Differential effects of pharmacologic agents on the reverse passive Arthus reaction in guinea pigs.

Five different pharmacologic agents were examined for their effects upon edema, hemorrhage, and vascular infiltration by neutrophils in the reverse passive Arthus reaction (RPAR) in guinea pigs. Two agents, colchicine (3.0 mg/kg p.o.) and ibuprofen (100 mg/kg p.o.) significantly inhibited all three parameters of RPAR. Cobra venom factor (100 units/kg i.p.) inhibited edema and hemorrhage but it did not inhibit neutrophil infiltration. Aminophylline and sulfinpyrazone (100 mg/kg p.o.) inhibited only hemorrhage; they did not inhibit edema or neutrophil infiltration. The results from these studies with five chemically or biologically unrelated pharmacologic agents suggest that the RPAR in guinea pigs can be separated into its basic components (edema, hemorrhage, and neutrophilic infiltration) by selective inhibitors. Inhibition of edema and hemorrhage, or hemorrhage alone of the two-hour RPAR in guinea pigs is not dependent upon inhibition of neutrophilic infiltration.

Comparative nephrotoxicity of hydroxygentamicin and other aminoglycosides in rats.

The nephrotoxicity of hydroxygentamicin and amikacin was examined in young adult Fischer 344 rats. Serum creatinine (SCr) and urea nitrogen (BUN) levels were not significantly affected following sc injection of 80 or 160 mg/kg/day of hydroxygentamicin for 15 days. However, 250 mg/kg of amikacin produced significant increases in both parameters and in kidney/body weight ratios. The ratios were also significantly increased after 80 or 160 mg/kg of hydroxygentamicin, but kidneys of rats receiving amikacin were considerably heavier than those of rats treated with hydroxygentamicin. The antibacterial potency of 250 mg/kg of amikacin is comparable to that of 100 mg/kg of hydroxygentamicin. Additional studies, directly comparing hydroxygentamicin, a mutational biosynthetic, with gentamicin or netilmicin, all at 40, 80, and 160 mg base/kg, and incorporating renal function parameters as well as SCr, BUN, organ weight, tissue concentration, and kidney histopathology, revealed a characteristic pattern typical of aminoglycoside nephrotoxicity in mature adult male rats. In most parameters, values in rats given hydroxygentamicin or netilmicin were normal and comparable to those in controls, but kidney/body weight ratios were significantly increased at high doses. However, kidneys of rats medicated with gentamicin at comparable doses were considerably heavier than those of hydroxygentamicin-treated rats. Significant nephrotoxicity also was seen in rats given low doses of gentamicin or netilmicin. Eosinophilic granulation and vacuolization of renal proximal tubular epithelium, interstitial inflammation, and tubular dilation were observed microscopically with all three drugs in the following descending order of severity: gentamicin greater than netilmicin greater than hydroxygentamicin. The effects on proximal tubular epithelial cells following treatment with amikacin, netilmicin, or hydroxygentamicin correlated reasonably well with renal drug concentrations, but drug concentrations of gentamicin, which produced the most extensive kidney injury, were lower than those of the other three aminoglycosides. Elevated SCr or BUN were indicative of the presence of nephrosis, but early stages of tubular epithelial degeneration were not predicted by increases in BUN or SCr. Although minimal or mild nephrosis was seldom predicted by polyuria, proteinuria, or changes in osmolality, effects observed in renal function parameters usually correlated well with renal histopathology. However, a decrease in osmolality correlated best with enlarged kidneys and changes in renal morphology.

Ameloblastic odontoma in a rat.

A spontaneous ameloblastic odontoma was found in an 86-week-old male Fischer 344 rat. Radiographic and histopathologic characteristics confirmed the diagnosis as a true benign neoplasm.

Non-reversibility of vinyl chloride carcinogenesis in rodents.

A review of the data obtained from various studies on carcinogenicity of vinyl chloride (VC) in rodents, particularly on the effect of dose, age, duration of exposure and potential reversibility of lesions, revealed that vinyl chloride-induced carcinogenicity in rodents was dose and time related; no recovery occurred in mice even after only 1 month of VC exposures or in rats after 6-month exposures. In addition, younger animals (2 months old) were more susceptible to VC-induced carcinogenicity than animals held for 6 or 12 months prior to exposure. Initial 6 or 12 month exposures were adequate to detect the carcinogenic potential of VC. The above information was used as a basis for discussion on design of carcinogenicity studies. Possibility of determining the carcinogenic potential of a compound in a shorter period than the traditional 2 year studies in rodents was discussed in consideration with appropriate doses, species, age and exposure duration. Although this approach may be applicable to a strong carcinogen, it was not considered practicable in case of weak or unknown carcinogens.

Carcinogenicity of vinyl chloride and vinylidene chloride.

Exposure of mice to 50, 250, or 1000 ppmm of vinyl chloride (VC) in the air for 6 h/d, 5 d/wk, caused a high incidence of bronchioloalveolar adenoma, mammary gland tumors, and hemangiosarcoma. Mammary gland tumors occurred in the females and included ductular adenocarcinoma and squamous and anaplastic cell carcinomas with metastasis to the lung. Hemangiosarcoma occurred in the liver and, to a lesser extent, in various other organs. The incidence and severity of these tumors increased with the concentration of VC and the length of exposure. Malignant lymphoma involving various organs was observed in several mice. Rats were more resistant to the carcinogenic effects of VC. Exposure of rats to 250 or 1000 ppm of VC caused hemangiosarcoma in the liver. Many rats with hepatic hemangiosarcoma also developed hemangiosarcoma in the lung. Extrahepatic hemangiosarcoma also occasionally occurred in other organs. Exposure to 55 ppm of vinylidene chloride (VDC) caused hepatic hemangiosarcoma and probably bronchioloalveolar adenoma in mice. Hemangiosarcoma also occurred in the mesenteric lymph node or subcutaneous tissue in two rats exposed to 55 ppm of VDC.

Inhalation toxicity of vinyl chloride and vinylidene chloride.

Exposure of mice to 1000 ppm of vinyl chloride (VC), 6 hr/day, 5 days/week, caused some acute deaths with toxic hepatitis and marked tubular necrosis of the renal cortex. Starting the sixth month, mice exposed to 1000, 250, or 50 ppm of VC became lethargic, lost weight quickly, and died. Only a few mice exposed to 50 ppm survived for 12 months. Pulmonary macrophage count was elevated in some mice. There was a high incidence of bronchiolo-alveolar adenoma, mammary gland tumors including ductular adenocarcinoma, squamous and anaplastic cell carcinomas with metastasis to the lung, and hemangiosarcoma in the liver, and, to a lesser extent, in some other organs. The incidence of these tumors quickly increased, and the severity was in direct proportion to the levels of VC and the length of exposure. Malignant lymphoma involving various organs was observed in a few mice. Rats were more resistant to the toxic effects of VC. Exposure to 1000 ppm slightly depressed the body weight of the females. Exposures of 250 or 1000 ppm caused a number of deaths and hemangiosarcoma in the liver starting the ninth month. Most rats with hepatic hemangiosarcoma also developed hemangiosarcoma in the lung. Hemangiosarcoma occasionally occurred in other tissues of one or two rats exposed to 50 ppm or higher level of VC. Exposure of mice to 55 ppm of vinylidene chloride (VDC) also caused a few acute deaths and a few hepatic hemangiosarcomas. Inflammatory, degenerative, and mitotic changes occurred in the liver. No mouse exposed to VDC developed any mammary gland tumors. Several mice had bronchioloalveolar adenoma. Exposure of rats to 55 ppm of VDC slightly depressed the body weight. Hemangiosarcoma occurred in the mesenteric lymph node or subcutaneous tissue in two rats.