cell metaplasia.
Pulmonary Neoplasms in Rats That Inhaled Cerium-144 Dioxide
Authors: Hahn Fletcher F. , Lundgren David L.
Published: September 2009

The lung neoplasms induced in rats by inhaled, internally deposited 144CeO2 were described and classified using histologic criteria. F344 rats were exposed once or repeatedly by inhalation to 144CeO2 and observed for their life span. There was significant life shortening only in those rats with the highest radiation doses. In these rats, there was a high percentage of squamous cell carcinomas of the lung, as well as much lower percentages of adenocarcinomas of the lung, hemangiosarcomas of the lung, and pleural mesotheliomas. At lower doses, adenocarcinomas were the most predominant tumor. These adenocarcinomas were subdivided based on their histologic pattern: alveolar, papillary, tubular, or undifferentiated. Neither the mode of exposure (single or repeated) nor the sex of the rat influenced the lung tumor incidence or tumor type. The lung neoplasms induced by this beta-emitting radionuclide are similar in nature to those induced by alpha-emitting radionuclides deposited in the lung in rats. However, the radiation-induced squamous cell carcinomas of the lung differ from those induced by heavy particle loads of nonradioactive compounds. The radiation-induced squamous cell carcinomas occur in higher incidence and have a more malignant behavior than those induced by heavy particle loads.
Dose-Dependent Renal Tubular Toxicity of Harman and Norharman in Male F344 Rats
Authors: Hagiwara Akihiro , Asakawa Emiko , Kurata Yasushi , Sano Masashi , Hirose Masao , Ito Nobuyuki
Published: September 2009

The renal toxicity of harman and norharman, administered for 2 or 4 weeks at dietary levels of 1,000, 500, or 0 parts per million (ppm), was investigated in 6-week-old male F344/DuCrj rats. Although rats fed 1,000 ppm harman or norharman, but not the 500 ppm level, demonstrated marked body weight retardation from 1 week to termination, no mortalities occurred. Marked elevation of water consumption was evident in rats given harman or norharman at 1,000 ppm, but not at 500 ppm, together with large increases in urine of low specific gravity. Urinary lysosomal enzymes ( N-acetyl-βT-D-glucosaminidase, NAG, and lactate dehydrogenase, LDH) and sugar levels were increased, and the brush border enzymes (γ-glutamyl transpeptidase, GGT, and alkaline phosphatase, ALP) decreased. Furthermore, serum biochemistry revealed clear elevation of parameters indicating renal toxicity in these rats. Histopathologically, rats fed 1,000 ppm harman or norharman, but not 500 ppm, demonstrated focal toxic renal degenerative/necrotic and regenerative lesions in proximal, distal, and collecting tubules. These changes were associated with a clearly increased labeling index (LI) of the nuclei of renal tubular epithelial cells on immunohistochemical staining for 5-bromo-2′-deoxyuridine (BrdU). Chemical specific crystal formation within tubular lumina was evident in rats fed 1,000 ppm, but not 500 ppm, this being considered the cause of the renal tubular lesions. It was concluded that harman and norharman exert renal toxicity at the dietary level of 1,000 ppm, but not 500 ppm, in male F344 rats.
Neoplasms and Related Proliferative Lesions in Control Sprague-Dawley Rats from Carcinogenicity Studies. Historical Data and Diagnostic Considerations
Authors: Mcmartin Donald N. , Sahota Pritam S. , Gunson Diane E. , Hsu Helen Han , Spaet Robert H.
Published: September 2009

Historical data are presented for neoplasms and related proliferative lesions from 1,170 Sprague-Dawley rats that served as controls in 9 carcinogenicity (2 year) studies conducted in the Safety Evaluation Facility of Ciba-Geigy Corporation, Summit, New Jersey. The most common neoplasm was pituitary adenoma, which occurred in 62.2% of the male and 84.7% of the female rats. Incidences of other neoplasms that occurred in more than 6.0% of the rats were, for males, benign pheochromocytoma (19.0%), cutaneous keratoacanthoma (7.9%), pancreatic islet cell adenoma (7.5%), benign testicular interstitial cell tumor (6.5%), and thyroid C-cell adenoma (6.5%). For females these incidences were mammary fibroadenoma (31.3%), mammary adenocarcinoma (16.8%), and mammary adenoma (6.5%). Focal cortical hypertrophy/cystic degeneration of the adrenal, a focal nonneoplastic lesion of zona fasiculata cells that often degenerate into large cysts, was present in 23.4% of all male and 82.7% of all female rats. Criteria for the differential diagnoses of selected neoplasms and related lesions are presented.
Tumor-Promoting Effects of Both Iodine Deficiency and Iodine Excess in the Rat Thyroid
Authors: Kanno Jun , Onodera Hiroshi , Furuta Kyoko , Maekawa Akihiko , Kasuga Tsutomu , Hayashi Yuzo
Published: September 2009

Thyroid tumor-promoting effects of iodine deficiency and iodine excess were investigated in a rodent 2-stage model to estimate an optimal iodine intake range that would not effectively promote development of thyroid neoplasia. Six-week-old male F344 rats were given a single subcutaneous injection of 2,800 mg/kg body weight N-bis(2-hydroxypropyl)-nitrosamine (DHPN) or saline vehicle, maintained on Remington's iodine-deficient diet (21 ± 2 ng/g iodide), and supplemented with various amounts of potassium iodide up to 260 mg/liter in drinking water to generate conditions ranging from severe iodine deficiency to severe iodine excess. In DHPN-treated rats, both conditions significantly increased thyroid follicular tumorigenesis. In DHPN-untreated rats, iodine deficiency produced diffuse thyroid hyperplasia, characterized by small follicles with tall epithelium and reduced colloid, together with a decrease in thyroxine (T4) and an increase in thyroid-stimulating hormone (TSH). On the other hand, iodine excess produced colloid goiter, characterized by large follicles with flat epithelium and abundant colloid admixed with normal or small-sized follicles lined by cpithelium of normal height, together with normal serum T4 and slightly decreased TSH. These effects were directly proportional to the severity of iodine deficiency or extent of iodine excess and suggest that each condition has a different thyroid tumor promotion mechanism. Iodine intakes that showed the least tumor promotion were 2.6 and 9.7 μg/rat/day in this study. Promoting mechanisms and the problem of statistically estimating recommended daily iodine intake range are briefly discussed.
Histiocytic Sarcoma in an Aging Gerbil
Authors: Chen Hsien C. , Slone Theodore W. , Frith Charles H.
Published: September 2009

A histiocytic sarcoma in an aging female gerbil is described. The neoplasm primarily involved the spleen and liver, and these organs were considered the primary sites of neoplastic origin. No neoplastic infiltration was noted in the uterus or ovaries as is commonly seen in the female mouse. This is the first report of histiocytic sarcoma in gerbils.
Osteochondroma in Laboratory Rats: A Report of 3 Cases in a Fischer-344, a Sprague-Dawley, and a Wistar Rat
Authors: Ernst Heinrich , Sander Erich , Karbe Eberhard , Nolte Thomas , Mohr Ulrich
Published: September 2009

Three cases of osteochondroma in a male Sprague-Dawley (SD) rat, a female Fischer (F344) rat, and a male Wistar rat are described. The rats were aged between 26 and 30 months. All osteochondromas were considered to be of spontaneous origin. The Wistar rat had multiple osteochondromas on both hind legs, the skull base, and a lumbar vertebra, whereas each of the F344 and SD rats was affected by a solitary osteochondroma, also on a lumbar vertebra. The lumbar osteochondromas were similar in appearance in all rats and consisted of a central core of trabecular bone, interspersed with fatty marrow and covered by a cap of hyaline cartilage. The additional tumors in the Wistar rat represented different developmental stages of osteochondroma with or without endochondral activity. The osteochondromas in the rats were morphologically similar to those described in humans and some domestic animal species.
Mesenteric Lymph Node Hemangiomas of Wistar Rats
Authors: Reindel James F. , Dominick Mark A. , Gough Alex W.
Published: September 2009

Vascular tumors in rodent mesenteric lymph nodes are uncommon. Fifty-seven of these neoplasms were identified in control and treated Wistar rats from 6 tumor bioassays. Tumor incidence ranged from 0.75% to 5.50% and was higher in males than females (2:1). Lesions, noted as incidental necropsy findings or in routine histologic sections, were typically solitary and restricted to nodal and perinodal tissue. Additional solitary vascular tumors were identified in skin of 3 rats and pararenal lymph node of I rat. Distinct metastases were not evident. When apparent grossly, affected nodes were red to purple, hemorrhagic, and/or enlarged. Histologically, all tumors were composed of variably sized, endothelial-cell-lined, blood-filled spaces separated by variable amounts of poorly cellular stroma. Nodal effacement was common in larger tumors. Approximately half of the tumors had features of typical cavernous hemangiomas. The remaining tumors had slightly more aggressive features consisting of single or multiple foci of lymph node capsule invasion, presence of tumor cells in muscular blood vessels, or cellular atypia with variable mitotic activity. Death due to tumor rupture and consequent hemoperitoneum occurred in 1 rat only.
Environmental Tobacco Smoke: Current Assessment and Future Directions
Authors: Smith Carr J. , Sears Stephen B. , Walker James C. , Deluca Patricia O.
Published: September 2009

Scientific information on environmental tobacco smoke (ETS) is critically reviewed. Key areas addressed are: differences in chemical composition between mainstream smoke, sidestream smoke, and ETS; techniques for measurement of ETS; epidemiology; in vitro and in vivo toxicology; and chamber and field studies of perceptual or physiological effects. Questions concerning estimation of ETS exposure, suitability of various biomarkers, calculation of lifetime dose, control of confounding variables, use of meta-analysis, and the relationship between ETS concentrations and human responses all emphasize the need for additional research in order to assess potential effects of ETS on health or comfort.
Development of an Animal Model for Testing Human Breast Implantation Materials
Authors: Devor Deborah E. , Waalkes Michael P. , Goering Peter , Rehm Sabine
Published: September 2009

Although breast implant materials have been tested in laboratory species since the early 1950s, a standardized evaluation system does not currently exist in which human-made polymers are exposed directly to the mammary milieu of female animals. The present study evaluated such a model as the basis for future experiments on long-term tissue effects. Polyesterurethane disks, 6 mm in diameter × 3 mm thick, were inserted bilaterally beneath the axillobrachial and inguinal mammary/fat pads of 50 9-wk-old female B6D2F1 mice (4 implants each). Implant sites were examined histologically at time points 24 hr to 47 wk after surgery. An acute inflammatory reaction at the implant edges began within 24 hr, and macrophages were found lining the smooth polyurethane fiber surfaces at the periphery by day 2. Multinucleated foreign body giant cells formed by day 4, and by week 4 giant cells contained polyurethane fragments within the cytoplasm, implying degradation of the material. Implant sites showed declining subacute inflammatory responses and increasing fibrosis by week 5. By 13 wk, the polyurethane disks appeared to be integrated into the growing adipose and mammary tissues. Although not apparent on gross inspection, microscopic examination showed that polyurethane fibers moved progressively into adjacent tissues and were always associated with chronic granulomatous inflammation. Histologic findings in the present study are strikingly similar to the human response to polyurethane-coated breast implants. These results suggest the applicability of this model to appropriately test mammaplasty materials in mammary tissues.
Ocular Changes Induced in the Beagle Dog by Intravenous Infusion of a Novel Dopaminergic Compound, FPL 65447
Authors: Kerry Philip J. , Wakefield Ian D. , Evans John G.
Published: September 2009

FPL 65447, a selective D1receptor agonist with a potential for the acute treatment of renal and cardiac failure and of sepsis and septic shock, was administered to beagle dogs by continuous intravenous infusion for a maximum of 14 days. Ophthalmoscopical examination revealed dose-related changes in the eye and associated structures, consisting of foci of retinal discolouration, corneal changes including oedema, keratitis, opacities and neovascularisation, and inflammation of the iris, periorbital tissues, and adnexa. Microscopical examination confirmed the presence of inflammatory lesions in the eye. These were predominantly histiocytic and were mainly focal circumscribed lesions. More diffuse inflammation with a granulocytic and lymphocytic component was also encountered in the limbus and uveal tract. A predominantly interstitial histiocytic adenitis involving various glandular structures associated with the eye and adnexa was also identified. Possible mechanisms to account for the histiocytic changes are discussed.
Iron-Induced Myocardial and Hepatic Lysosomal Abnormalities in the Guinea Pig
Authors: Adams E. Terence , Schwartz Kenneth A.
Published: September 2009

The guinea pig model of iron overload, described in the preceding article, was used to investigate the mechanism of excess iron toxicity in hepatic and cardiac tissues. Effects of iron overload on both lysosomal membrane fragility and membrane peroxidation were studied. The free activity of selected myocardial and hepatic lysosomal enzymes, in addition to serum activity, was measured in guinea pigs treated with iron dextran (0.25, 0.5, 1.0, and 2.0 g Fe/kg body weight); controls received dextran. Levels of malondialdehyde were also determined in whole homogenates of heart and liver in animals loaded with 0.5 and 1.5 g Fe/kg of iron dextran. Results indicated that the free activity of hepatic glucosaminidase (p < 0.05) and β-glucuronidase ( p < 0.05) were significantly elevated at all levels of iron loading; hepatic acid phosphatase was increased at all but the lowest iron dose. Similarly, increased serum glucosaminidase activity was observed ( p < 0.01) at all dose levels. When compared to pooled controls, the free activity of myocardial glucosaminidase was also elevated ( p < 0.05) at all levels of loading. However, myocardial acid phosphatase was increased only at the highest iron dose ( p < 0.01). Increased malondialdehyde was measured at the high iron dose (1.5 g Fe/kg) in whole homogenates of both heart and liver ( p < 0.01). We conclude that iron loading in this model profoundly alters the stability of hepatic and myocardial lysosomal membranes; furthermore, changes in serum glucosaminidase activity may be reflective of modified tissue lysosomal properties. Elevated levels of malondialdehyde in whole homogenates suggest that iron-mediated lipid peroxidation may be responsible in part for enhanced lysosomal membrane fragility.
Multinucleated Hepatocytes Induced by Rifabutin in Rats
Authors: Scampini Giovanna , Nava Alberto , Newman Arthur John , Torre Paola Delia , Mazuéa Guy
Published: September 2009

Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose- and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery (12 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors.

MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.
Effect of Alternate-Day Hydrocortisone Therapy on the Immunologically Immature Rat. II: Changes in T- and B-Cell Areas in Spleen
Authors: El Fouhil Ahmed F. I. , Iskander Fakhry A. , Turkall Rita M.
Published: September 2009

The histologic effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19 after birth, was studied on the spleen of the immunologically immature rat. Two days after the cessation of treatment, the periarteriolar lymphatic sheaths were found to be largely depleted of small lymphocytes. Immunoperoxidase studies confirmed a depletion of T lymphocytes. The effects of hydrocortisone on the thymus seem to be more important than its direct lymphocytolytic effect in producing this splenic lesion. In contrast, no apparent change in the number of medium-sized B lymphocytes in the marginal zone was detected. Medium-sized B lymphocytes of the spleen, reported to be responsible for IgM synthesis, appeared to be subjected to a different mechanism of hydrocortisone action, other than lysis, resulting in a decrease in antibody production. Primary follicles were not seen in spleens of hydrocortisone-treated rats. Twenty-three days after treatment, spleens had a histologically normal appearance.
Intratubular Spermatic Seminoma in a Fischer-344 Rat
Authors: Nyska Abraham , Harmelin Alon , Sandbank Judith , Scolnik Marissa , Waner Trevor
Published: September 2009

A case of a spontaneous intratubular spermatic seminoma is described in a 98-wk-old Fischer-344 (F-344) rat. The differential diagnosis of spermatic seminoma from the other morphological forms of the tumor was based on the recognition of 3 cell types. The tumor cells were positive for S-100 antigen and cytokeratin. To the best of our knowledge, this is the second case of a seminoma reported in an F-344 rat and the first dealing with electron microscopic and immunohistochemical features of this tumor.