The toxicological correlation between blood biochemical parameters and liver histopathological findings was summarized mainly in rats and dogs on the basis of our experiments and published papers. In rats and dogs with hepatocytic necrosis, GPT and GOT increased with a good correlation to necrotic severity. In dogs with cholestasis, ALP, γ-GTP, T.BIL and BSP retention rates increased. In mixed types of hepatitis or cholestasis and hepatic necrosis, GPT, GOT and ALP increased in rats and dogs and additionally γ-GTP and BSP retention rates increased in dogs. In hepatic steatosis, CHOL and TRIG decreased in rats and dogs. In hepatic injury due to accumulation of foreign materials or cell compornents and sinusoidal cell injury, no specific correlation with biochemical parameters was noted.
To establish an animal model of chronic cadmium nephropathy and osteopathy, we intraperitoneally administered 0.228 mg CdCl2 (Cd) or normal saline (NS) to 52 female Sprague-Dawley (S.D.) rats 3 times a week for 16 months following ovariectomy (OV) or sham surgery (Sham), dividing the animals into three experimental groups (OV-Cd, Sham-Cd and OV-NS). Two groups of male S.D. rats were also administered Cd or NS (22 animals; Male-Cd and Male-NS). Cd-administered rats gained significantly less body weight than NS rats after 16months of experiments with no signs of emaciation. Serum creatinine levels and Cd contents in the kidney had significantly increased in the Cd-administered rats. OV-Cd rats showed significant decreases in PTH levels and increases in calcium contents in the kidney and other organs. Kidneys of Cd-administered rats showed atrophy, dilatation, and interstitial fibrosis of tubules. Sclerosis and collapse of the glomeruli were observed in the Cd groups with no proliferation in mesangial cells or matrix. The Haversian canal system of the Cd-administered rats disappeared and was replaced by a large quantity of degenerated, necrotic, and restorative tissues. Bone histomorphometric parameters showed that osteoid volume and osteoid surface had significantly increased in the Male-Cd group. In contrast, decreases in bone mass and increases in fibrous tissue were found to be more prominent in the OV-Cd group. Our results have demonstrated for the first time that long-term, 1ow-dose CdCl2 administration to ovariectomized S.D. rats is capable of inducing irreversible nephropathy with osteopathy exhibiting pathological and bone histomorphometric characteristics that are very similar to those of Itai-Itai disease.
Observations were made on the increase in the frequency of sister-chromatid exchanges (SCEs) induced by a nitric oxide (NO) releaser (NOR4) and NaNO2 in Chinese hamster lung cells (CHL/IU). During these observations, NaNO3 did not have any effect on SCE induction. NOR4- and NaNO2-induced SCE frequencies decreased due to treatment with bovine serum (10%), bovine serum albumin (BSA, 0.1%, 1.0%), oxyhemoglobin (Hb, 10μM), and superoxide dismutase (SOD, 250U/ml), but not with glutathione (oxidized and reduced forms), cysteine, cystine and catalase:. NO2-concentrations decreased with Hb, but not with any other agent, indicating that NO and/or NO2- have a strong binding reaction with Hb. The mechanism for a decrease in genotoxicity due to SOD is still unclear. However, it would appear that S-nitrosothiols in the cells can be stabilized by SOD in consideration of the S-nitrosothiols stabilizing effect of SOD reported by Kowaluk et al. (1990). In the presence of NO and superoxide anions, genotoxicity seemed to be decreased by catalase and SOD, since the former decreases the superoxide anion-induced SCE frequency, and the latter, the NO-induced frequency.
Pamiteplase (genetical recombination), YM866, is a novel recombinant modified human tissue-type plasminogen activator developed by Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan. An intended route of administration in the clinical use of this drug is intravenous administration. We conducted an intravenous fertility and general reproduction studies of this drug in male and female rats and teratology study of this drug in rabbits at the dose levels of O (vehicle control), 0.1, 0.3 or 1 mg/kg/day. In the rat, no treatment-related abnormalities were observed up to the maximum dose in parental animals and their offspring. In the teratology study in rabbits, prolonged coagulation time at the injection site was observed at 0.3 mg/kg or more. One death and one abortion occurred at 1 mg/kg on days 22 and 23 of pregnancy, respectively. No toxic effects on the litters were observed up to the maximum dose. Results of evaluation of the mutagenicity of YM866 and its ability to induce chromosome aberrations using the L5178Y TK+/- mouse lymphoma assay, human lymphocyte chromosome aberration assay and the micronucleus assay in mice were negative. Evaluation of the immunogenicity of YM866 by repeated intravenous injection in chimpanzees elicited no confirmed antibody titers.
The histology and porphyrin content of the Harderian gland and the serum prolactin levels were examined in male B6C3F1 mice treated with neuroleptic buty-rophenones (timiperone and haloperidol) and treated concurrently with timiperone and 2-bromo- α -ergocryptine (bromocriptine), a potent suppressor of prolactin. Light-microscopically, both timiperone and haloperidol increased the number of accretions of porphyrin pigment within the Harderian gland lumina. Timiperone treatment of mice increased both the porphyrin content of the Harderian gland and the serum prolactin levels. Administration of bromocriptine to timiperone-treated mice distinctly prevented the rise in both tissue porphyrin and serum prolactin levels. In intact mice, bromocriptine also exerted inhibitory effects on both the Harderian gland potphyrin content and the serum prolactin level. Electron microscopic investigation revealed that the cytoplasm of type A cells in the Harderian glands of mice treated with timiperone contained trilaminar profiles similar to those seen in the intraluminar pigment masses. These results indicate that timiperone accelerates porphyrin secretion from the type A cells of the mouse Harderian gland by increasing the serum prolactin levels.
The effect of blood collection imitating a one-month toxicokinetic study on hematological parameters was studied in male rats (6 weeks of age at the beginning of the experiment). Three groups were established according to blood sampling points per day; Group I (3 points), Group II (5 points) and Group III (10 points). These repeated blood samplings were carried out on the first and last days of this study, and one-point blood sampling was also done every week during the experiment. In each sampling, 0.3ml of blood was collected from the jugular vein. There were no changes in Group I, but in other groups, especially in Group III, red blood cell counts, hematocrit and hemoglobin concentration decreased during repeated blood sampling. On the other hand, white blood cell counts also decreased, but recovered within 24 hr. Platelet counts did not show any decrement. From the present result, less than 0.9 ml of blood per day is conceivable as the volume without causing changes in hematological parameters. The baseline of the sampling volume can become one reference for toxicokinetic and toxicological studies.
Male F-344 rats were exposed by inhalation to gaseous formaldehyde at 0.3, 2, and 15 ppm 6 h/day, 5 days/week for 28 months. Nasal tumors were macroscopically evident in the 15 ppm group from the 14th month and 8 of 32 rats bore such tumors at the 24th month. Histopathological examination revealed both squamous cell papillomas and carcinomas. No nasal tumors were observed in the lower exposure groups (0.3 and 2ppm groups). In the high exposure group (15 ppm group), frequent face washing, coughing and/or crouching position, lacrimation, nasal discharge, and yellow discoloration of the haircoat were observed. Significant decrease in food consumption and body weight was noted, and 20 (88.3%) rats died by the 24th month. Reduced triglyceride levels and liver weights, presumed to be related to the drop in food intake, were also seem in the 15 ppm group. Epithelial cell hyperplasia, hyperkeratosis, and the squamous metaplasia were apparent in all exposure groups. Inflammatory cell infiltration, erosion or edema were evident in all groups, including the 0 ppm and room (RC group) controls. In this; study, a no effect level of formaldehyde vapor could not be obtained because toxicological signs were obvious even with the low exposure group. The benchmark doses for squamous metaplasia and epithelial hyperplasia were 0.25 and 0.24 ppm, respectively.
A six-month repeated-dose dermal toxicity study followed by a 30-day recovery test of hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC), a new cellulose derivative used as a thickener for topical pharmaceuticals, was conducted using rats. Aqueous paste of HM-HPMC was applied to the skin of rats once daily at dose levels up to 60 mg/kg/day, which was the highest dose that could be administered. Items checked included general signs, urinalysis, hematology, ophthalmology, and histopathology. One rat died during the administration period owing to a malignant tumor in the hemopoietic system, which was not attributed to the test substance. Statistically significant differences were found in some test results, but those were not dose-dependent and were considered to be incidental or spontaneous. It was concluded that the test substance was not toxic upon chronic dermal administration at dose levels up to 60 mg/kg/day.