Journal of Toxicologic Pathology
Online ISSN : 1881-915X
Print ISSN : 0914-9198
ISSN-L : 0914-9198
3 巻, 1 号
選択された号の論文の12件中1~12を表示しています
  • PROFILES OF SPONTANEOUS AND INDUCED TUMORS IN ANIMALS AND A NEED FOR A REVISED CARCINOGEN BIOASSAY
    榎本 眞, 小林 克己, 井上 博之
    1990 年 3 巻 1 号 p. 1-17
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Naturally-occurring tumors, which generally increase in incidence with age in control rats or mice in 2-year carcinogenicity bioassays, show occasionally an increased or decreased incidence in animals dosed with chemical substances. Analyses of these tumors showing dose-related increases or decreases in their incidence rates in the chronic toxicity and oncogenicity studies of chemicals including 11 tests using F344 rats and 14 tests using B6C3F1 mice carried out in our Center for the past 8 years, revealed that they were exclusively naturally-occurring tumors commonly seen in these animals. These lesions included pituitary tumor, C-cell tumor of the thyroid, and mononuclear cell leukemia in F344 rats and bronchiolar/alveolar adenoma of the lung, hepatocellular adenoma, hepatocellular adenoma plus carcinoma, malignant lymphoma, and forestomach papilloma in B6C3F1 mice.
    One approach to understand the changes in the incidence rates of the naturally-occurring tumors is to elucidate the biological effects of the test chemical. Another approach is to identify sets of modifying factors, including nutritional effects, hormonal-imbalances, and other age-associated lesions, as seen in the roles of chronic nephropathy, myeloproliferative changes, and hyperplasias of the various endocrine organs in the development of tumors in corresponding tissues.
    The profile approach to induced rodent tumors in the past has revealed several characteristics. Among them, first, induced tumors show early development, mostly within a period less than 52 or 78 weeks of the treatment. Second, the dose levels of each chemical appear likely to have a minimum as well as an upper limit in the amount needed to induce tumors. Consequently, the current carcinogenicity tests using unusually high amounts of chemicals in a pure form will be able to demonstrate tumor induction, if they are really carcinogenic, before the onset of the spontaneous tumors, which are mostly seen mixed with a variety of non-neoplastic lesions in the same groups of animals after 78 weeks of the treatment. This means that the detection of possible chemical carcinogens would be more efficient and accurate by shortening the test period from 104 to 78 weeks in tests using F344 rats and B6C3F1 mice. Addition of a satellite test for interim observation of the pathological findings at 52 weeks, to this new way of testing will give more useful information on early changes and the morphogenesis of tumors induced by chemical substances.
  • 山崎 寛治, 板倉 智敏
    1990 年 3 巻 1 号 p. 19-27
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Histological and histochemical studies were made of the femur, patella, and sternum of 20 clinically normal Sprague-Dawley rats at 6 and 12 months of age. Histological changes consisted of loosening of the matrix and degeneration of the chondrocytes of the articular cartilage in the femur and patella. These changes were detected in the femur at 12 months of age and patella at 6 and 12 months of age. In the femur, erosion was also observed at 12 months of age. Furthermore, proliferation of chondrocytes in the radial zone of the femur and marginal chondrophyte in the patella were seen at 12 months of age. In the growth plate, degeneration of the matrix and necrosis were seen in the femur and sternum at 6 and 12 months of age. Closure of the growth plate began in the femur at 12 months of age. Histochemically, glycosaminoglycans (GAGs) were detected in the transitional and radial zones of the articular cartilage of the femur, and these decreased in the transitional zone with increasing age. The changes in the patella were essentially the same as those in the femur. GAGs, especially hyaluronic acid, were increased in the area of proliferated chondrocytes in the femur and marginal chondrophyte of the patella. GAGs were widely distributed in the growth plate of the femur and sternum at 6 months of age. Reduction of GAGs was conspicuous in the femur at 12 months of age.
  • 大塩 至, 荻野 利彦, 加藤 博之, 長嶋 和郎
    1990 年 3 巻 1 号 p. 29-38
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    In order to clarify the teratogenic mechanism of oligodactyly, we have carried out some experimental studies in rats. In this paper we report the results and discuss the teratogenic mechanism of the anomalies of the extremities.
    1. Ulnar ray deficiency, cleft hand, central ray polydactyly, and central ray syndactyly were induced in W: Gun rats, and radial ray deficiency was induced only in W KAH/H km rats. The features of these anomalies in rats were the same as in humans. The critical periods of ulnar ray deficiency and radial ray deficiency seemed to be earlier than those of central polydactyly, syndactyly, and cleft hand. The critical period of cleft hand was identical to those of central polydactyly and central syndactyly, and advanced cases of central polydactyly or syndactyly in which the fusion area extended as far as the proximal phalanx and metacarpus, became identical to the cleft hand. These findings suggest that radial and ulnar ray deficiencies belong to longitudinal ray deficiency, and the central polydactyly, syndactyly, and cleft hand might be formed by the same teratogenic mechanism, that is, failure of separation of finger ray.
    2. DNA synthesis and cell condensation in the developing hand plate of normal and preaxial oligodactylic rats treated with myleran on the day of 12.0th gestation were examined using a BrdU/anti-BrdU immunohistochemical study. DAN-synthesizing cells were distributed uniformly in the mesenchyme of the hand on day 12.0 in normal rat embryos. From day 13.0. these cells were distributed in the interdigital mesenchymal areas, leaving rare labeled cells in the sites of cell condensation. When the labeled mesenchymal cells were followed from day 12.0 until day 14.0, they were found to be concentrated in the digital rays. We concluded that cell migration rather than cell proliferation in the digital-ray area could be an initial step in digital-ray formation. In the oligodactylic hand plate, mesenchymal cell condensation was delayed and preaxial digital rays were not formed. On day 13.0 the number of DNA-synthesizing cells was much less than normal in all areas of the hand plate, and cell necrosis of the epidermis and mesenchyme near the epidermis was prominent. On day 14.0, DNA-synthesizing cells decreased in the epidermis rather than in the mesenchyme. From these results, we conclude that the mechanism of this oligodactyly could involve a mesenchymal cell deficit and restriction of migration.
  • 佐藤 達資
    1990 年 3 巻 1 号 p. 39-44
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Two subcutaneous transplantable rat osteosarcoma lines were established serially and used to analyze the mechanism of radiographic sclerotic changes in human osteogenic sarcomas following chemotherapy. Primary osteogenic sarcomas were induced in the left humerus (POA) and in the right femur (POB) by [32P]H3PO4 in one F344 male rat. Pieces of POA or POB tumors measuring about 1mm3 were transplanted subcutaneously into syngeneic male rats up to the 22nd generation, for a period of three years and six months. Both the POA and POB lines maintained osteoid and bone formation, and alkaline phosphatase (ALP) activity. Moreover, tumor nodules grown after transplantation of the POA or POB line showed severe radiographic sclerotic changes three or four weeks after a single dose of cis-diamminedichloroplatinum (CDDP). Histologically, the sclerotic changes were caused by increased bone formation.
  • 永原 則之, 北村 均, 蟹沢 成好, 多田 万里子
    1990 年 3 巻 1 号 p. 45-52
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Extending our previous studies, we hypothesized that glycerol enhances 4-nitroquinoline 1-oxide (4NQO)-induced pulmonary tumorigenesis in mice by increasing the metabolic activation of 4NQO to the ultimate carcinogen 4-hydroxyaminoquinoline 1-oxide (4HAQO) in bronchiolar cells. To test this, we examined whether glycerol affects the formation of 4HAQO-DNA adducts in the lung. Sequential changes in the level of total 4NQO and its metabolites in serum and lung tissue were also studied. Male ddY mice were injected subcutaneously with a mixture of [3H]4NQO at a dose of 10mg/kg body weight with or without subsequent administration of 5% glycerol solution as drinking water for a fixed period, and the radioactivity in each compartment was determined sequentially until the end of the 7th week. The results showed that 1) glycerol did not alter either level or the pattern in change of the amount of 4NQO and its metabolites in serum, lung tissue, and lung DNA. 2) the DNA adduct, which was rapidly reduced during the first week, remained constant (1 adduct/106 nucleotides) after the 3rd experimental week, and 3) radioactivity was detected almost exclusively in DNA after the 4th experimental week. It is concluded that enhancement of 4NQO-induced murine pulmonary tumorigenesis by glycerol is not associated with the amount of 4NQO-DNA adducts in the lung.
  • 今井田 克己, 古川 文夫, 豊田 和弘, 下地 尚史, 岡宮 英明, 高橋 道人, 長谷川 良平
    1990 年 3 巻 1 号 p. 53-56
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    The promoting potential of ethoxyquin, an antioxidant, was investigated on two-stage glandular stomach carcinogenesis in rats. After simultaneous administration of N-methyl-N'-nitro-Nnitrosoguanidine (MNNG, 100ml/L in the drinking water) and sodium chloride (NaCl, 10% in basal diet) to group I or these agents singly to groups 2 and 3, respectively, for the first 8 weeks, the animals received a 1% ethoxyquin supplement in the basal diet for the following 32 weeks. Group 4 rats received the MNNG and NaCl combination and were then maintained as controls. The resultant incidences of carcinomas arising in the pyloric mucosa of rats in groups 1 to 4 were 8/17 (47%), 1/16 (6%), 0/16 (0%), and 2/10 (20%), respectively, with the group 1 incidence being significantly higher than that of group 2 or 3. These results clearly showed that promotion by ethoxyquin was observed only after simultaneous treatment with MNNG and NaCl, but not after MNNG treatment without NaCl.
  • 高島 吉治, 丸山 博司, 北澤 俊治, 中江 大, 堤 雅弘, 伝田 阿由美, 小西 陽一
    1990 年 3 巻 1 号 p. 57-63
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    The initiating potential of acetaminophen (APAP) was investigated in prexisting fatty liver induced by choline-devoid (CD) diet in male F344 rats. APAP was intragastrically administered at the single necrogenic doses, 0.5g/kg, 1.0g/kg, 1.5g/kg body weight, Diethylnitrosamine (DEN) at 20mg/kg body weight was intraperitoneally injected after 4 weeks feeding of CD or choline-supplemented diet. In the CD treated animals, DEN significantly increased the number and area of both glutathione Stransferase placental form (GST-P) and γ-glutamyl transferase (GGT) -positive foci and nodules but APAP did not enhance at all. These results indicate that APAP does not possess significant initiating activity in damaged liver of rats.
  • 吉村 愼介, 今井 清
    1990 年 3 巻 1 号 p. 65-89
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Pathological changes occurring in nervous system were systemically examined after treatment with various drugs or chemicals. Low-dose and chronic treatment mostly produced distal axonopathy either in central nervous system (by chinoform or its related compound, 5, 7-dichloro-8-hydroxyquinoline), or in peripheral nervous system (by 2-methylaminocarbothioyl-2-(2-pyridyl) tetrahydrothiophene), or even in both (by 2, 5-hexanedione (2, 5-HD) and acrylamide (ACR)). Many of these axonopathies were characterized by accumulation of certain organella, neurofilaments by 2, 5-HD or ACR, or vesicular and tubular organelles by 2-methylaminocarbothioyl-2-(2-pyridyl) tetrahydrothiophene, while no characteristic feature was detected in the axonopathy by chinoform. High-dose and short-term treatment, on the other hand, commonly induced edematous or necrotic changes in the particular regions, such as hippocampus by chinoform, cerebellar and vestibular nuclei by 2, 5-HD or misonidazole, entopeduncular nuclei by misonidazole, and cerebellar cortex by misonidazole or ACR. It is considered necessary to find a common and diverse molecular structure or biochemical feature among many neurotoxic chemicals concerning patterns of morphologic changes in order to evaluate the pathogenesis of neurotoxicity.
  • 吉村 愼介, 斉藤 義明, 山口 肇, 今井 清
    1990 年 3 巻 1 号 p. 91-96
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    High dose (700 or 500mg/kg/day) of 2, 5-hexanedione was orally administered to female Sprague-Dawley rats for 2 to 6 weeks. and the cerebellar and vestibular nuclei were examined ultrastructurally. Abnormal gait was observed at the 2nd week (700mg/kg) or the 3rd week (500mg/kg) of treatment, and one of six animals dosed 700mg/kg died at the 4th week of experiment. In the histopathological examination of the dead rat, edema and petechial hemorrhage were noted in the thalamus and vacuolation was observed in the cerebellar nuclei. Ultrastructural examination of the cerebellar and vestibular nuclei of the rats, which were dosed 700mg/kg for 2 weeks and fixed with an isotonic neutral fixative by gentle perfusion method, revealed dilatation of the periaxonal space, axonal degeneration, and extracellular edema. Nerve endings in these nuclei were occasionally detached from the nerve cells, and some of the endings were degenerated or destroyed. In the animals which survived and administered for a longer period, however, there were accumulation of neurofilaments and swelling of the nerve endings.
  • 日浅 義雄, 北掘 吉映, 森本 純司, 小西 登, 大嶋 正人
    1990 年 3 巻 1 号 p. 97-104
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    In the first experiment, the carcinogenic potential of diethylene glycol added to the drinking water of male and female F344 rats was examined. Groups of 50 male and 50 female animals were given 2.5% (group I) or 1.25% diethylene glycol (group 11) or tap water (group III) to drink for 108 weeks. Hematological and laboratory examination of the serum and urine, and measurements of organ weights showed no significant differences between the groups in week 108. Tumors developed in the testis, uterus, pituitary gland, thyroid gland, and adrenal gland of both treatment and control rats, but the incidences of tumors and non-neoplastic lesions did not significantly differ between the three groups. In the second experiment, no renal promoting potential was evident for diethylene glycol, at 2.5% in the drinking water for 30 weeks, after initiation with N-ethyl-N-hydroxyethylnitrosamine. In contrast, 1% trisodium nitrilotriacetate monohydrate significantly enhanced kidney lesion development. Thus, no evidence was obtained that diethylene glycol exerts either carcinogenic or promoting effects in rats.
  • 増井 恒夫, 朝元 誠人, 長谷川 良平, 香川 雅孝, 福島 昭治
    1990 年 3 巻 1 号 p. 105-110
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    The effects of monosodium succinate, disodium succinate, and succinic acid on the development of hyperplastic or preneoplastic lesions in the urinary bladder of rats were investigated. These test chemicals were fed to rats after pretreatment for 2 weeks with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as 0.05% of the drinking water. Rats were subjected to unilateral ureter ligation at week 3 and killed at week 20 of the experiment. In the groups given disodium succinate or sodium citrate (positive control), the incidence of simple hyperplasia was significantly higher than that of the control group given the basal diet alone. The incidence and number per 10cm basal membrane of papillary or nodular hyperplasia of the urinary bladder were higher than the control in the groups given disodium succinate or sodium citrate, although the changes were not statistically significant, probably due to the short administration period of the test chemicals. The results support the significance of the presence of sodium ion and increased urinary pH as promoting factors for urinary bladder carcinogenesis.
  • 飯田 晶敏
    1990 年 3 巻 1 号 p. 111-123
    発行日: 1990/06/29
    公開日: 2009/02/12
    ジャーナル フリー
    Despite the fact that much is known about chronic renal disease, few studies have described renal osteodystrophy (ROD) in rats. The present study describes pathological features of spontaneously occurring ROD in 84 (70 males and 14 females) out of 545 (269 males and 276 females) aged rats used in life-span and carcinogenecity studies.
    1. Bone changes: The time course of histological change in the bone is as follows: 1) increased bone resorption with active osteoblasts (-increase in plasma PTH level), 2) proliferation of osteoblasts and fibrous connective tissue (marrow fibrosis) -reparative process, 3) osteoid formation (hyperosteoidosis) -defective rate of mineralization, and increase in matrix synthesis.
    2. Chronic renal disease: Histopathological changes in the kidney of ROD were typical of age-related renal disease in the various strains of rats and revealed an end-stage of renal damage. The lesion consisted of glomerular sclerosis, tubular dilatation with flattened epithelium and proteinaceous casts, and cell infiltration and fibrosis in the interstitium.
    3. Parathyroid hyperplasia (hyperparathyroidism): Both glands were grossly enlarged to 1-2 mm in diameter. Microscopically the chief cells were significantly increased in their size and number, indicating that the gland enlargement was due to both hyperplasia and hypertrophy of these cells.
    4. Metastatic calcification: Metastatic calcification in the soft tissue was found in most cases with ROD. The deposit was present in multiple sites, particularly in the aortic media, medium-sized arteries of various organs, lung, stomach, and kidney.
feedback
Top