bluuebunny/crossref_metadata_2025 huggingface dataset:
Omeprazole: Its Influence on Gastric Acid Secretion, Gastrin and ECL Cells
Authors: Larsson Håkan , Håkanson Rolf , Mattsson Hillevi , Ryberg Birgitta , Sundler Frank , Carlsson Enar
Published: September 2009

The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H2-receptor antagonists. In life-long oncogenicity studies of these H2-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the “Gastrin Hypothesis” to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H2-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible. Control plasma gastrin levels were reached within a few days of stopping long-term treatment, and the ECL-cell density was back to normal 20 weeks after discontinuing 10 weeks of treatment with high-dose omeprazole. We conclude from these studies that the ECL-cell hyperplasia seen in rats after long-term treatment with gastric acid secretion inhibitors is reversible and secondary to the hypergastrinemia, and is not caused by the drugs per se. Furthermore, although the gastrin mechanism for the regulation of the ECL cells seems to be similar in different species, there are quantitative differences with regard to the ECL-cell density and possibly also the sensitivity of ECL cells to gastrin.
Gastric ECL-Cell Hyperplasia and Carcinoids in Rodents Following Chronic Administration of H2-Antagonists SK&F 93479 and Oxmetidine and Omeprazole
Authors: Betton Graham R. , Dormer Charles S. , Wells Terry , Pert Pauline , Price Carolyn A. , Buckley Peter
Published: September 2009

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.
Mortality, Major Cause of Moribundity, and Spontaneous Tumors in CD-1 Mice
Authors: Maita Keizo , Hirano Masahiro , Harada Takanori , Mitsumori Kunitoshi , Yoshida Akiyoshi , Takahashi Kimimasa , Nakashima Nobuaki , Kitazawa Toshiaki , Enomoto Akiko , Inui Kosei , Shirasu Yasuhiko
Published: September 2009

Mortality, major causes of moribundity, and spontaneous tumors in CD-1 mice were studied in 891 males and 890 females, which were used as controls in 11 different 2-year chronic and oncogenicity studies during the past 5 years. Average mortality of males and females at 83 weeks of age was 32.6% and 28.6%, respectively, and at 109 weeks of age was 66.4% and 63.3%, respectively. Mortality was significantly lowered in males and females born after 1980 in accordance with an abruptly decreased occurrence of systemic amyloidosis in these animals. The major cause of death or moribundity included systemic arteritis, systemic amyloidosis, auricular thrombosis, glomerulosclerosis, lymphoma, and pulmonary adenocarcinoma in both sexes. Dysuria and hepatocellular carcinoma in males and mammary adenocarcinoma in females were also critical lesions. The major tumors occurring at more than 3% incidence were systemic lymphoma, adenoma/adenocarcinoma of the lung, adenoma/carcinoma of the liver and adenoma/adenocarcinoma of the Harderian gland for males, and systemic lymphoma, adenoma/adenocarcinoma of the lung, adenoma/carcinoma of the liver, leiomyoma/leiomyosarcoma of the uterus, adenoma/adenocarcinoma of the pituitary (anterior), adenoma/adenocarcinoma of the mammary gland and adenoma/adenocarcinoma of the Harderian gland for females. Intra-laboratory heterogeneities in the incidence were recorded as follows: systemic lymphoma in 1 of 11 control groups (1/11) and adenoma/adenocarcinoma in 1/11 for males, and systemic lymphoma in 3/11, adenoma/adenocarcinoma of the lung in 2/11, adenoma/adenocarcinoma of the liver in 1/11, and adenoma/adenocarcinoma in 1/11 for females.
Dose-Response Relationship of Diethylnitrosamine-Initiated Tumors in Neonatal Balb/c Mice: Effect of Phenobarbital Promotion
Authors: Klaunig James E. , Pereira Michael A. , Ruch Randall J. , Weghorst Christopher M.
Published: September 2009

The dose-response of diethylnitrosamine (DENA) initiation of hepatocarcinogenesis was determined in infant Balb/c male mice with and without subsequent phenobarbital treatment. Male Balb/c mice received a single intraperitoneal injection of DENA (0, 2.5, 10.0, 25.0 or 50.0 μg/gbw) in saline on day 15 of age. Ninety mice were treated at each dose level. At weaning, mice received either deionized drinking water (45 mice per group) or deionized drinking water containing 500 mg/L sodium phenobarbital (PB) (45 mice per group). Mice from each group were sacrificed 12, 24, and 40 weeks post-weaning. Liver and lung tumors were found in DENA-only-treated and DENA + PB-treated mice. In DENA-only-treated mice, the incidence and number of hepatic adenomas were similar (not dose-dependent) at DENA doses of 10, 25, and 50 μg/gbw at each of the 3 sampling times. DENA-only-treated mice did display a time-related increase in hepatic adenoma incidence and number at each dose. In PB-treated mice, the hepatic adenoma number was dependent upon the dose of DENA between 2.5 and 50 μg/gbw. PB treatment following DENA administration resulted in a decrease in the time required for the detection of hepatic adenomas and increased the number of hepatic adenomas at most sampling times compared to the mice that received DENA only. Hepatocellular carcinomas (HPC) were detected in mice receiving the highest DENA doses (25 and 50 μg/gbw). PB treatment increased the number and incidence of HPC and decreased the time of first detection of HPC. The incidence and number of lung adenomas per mouse induced in DENA-treated mice was linearly proportional to the DENA dose. PB had no influence on the incidence or number of DENA-induced lung adenomas.
The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells
Authors: Capen Charles C. , Martin Sharron L.
Published: September 2009

The mammalian thyroid gland is composed of 2 distinct endocrine cell populations concerned with the synthesis of 2 different classes of hormones. Follicular cells secrete the metabolically active iodothyronines whereas the C- (parafollicular) cells are concerned with the production of calcitonin, a hormone that influences blood levels of calcium and phosphorus, and bone cell metabolism. The synthesis of metabolic thyroid hormones is different than in other endocrine glands because the final assembly of hormone occurs within the follicular lumen. This extracellular synthesis of thyroid hormones is made possible by thyroglobulin, a glycoprotein synthesized by follicular cells. The secretion of thyroid hormones under the influence of pituitary thyrotrophin (TSH) from stores in the luminal colloid is initiated by elongation of microvilli and formation of pseudopods. FD&C Red No. 3 is a tetraiodinated derivative of fluorescein which in lifetime studies increases the incidence of thyroid follicular cell adenomas in male Sprague-Dawley rats. The striking changes in circulating levels of thyroid hormones and morphologic evidence of follicular cell stimulation are the result of alterations in the peripheral metabolism of thyroxine. An inhibition by FD&C Red No. 3 of 5′-deiodinase in the liver and kidney would explain the lower serum triiodothyronine (T3) levels. The pituitary, sensing the lowered circulating levels of T3, increased the secretion of thyroid stimulating hormone which resulted in the morphologic evidence of follicular cell stimulation in the long-term studies. Other xenobiotics increase the incidence of thyroid tumors in rodents by a direct effect on the thyroid gland to disrupt 1 of 3 or more possible steps in the biosynthesis of thyroid hormones. Physiologic perturbations alone, such as iodine deficiency or partial thyroidectomy, can disrupt thyroid hormone economy in rodents and, if sustained, increase the development of thyroid tumors. The wide variety of drugs, chemicals, and physiologic perturbations which increase thyroid tumor development appear to act through a secondary (indirect) mechanism to promote tumor development by causing a long-standing hypersecretion of thyroid stimulating hormone. Nodular and/or diffuse hyperplasia of C-cells occurs with advancing age in many strains of laboratory rats and in response to long-term hypercalcemia in certain animal species and human beings. Focal or diffuse hyperplasia of ten precedes the development of C-cell neoplasms. Radiation and the feeding of diets high in vitamin D resulting in hypercalcemia have been reported to increase the incidence of C-cell tumors in rats.
The Rat Adrenal Medulla
Authors: Tischler Arthur S.
Published: September 2009

Adult adrenal medullary cells, in many strains of rats, develop diffuse and nodular hyperplasia and neoplasia under a variety of conditions. Both endogenous and exogenous factors affect the development of these proliferative changes. The former include the animals's train, age, and sex. The latter include drugs and other environmental agents, diet, and perhaps stress. Adrenal medullary neoplasms which arise under diverse circumstances of ten closely resemble each other both morphologically and functionally, and exhibit characteristics of immature chromaffin cells. Recent data indicate that normal, mature-appearing epinephrine-and norepinephrine-type chromaffin cells are able to divide, and suggest that signals which regulate chromaffin cell function also regulate cell proliferation. Prolongation of these signals or superimposed abnormalities might initiate pathological proliferative states. It remains to be determined whether the mechanisms which promote or prevent cell proliferation in the adult adrenal are related to those involved in normal development.
Recent Advances in the Structure and Function of the Parathyroid Gland in Animals and the Effects of Xenobiotics
Authors: Capen Charles C. , Rosol Thomas J.
Published: September 2009

Parathyroid glands in animals consist of a single basic type of secretory cell concerned with the elaboration of one hormone. Parathyroid hormone is the principal hormone involved in the minute-to-minute fine regulation of blood calcium in mammals. A larger biosynthetic precursor of parathyroid hormone is first synthesized on ribosomes of the endoplasmic reticulum in chief cells. Pre-proparathyroid hormone is rapidly converted to proparathyroid hormone in the Golgi apparatus. Active parathyroid hormone is packaged into membrane-limited secretory granules that are stored in the cytoplasm until secretion is stimulated. Parathyroid cells in most animals store relatively small amounts of preformed hormone but are capable of responding to minor fluctuations in calcium ion concentration by rapidly altering the rate of hormonal synthesis and secretion. Recently synthesized and processed active parathyroid hormone may be released directly in response to increased demand and bypass the storage pool of mature secretory granules. Relatively few chemicals or experimental manipulations significantly increase the incidence of parathyroid tumors. Irradiation increases the development of parathyroid adenomas in rats and the incidence is modified by feeding diets with variable amounts of vitamin D. Parathyroid adenomas have been encountered infrequently following the administration of a variety of chemicals in 2-year bioassay studies in Fischer rats; however, the incidence increases dramatically when comparing 2-year studies to lifetime data.
The Role of Chemicals in the Etiology of Diabetes Mellitus
Authors: Wilson Glenn L. , LeDoux Susan P.
Published: September 2009

Diabetes mellitus is a collection of diseases that culminate in defects in carbohydrate metabolism and result in inappropriate hyperglycemia. Most individuals with this disease can be categorized into 1 of 2 groups, depending upon their insulin requirements. Individuals who require insulin therapy to maintain life have been designated as having insulin-dependent diabetes mellitus (IDDM), while individuals who can live without insulin treatment have been classified as having noninsulin-dependent diabetes mellitus (NIDDM). The single most important pathological finding in IDDM is a substantial reduction in the number of insulin-secreting pancreatic beta cells. Compelling experimental and epidemiological evidence indicates that, at least in some forms of IDDM, environmental factors, such as chemical toxins, play an important role in the etiology of this disease. Chemical toxins can precipitate IDDM through a variety of mechanisms. They can poison beta cells directly and cause the destruction of a critical mass of beta cells; alternatively, they can trigger autoimmune processes directed against beta cells; or, finally, they can augment the diabetogenic properties of another agent, such as a virus, to hasten the onset of clinical manifestations. In NIDDM, impaired beta cell function appears to be the initial event observed at the onset of this syndrome. Functional defects similar to those seen in NIDDM can be produced in laboratory animals using a specific beta cell toxin. These animals develop permanent glucose intolerance and insulin resistance as a consequence of beta cell alteration. A variety of other chemicals also have been found to produce glucose intolerance; however, this condition is transient and is resolved when the chemical is removed. This review will focus on a discussion of chemicals that are known to cause IDDM, NIDDM or transient glucose intolerance and their putative mechanisms of action. Additionally, new methods for identifying and evaluating potential toxins will be considered.
Comparative Aspects of Contraceptive Steroids: Effects Observed in the Monkey
Authors: Valerio Marion G.
Published: September 2009

The use of the non-human primate in long-term studies of contraceptive steroids has been questioned because of time, expense and apparent lack of results predictive for humans. Controversies have arisen primarily over the occurrence of mammary nodules in studies of different contraceptive steroids and the occurrence of uterine tumors in 2 high-dose group monkeys in the Depo-Provera study. The long-term studies have been criticized because of the experimental design and the small number of monkeys per dose group. Individual studies by themselves did not reveal lesions other than those expected from an exaggerated pharmacologic response of target tissues; however, a pattern may emerge from reviewing and combining results of different studies that indicate the results of these studies are in agreement with the clinical findings in man. Effects of contraceptive steroids on the mammary gland and genital organs will be discussed. Data from 17 contraceptive steroid studies involving 264 untreated control and 733 treated non-human primates were available.
Physiology of the Male Reproductive System: Endocrine, Paracrine and Autocrine Regulation
Authors: Heindel Jerrold J. , Treinen Kimberley A.
Published: September 2009

This presentation reviews the male reproductive system, concentrating on newer advances in our knowledge of its physiology, biochemistry, and regulation, and introduces the topic of male reproductive toxicology. GnRH is the hypothalamic peptide responsible for the stimulation of LH and FSH release from the pituitary. It is synthesized as a pro-hormone, processed in the hypothalamus and released into the portal system in a pulsatile fashion. The timing of these pulses is critical to the release of LH and FSH into the general circulation. While LH and FSH are the main trophic hormones for the testis, we now realize the importance of not only endocrine control, but also of paracrine and autocrine regulation. Specifically, the local control of Leydig cells, Sertoli cells, and germ cells appears to be modulated by numerous growth factors and local regulators arising from within the testis. This point is emphasized both during a discussion of the interaction of the various cell types in the testis and during a discussion of spermatogenesis, where techniques which show stage-specific secretions are highlighted. Newest advances in the mechanism of action of steroidal and peptide hormones are also emphasized with special reference to the possible interaction between toxicants and endocrine control of the reproductive system. This update of the reproductive system “sets the stage” for an in-depth examination of the site and mechanism of action of reproductive toxicants.
Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor
Authors: Gibson John P. , Yarrington John T. , Loudy David E. , Gerbig Clifford G. , Hurst Gail H. , Newberne James W.
Published: September 2009

The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree of acute toxicity in several animal species. Oral administration of the drug at 1,000 mg/kg/day for 2-4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3-4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas of white matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 mg/kg/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any effect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels of GABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.
The Histopathological and Biochemical Response of the Stomach of Male F344/N Rats Following Two Weeks of Oral Dosing with Ethyl Acrylate
Authors: Frederick Clay B. , Hazelton George A. , Frantz Jerry D.
Published: September 2009

Male F344/N rats were dosed with ethyl acrylate (EA) either by daily gavage or in the drinking water for 2 weeks. The gavage dose levels were 0, 2, 10, 20, 50, 100, and 200 mg/kg; the drinking water dose concentrations were 0, 200, 1,000, 2,000, and 4,000 ppm (corresponding to 0, 23, 99, 197, and 369 mg/kg/day, respectively). In those animals dosed by gavage, irritation of the forestomach increased in incidence and severity over the 20-200 mg/kg dose range. In those animals dosed with EA in the drinking water, a much lower incidence of forestomach irritation and less severe lesions were observed at corresponding dose levels. No lesions were observed in the glandular stomach from cither of the 2 modes of oral administration. Following 2 weeks of gavage dosing with EA, the total non-protein sulfhydryl (NPSH) content of the forestomach and glandular stomach, and the NPSH concentration of the liver were determined 2-24 hr after the last gavage dose. Animals dosed at 200 mg/kg reached approximately 11% of the initial NPSH content in the forestomach at 6 hr after dosing. NPSH depletion of this magnitude has been associated with cytotoxicity of other tissues in other studies. By contrast, either the glandular stomach nor liver were depleted of NPSH to levels generally associated with toxicity. These observations arc consistent with the conclusion that bolus dosing of EA induces severe depletion of critical cellular thiols in the forestomach with toxic consequences, but not in the glandular stomach or liver. Changing the mode of oral administration for EA to continued small doses in the drinking water allowed efficient detoxification and did not induce sulfhydryl depletion or comparable forestomach toxicity at the same daily body burden.
Effects of the Peroxisome Proliferator Di(2-Ethylhexyl)Phthalate on Enzymes in Rat Liver and on Carcinogen-Induced Liver Altered Foci in Comparison to the Promoter Phenobarbital
Authors: Maruyama Hiroshi , Tanaka Takuji , Williams Gary M.
Published: September 2009

The livers of rats given either the peroxisome proliferating hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) following initiation by 2-acetylaminofluorene (AAF) or the neoplasm promoter phenobarbital (PB) were studied for changes in 8 histochemical properties. Male F344 rats were fed 200 ppm AAF for 7 weeks to induce hepatoccllular altered foci, and were then fed diets containing either no chemical, 12,000 ppm DEHP or 500 ppm PB for 24 weeks. In hepatocytes, DEHP increased alkaline phosphatase activity throughout the lobule, but reduced gamma-glutamyltransferase (GGT) activity in periportal hepatocytes. PB, in contrast, increased GGT activity in periportal hepatocytes. In foci that were induced by AAF, DEHP reduced the histochemical activity of GGT and did not increase the number, mean volume or volume % of foci detected by deficiencies in iron storage, glucose-6-phosphatase, adenosine triphosphatase or fibronectin. PB enhanced the expression of all 8 phenotypic abnormalities in foci such that either more profiles were detected or the area of foci was increased.
Capsaicin Pretreatment Modifies Hydrogen Sulphide-Induced Pulmonary Injury in Rats
Authors: Prior Michael , Green Francis , Lopez Alfonso , Balu Amba , DeSanctis George T. , Fick Gordon
Published: September 2009

One of the major target organs of hydrogen sulphide gas is the lung. Exfoliation of upper respiratory epithelia and pulmonary edema are prominent effects. Various neuropeptides contained in afferent C-fibres are intimately associated with the epithelia of the conducting airways and are liberated upon exposure to noxious gases. We sought to determine their role in the pathogenesis of hydrogen-sulphide-induced pulmonary injury by pretreating rats with the neurotoxin, capsaicin, which is known to ablate a subpopulation of vagal afferent C-fibres. Groups of capsaicin and saline (control) pretreated Fischer 344 rats were exposed to an edemogenic concentration of hydrogen sulphide (525-559 mg/rn3) for 4 hr. Mortality was significantly greater ( p < 0.01) in the capsaicin treated rats (12/12) compared to the control animals (2/12). Pulmonary injury was also more severe in the capsaicin pretreated animals as assessed by lung water content, histological grade of pulmonary edema and protein in the broncho-alveolar fluid. Animals depleted of substance P exhibited a significantly greater ( p < 0.01) degree of bronchial epithelial cell exfoliation and ulceration following exposure to hydrogen sulphide. These experiments indicate that capsaicin sensitive sensory nerves may play a major role in pulmonary defense against the effects of inhaled toxic gases such as hydrogen sulphide.
Effect of Glycerol on Cell Kinetics and Tumorigenesis in Mouse Lung Following Urethan Administration
Authors: Nagahara Noriyuki , Kitamura Hitoshi , Inoue Tohru , Ogawa Takehiko , Ito Takaaki , Kanisawa Masayoshi
Published: September 2009

Extending previous studies, we hypothesized that glycerol modulates pulmonary tumorigenesis in mice through metabolic activation in bronchiolar cells. To test this, we examined the effects of glycerol on pulmonary cell kinetics and tumorigenesis induced by urethan. Male ddY mice were given 1 mg/g urethan and/or 5% glycerol solution for a fixed period. [3H]Thymidine autoradiography revealed that glycerol administration significantly suppressed the urethan-induced facilitation of cell kinetics of the bronchiolar cells ( p<0.05), but not that of the alveolar wall cells. Furthermore, glycerol did not affect urethan-induced pulmonary tumorigenesis. These findings suggest that glycerol modifies the metabolism of carcinogens in the bronchiolar epithelium.
Pathology and Cell Proliferation Induced by Intra-nasal Instillation of Aldehydes in the Rat: Comparison of Glutaraldehyde and Formaldehyde
Authors: St. Clair Mary Beth G. , Gross Elizabeth A. , Morgan Kevin T.
Published: September 2009

The relative toxicities of formaldehyde and glutaraldehyde to the rat nasal epithelium were determined following intra-nasal instillation of aqueous solutions of these compounds into one nostril of male Fischer 344 (F-344) rats. Lesions identical in appearance to those resulting from acute inhalation exposure to formaldehyde were induced by both compounds in a concentration-dependent manner. Treatments included-India ink or 1 m methylene blue (for instillation deposition studies); sterile saline (vehicle control); 40, 200, 400, and 800 mm formaldehyde; and 10, 20, and 40 mm glutaraldehyde. Dye-treated rats were sacrificed immediately, and nasal passages were examined to determine the localization of instilled materials. Three days after treatment, all other animals received a single ip injection of 5-bromo-2'-deoxyuridine 2 hr prior to sacrifice, and the nasal passages were prepared for histopathology and cell proliferation studies. While sterile saline and 10 mM glutaraldehyde induced no significant epithelial changes, 20 and 40 mM glutaraldehyde induced extensive lesions in the treated side of the nose. Aldehyde-induced lesions included inflammation, epithelial degeneration, respiratory epithelial hypertrophy, and squamous metaplasia in association with marked increases (3-8-fold) in labeling index for both compounds. Formaldehyde induced similar lesions but required concentrations of 200 mM or more to elicit a toxic response. Thus, glutaraldehyde is approximately an order of magnitude more toxic to the nasal epithelium than formaldehyde. These studies also indicate that the nose is very resistant to the aldehydes studied, requiring instillation of millimolar concentrations before toxic responses occurred.
The Ultrastructure and Histology of Cholangiocellular Carcinomas in English Sole (Parophrys vetulus) from Puget Sound, Washington
Authors: Stehr Carla M. , Myers Mark S.
Published: September 2009

The ultrastructure and histology of cholangiocellular carcinomas from feral English sole (Parophrys vetulus) living in polluted waterways of Puget Sound, WA. are described. Electron microscopy confirmed that biliary epithelial cells were the main proliferative cell type composing this variety of neoplasm. The arrangement of these cells varied from well-organized multiple bile duct-like structures to disorganized multilayered sheets of poorly differentiated biliary epithelial cells. A fibrous stroma consisting of multiple layers of collagen fibers and fibroblasts, with macrophages and various blood cell types scattered among these layers occurred between bile duct-like structures or aggregates of biliary epithelial cells. Hepatocytes were not apparent in these neoplasms except within small necrotic regions surrounded by neoplastic biliary epithelial cells. No viruslike particles were observed among the cases examined in this study.
Myopathic Alterations in Extraocular Muscle of Rats Subchronically Fed Pyridostigmine Bromide
Authors: Schuschereba Steven T. , Bowman Phillip D. , Vargas Joseph A. , Johnson Thomas W. , Woo Frank J. , McKinney LuAnn
Published: September 2009

To determine if alterations in extraocular muscle morphology occur after subchronic oral administration of pyridostigmine bromide, rats were continuously fed 90 mg/kg in meal and examined at 1,2, 4, 7, and 15 days. Within the first day, blood acetylcholinesterase activity was reduced by 87% and remained inhibited by 74-91% during the study. Light microscopy demonstrated that by day 1 approximately 3% of the extraocular myofibers were shrunken and invaded by inflammatory cells. The most severe degenerative changes consisting of vacuoles and inflammatory cell infiltration occurred at day 1 with progressively less severe changes at days 2 and 4. At days 7 and 15,1.3-4.5% of the myofibers still exhibited damage. Ultrastructurally, all presynaptic areas were normal but the postsynaptic areas of affected myofibers at days 1,2, and 4 showed myofilament and Z-band dissolution, mitochondrial inclusions, subneural fold and T-tubule/sarcoplasmic reticulum vacuolization and subneural fold depth reduction. By days 7 and 15, these changes were diminished in some cases and in others alterations appeared similar to day 1. We conclude that subchronic feeding of pyridostigmine bromide induces myopathic rather than neurogenic changes in rat extraocular muscle and that the myopathy is different in these muscles than in the diaphragm from the same rats.
Morphometric Assessment of Thymic Size Variation in Laboratory Rabbits
Authors: Maurer James K. , Gibbons Beth A. , Bruce Robert D.
Published: September 2009

Sections of thymus from New Zealand white rabbits used as controls in 28-day and 91-day percutaneous toxicity studies conducted at different laboratories were morphometrically assessed. Measurements of total thymic area, medullary area, and cortical area were greater for 28-day vs 91-day studies conducted at a given laboratory, but varied from one laboratory to another. Relative thymic measurements (percent medulla, percent cortex, and medullarcortex ratio) were similar for studies conducted at each laboratory and from one laboratory to another regardless of study duration. A decrease in thymic size occurred between approximately 16 and 25 weeks of age (i.e., 28-day studies vs 91-day studies) due to proportionally equivalent decreases in both the cortical and medullary areas. The consistency of the relative measurements can be used to assist in distinguishing changes in thymic size due to aging from changes in size due to stress or toxicity which would be expected to differentially affect the cortical and medullary areas. Appreciation of the normal variation in thymic size is needed when evaluating results of toxicity testing in rabbits. Data are provided as to the degree of normal variation of rabbit thymic size expected within and across percutaneous toxicity studies, with considerations for interpreting such data.
Spontaneous Primary Astrocytoma in the Spinal Cord of a Mouse and a Rat
Authors: Frith Charles H. , Chandra Manik
Published: September 2009

A spontaneous astrocytoma was observed as an incidental finding in the thoracic spinal cord of a control Charles Rivers CD-1 female mouse from a 2 yr oncogenicity study. An astrocytoma was also observed in the lumbar spinal cord of a Charles Rivers Sprague-Dawley control, female rat from a 2 yr oncogenicity study. The mouse was clinically normal and was sacrificed at the end of the 2 yr study. The rat was killed at 512 days of age because of posterior paralysis.
A 90-Day Continuous Vapor Inhalation Toxicity Study of JP-8 Jet Fuel Followed by 20 or 21 Months of Recovery in Fischer 344 Rats and C57BL/6 Mice
Authors: Mattie David R. , Alden Carl L. , Newell Teresa K. , Gaworski Charles L. , Flemming Carlyle D.
Published: September 2009

The kerosene-type jet fuel, JP-8, consists of a complex mixture of aliphatic and aromatic hydrocarbons. Because of the utility of JP-8, studies have been conducted to identify the potential long-term consequence of occupational inhalation exposure. Fischer 344 rats and C57BL/6 mice of both sexes were exposed to JP-8 vapors at 0, 500, and 1,000 mg/m3 on a continuous basis for 90 days, then followed by recovery until approximately 24 months of age. Occurrence of necrotizing dermatitis associated with fighting resulted in an increase in mortality in mice (male greater than female) during the 2 week to 9 month post-exposure recovery period. The male rat kidney developed a reversible ultrastructural increase in size and propensity for crystalloid changes of phagolysosomal proteinic reabsorption droplets in the proximal convoluted tubular epithelium. A specific triad of persisting light microscopic renal lesions occurred but functional change was limited to a decrease in urine concentration compared to controls that persisted throughout the recovery period. The response is comparable to the chronic effect of lifetime exposure of the male rat to unleaded gasoline, d-limonene, and p-dichlorobenzene, except for the absence of tubular tumorigenesis. The active toxicologic response presumably must occur over a greater proportion of the male rat's life span for the tumor component of this male rat hydrocarbon nephropathy syndrome. The predictiveness for humans must be questioned, since the pathologic response to JP-8 involved only one tissue in one sex of one species, and since the male rat response appears to be linked to an inherent renal protein peculiarity.
Strain A/J Mouse Lung Adenoma Growth Patterns Vary When Induced by Different Carcinogens
Authors: Gunning William T. , Castonguay Andre , Goldblatt Peter J. , Stoner Gary D.
Published: September 2009

The histogenesis of mouse lung adenomas is currently being investigated in several laboratories. Based upon studies of a limited number of carcinogens in different mouse strains, some investigators suggest that all lung adenomas in mice are derived from alveolar type II cells, whereas others suggest a Clara cell origin for a majority of the tumors. This report differs from previous investigations in that 12 different carcinogens were evaluated for the types of lung tumor growth patterns they induced in a single mouse strain (strain A mice). The carcinogens aflatoxin B, (AFB,), benzo(a)pyrene (BP), 1,2-dimethylhydrazine (DMH), 3-meth-ylcholanthrene (MCA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosomethylurea (MNU) induced tumors with a predominately solid/alveolar growth pattern, whereas N-nitrosodiethylamine (NDEA) induced predominantly papillary tumors. Most of the other carcinogens induced a higher proportion of lung tumors with the solid/alveolar growth pattern than with the papillary growth pattern; however, ratios between the 2 growth patterns varied. If, as suggested by others, solid tumors are derived from alveolar type II cells and papillary tumors from Clara cells, then carcinogens may differ with respect to their ability to transform one cell type or the other.
Nucleolar Organizer Regions in Cardiac Lesions Induced by Doxorubicin
Authors: Leblanc Bernard , Mompon Paul R. , Espérandieu Odile , Geffray Brigitte , Guillermo Christine
Published: September 2009

The use of the argyrophilic (Ag) staining technique for nucleolar organizer regions (NORs) revealed nuclear changes in myocytes of the left atrium of 10 rats treated twice a week for 6 weeks with doxorubicin (1 mg/kg body weight) iv and sacrificed after 6 weeks without treatment. The changes were easily detected qualitatively and further assessed by quantification. Cardiac myocytes of doxorubicin-treated rats had larger nuclei and/or a larger quantity of AgNORs that were either dispersed in a number of small dots or clustered in rounded, rod-shaped, or tortuous large structures. AgNOR alterations may reflect a defect of nucleolar association leading to an impairment of protein synthesis that could be involved in doxorubicin cardiotoxicity.
Studies on the Mechanism of Simvastatin-Induced Thyroid Hypertrophy and Follicular Cell Adenoma in the Rat
Authors: Smith Peter F. , Grossman Scott J. , Gerson Ronald J. , Gordon Lea R. , Deluca John G. , Majka James A. , Wang Regina W. , Germershausen John I. , MacDonald James S.
Published: September 2009

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phcnobarbilal (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose. Finally, the thyroid change with simvastatin is likely to result from increased thyroxine clearance and the consequent stimulation of this gland from increased serum TSH.
Long-Term Effects of an Inotropic Phosphodiesterase Inhibitor (ICI 153,110) on the Rat Salivary Gland, Harderian Gland, and Intestinal Mucosa
Authors: Westwood F. Russell , Iswaran T. Jega , Greaves Peter
Published: September 2009

The inotropic vasodilator, ICI 153,110, a phosphodiesterase inhibitor intended for the treatment of congestive heart failure, was administered to Alderley Park Wistar-derived rats for periods of up to 182 days. Treatment produced hypertrophy of salivary glands, hyperplasia of intestinal mucosa, and dacryoadenitis of the harderian gland. As the functions of these glandular tissues can be modified by factors which alter cyclic nucleotide metabolism, it is postulated that the glandular alterations produced by ICI 153,110 occurred as a result of phosphodiesterase inhibition.
Spongiosis Hepatis: Chemical Induction, Pathogenesis, and Possible Neoplastic Fate in a Teleost Fish Model
Authors: Couch John A.
Published: September 2009

Spongiosis hepatis (SH), first reported as a distinct lesion associated with certain forms of hepatic neoplasia in rats, has also been induced with chemicals, in a predictable fashion, in small teleost fishes being studied as carcinogenesis research models. The sheepshead minnow (Cyprinodon variegattis), exposed to N-nitrosodiethylamine (DENA) in sea water, provided the model for this study. The fish developed SH and presented a spectrum of developmental or progressive stages of the lesion over a 140 week holding period following a 6 week exposure to @ 57 mg/L DENA. The origin of SH in the fish model is homologous to that in the rat model, both species having the perisinusoidal cell (stellate cells of Ito) in the space of Disse as the cell of origin. Light (LM) and electron microscopy (EM) studies characterized the different pathogenetic stages of SH in liver of the sheepshead minnow and revealed a possible late transition of SH to putative polymorphic cell neoplasms. The possible preneoplastic or neoplastic nature of SH from its time of origin in chemically exposed fish to time of appearance of associated presumptive neoplasms is discussed. SH may be a bioindicator of exposure to certain chemicals in some vertebrate species, from fishes to mammals.
Hepatocarcinogenic Effect of Vinyl Carbamate in the C57B1/10J Strain Mouse
Authors: Wright Jayne A. , Marsden Alan M. , Willets Jonathan M. , Orton Telly C.
Published: September 2009

The genotoxic carcinogen vinyl carbamate was dosed to C57B1/10J strain mice for 35 weeks, and the study terminated after week 59. A main study group of 55 males and 50 females was dosed 6 mg/kg vinyl carbamate once weekly by intraperitoneal injection, whilst a reference group of 10 animals/sex were kept undosed. From week 39 onwards there was a high incidence of mortality, which was often associated with acute internal abdominal hemorrhage. Mice of both sexes killed from 34 weeks onwards frequently showed macroscopic evidence of blood-filled, cyst-like structures in the liver. Upon histopathological examination widespread peliosis hepatis was observed with frequent progression to hemangiomata and hemangiosarco-. mata. Trabecular hepatocellular carcinomata were also apparent, often within the same liver sections and invariably associated with peliosis hepatis. As a consequence of its tumor burden, the liver often showed hepatocyte atrophy, fibrosis, and coagulation necrosis. A small number of livers revealed hepatocellular adenomata and altered hepatocyte foci.
Liver Damaging Effect of Suramin in Normal and Carbon-Tetrachloride Treated Rats
Authors: Szende Béla , Lapis Károly , Jeney András , Simon Károly , Ördog András , Moldvay Judit
Published: September 2009

Male Fischer 344 (F344) rats were treated with phenobarbital + carbon tetrachloride (CC14) for 16 weeks to induce liver cirrhosis. Another group of rats received 50 mg/kg iv suramin once a week for 16 weeks. The third group of rats was treated with both phenobarbital + CC14 and suramin. After 16 weeks of suramin treatment, a massive periportal infiltration composed of macrophages, many of them containing glycosa-minoglycans in their cytoplasm, mast cells, and other inflammatory cells were observed. This lesion was added to the liver cirrhosis caused by CC14 in the group treated with suramin and CC14. The changes in glycosaminoglycan metabolism caused by suramin did not influence the CC14 cirrhosis. Since suramin has been reported to be a prototype of a new generation of antitumor compounds, we suggest caution in the use of chronic suramin treatment, especially in patients with livers which are already damaged.
Sustainability of Forestomach Hyperplasia in Rats Treated with Ethyl Acrylate for 13 Weeks and Regression after Cessation of Dosing
Authors: Ghanayem Burham I. , Matthews Hazel B. , Maronpot Robert R.
Published: September 2009

In a chronic study conducted by the National Toxicology Program (NTP), gavage administration of 100 or 200 mg ethyl acrylate (EA)/kg/day, 5 days/week, to F344 rats and B6C3F1 mice resulted in a significant dose-dependent increase in the incidence of squamous cell papillomas and carcinomas of the forestomach of both sexes of rats and mice. No increase in the incidence of tumors was observed at any other site in these rats. Chemically-induced cell proliferation is currently thought to play a role in the development and progression of chemically-induced neoplasia. Therefore, a stop-study was initiated where 100 or 200 mg EA/kg (in com oil) was administered daily, 5 days/week, for 13 weeks. Rats sacrificed at the end of the treatment regimen had severe epithelial hyperplasia of the forestomach. No lesions were observed in the glandular stomach or liver of EA-treated rats. Forestomach hyperplasia induced by EA included upward and downward cell proliferation. However, forestomachs of rats treated for 13 weeks and sacrificed 8 weeks after the last EA dose exhibited a significant decline in the incidence and severity of forestomach mucosal hyperplasia. Histopathologic evaluation of forestomachs of EA-treated rats (13 weeks) which were allowed a 19-month-recovery (with no exposure to EA) showed further decline in the incidence and severity of mucosal cell hyperplasia. These results indicate that gavage administration of EA to rats results in extensive and sustained forestomach mucosal hyperplasia. The sustainability of forestomach hyperplasia is apparently dependent on the continued exposure of rats to ethyl acrylate, and regressed after cessation of dosing. Furthermore, although enough post-treatment time was allowed for tumors to develop after cessation of EA administration, forestomachs exhibited a nearly complete recovery with no increased incidence of papillomas or carcinomas. It, therefore, remains to be determined what duration of exposure or other factors are critical for reversibility or progression of EA-induced forestomach mucosal hyperplasia to neoplasia.