The effect of D-galactosamine (GalN) on the blood clearance of 99mTc-phytate (99mTc-P) in dogs was examined, and the blood clearance test of 99mTc-P was compared with the cases of the serum transaminase and bilirubin test. Serum transaminase and bilirubin levels in dogs increased dose-dependantly after GalN administration, and the degree of increase in these parameters was much higher than the cases in rats. The disappearance rate of 99mTc-p from blood in dogs decreased with the increase in dose of GalN and with the passage of time after the GalN administration. Changes of the blood clearance of 99mTc-P after GalN treatment in dogs may be influenced by the disorder in the hepatocytes. The blood clearance test of 99mTc-P in dogs showed a sensitive reaction for the acute hepatic dysfunction induced by GalN equally to the serum transaminase and bilirubin test.
(-)15-Deoxyspergualin (DSP), a bacterial metabolite obtained from Bacillus laterosporus, was shown to effectively suppress autoantibody production in mice and alloimmune reaction in mice and rats. Its potential toxicity and safety margin in BALB/c mice were studied by administering the drug, 0.5-5.0 mg/kg body weight, s. c., 6 days/week for 3 months. The animals were weighed every two weeks, and their blood was drawn for hematological and liver function studies. Control animals showed a gradual increace in body weight from 17.8±1.1 g (SD) to 20.2±3.2 g during the 3 months of treatment. The body weight of 0.5 mg- and 2.5 mg-DSP group was not significantly different from that of the control group. In contrast, 5.0 mg-DSP group of animals showed significant decrease in their weight compared with the control after 5 weeks of treatment (P<0.01). They were then sacrificed. WBC in 0.5 mg-, 2.5 mg- and 5.0 mg-DSP groups were significantly lower compared with the control after 3 months of treatment. On the other hand, only 5.0 mg-DSP group showed significantly lower level in their RBC, Hb and Hct values (P<0.05). In contrast, platelet counts in 2.5 mg- and 5.0 mg-DSP groups significantly increased. No manifest effect due to DSP on differential count of leukocytes was observed, although on day 92, a significant difference was shown in the stab cells of the 0.5 mg-DSP group and in the eosinophils in the 2.5 mg-DSP. SGOT level following 5.0 mg-DSP treatment for 5 weeks was significantly elevated compared with the pre-treatment level (P<0.05). The present study shows that the safety limit of long-term treatment with DSP may be 2.5 mg/kg body weight or less and that DSP preferentially affects lymphoid organs, although higher dose of DSP may also be toxic to the bone marrow system.
Following the preceding report on hematological aspects in subacute toxicity of (-)15-deoxyspergualin (DSP), the present report dealt with the histopathological changes produced by DSP, 0.5-5.0 mg/kg, given to BALB/c mice for three months. At sacrifice, various internal organs such as heart, lungs, liver, spleen and kidneys, were taken, and their wet weights immediately measured. HE- or PAS-stained sections were histopathologically studied under light microscope. Additionally, frozen sections of the spleen were prepared to evaluate the effect of DSP on the lymphocyte surface markers like thy 1 and B220 by avidin-biotin complex (ABC) technique. Although the mean weights of lungs, liver, spleen and kidneys in the 0.5 mg- and 2.5 mg-DSP groups were not significantly different from those in the control animals, the weights of the heart, lungs, liver and spleen in the 5 mg-DSP group were significantly lower. Histopathological studies by light microscopy revealed no abnormalities in the heart, lungs, liver or kidneys taken from the mice given 0.5-5.0 mg/kg DSP. In contrast, significant changes were observed in the spleen and bone marrow of the 5.0 mg group of mice. Likewise, in the intestine of the 0.5-5.0 mg groups dose-dependent lesions, such as degeneration or disappearance of the mucosal epithelium, infiltration by inflammatory cells, and pseudo-membrane formation, was observed. By ABC technique, preferential decrease of B cells was seen in the splenic corpuscles of the DSP-treated mice. Histopathological changes due to DSP predominantly seen in the lymphoid and/or hematopoietic organs may be directly related to the immunosuppressive potency inherent to this drug. On the other hand, direct toxicolgical effect of DSP up to 5.0 mg/kg may not necessarily be of major significance, considering the normal histology in the heart, lungs, liver or kidneys.
Nephrotoxicity of some aromatic nitro-amino compounds were evaluated by urinary enzyme activities and renal histopathological changes. Male Fischer 344 rats were intraperitoneally injected with aniline, p-aminophenol, acetyl-p-aminophenol, p-chloroaniline, p-chloronitrobenzene, p-anisidine, or p-nitroaniline at 1.0 mmol/kg. In the rats injected with p-aminophenol, necrosis of renal tubular epithelial cells and remarkable elevation of urinary N-acetyl-β-D-glucosaminidase (NAG) and γ-glutamyltranspeptidase (γ-GTP) activities were observed. Injection with p-chloroaniline caused significant elevation of the urinary NAG and γ-GTP activities. p-Anisidine and p-nitroaniline induced swelling of the tubular epithelial cells and a significant elevation in urinary NAG activities in rats, which was also caused by p-chloronitrobenzene. However, administration of aniline or acetyl-p-aminophenol did not change either the urinary enzymes or renal histopathology. These results indicate that p-aminophenol is a highly nephrotoxic substance, and that nephrotoxicity of p-chloroaniline, p-chloronitrobenzene, p-anisidine and p-nitroaniline exceed that of acetyl-p-aminophenol which has been known to cause a renal damage.
Allergic cutaneous responses were induced by intradermal injection of penicillin G (PCG) and PCG-bovine serum albumin (BSA) conjugates onto the back of guinea pig actively immunized with PCG potassium (25 mg/animal) incorporated in Freund's complete adjuvant. The PCG-induced response was characterized macroscopically by erythema and edema with a maximum level at 24 hrs after elicitation and microscopically by the infiltration with basophils, macrophages and lymphocytes following with neutrophils. In addition, intensity of macrophage-infiltration shared a similar time course change with those of erythema and edema. These suggest that this response is associated to a delayed type hypersensitivity of Jones-Mote type. On the other hand, in the PCG-BSA-induced response the edema with erythema at the early phase was a noticeable observation and this response disappeared within 12 hrs, although the erythema continued by 24 hrs. Microscopically, the degranulation of mast cells and severe infiltration with neutrophils in the early phase and the infiltration of eosinophils in the late phase accompanying the infiltration with monocytes, basophils and lymphocytes were characteristic findings, which suggest that PCG-BSA response is a similar hypersensitivity to an atopic dermatitis. As mentioned above, we confirmed two types of allergic cutaneous responses in the guinea pig immunized with PCG.
Three groups of rats were exposed by inhalation to either clean air (control group) or styrene monomer at 25 and 50 ppm (styrene-exposed groups) for 7 h/day, 6 day/week, from 1 to 48 days of age. Compared to control group, Styrene-exposed groups showed significant delay in the following developmental indices : body weight gain, appearance of pinna detachment and incisor eruption. With respect to open-field activity, the styrene groups indicated longer latency to enter the field, less number of squares crossed and fewer rearings than those of controls. In the avoidance behavior aspect, the styrene groups attained less achievement level in avoidance rates than that of the control group. Dose-related trends were found between the two exposed groups in body weight increment, exploratory and avoidance behavior. Sex differences were seen on these factors also. These results suggest that at postnatal exposure of low-levels to styrene affects behavior and development in rats.