Toxicity studies of intravenously administered BCG in baboons

Summary The toxicity of fresh preparations of BCG administered intravenously as single or weekly repeated doses of 1 g, 100 mg, 10 mg, and 1 mg, was studied in 9 adult baboons. Clinical, biochemical, histologic, and bacteriologic examinations were performed. Tissues for histopathologic and bacteriologic examinations were obtained by laparotomy and biopsy, or by autopsy. Four and 5 months after the first injection, the surviving animals were killed purposely for examination. With high doses of BCG (2 g, 1 g, 500 mg) the severe toxicity with death of 2 animals was demonstrated. Diffuse cellular infiltrations of macrophages and lymphocytes in the liver, spleen, lungs, and lymph nodes, with formation of early, typical granulomas and great numbers of cultivable units of BCG were found in these animals. With small doses of BCG, general granulomatous reactions occurred in all organs sampled. Four months after BCG injection, granulomas had regressed, but viable organisms persisted in the lymph nodes. Future investigations may prove feasible the possibility of immunotherapy with small doses of BCG administered intravenously, since live bacilli persist for months after injections, presumably creating the chronic BCGitis necessary for effective immunotherapy. Reprint requests should be addressed to: Institut de Cancérologie et d'Immunogénétique (INSERM)     

Magnetic resonance of a dextran-coated magnetic fluid intravenously administered in mice

Magnetic resonance was used to investigate the kinetic disposition of magnetite nanoparticles (9.4 nm core diameter) from the blood circulation after intravenous injection of magnetite-based dextran-coated magnetic fluid in female Swiss mice. In the first 60 min the time-decay of the nanoparticle concentration in the blood circulation follows the one-exponential (one-compartment) model with a half-life of (6.9 +/- 0.7) min. The X-band spectra show a broad single line at g approximately 2, typical of nanomagnetic particles suspended in a nonmagnetic matrix. The resonance field shifts toward higher values as the particle concentration reduces, following two distinct regimes. At the higher concentration regime (above 10(14) cm(-3)) the particle-particle interaction responds for the nonlinear behavior, while at the lower concentration regime (below 10(14) cm(-3)) the particle-particle interaction is ruled out and the system recovers the linearity due to the demagnetizing field effect alone.     

The distribution in mice of intravenously administered labelled Candida albicans.

The time dependence of the distribution of intravenously injected radiolabelled Candida albicans in the body of mice was studied. The Candida cells were labelled by cultivating them 7 days at 28 degrees C in a medium containing one of the following radionuclides: 46Sc, 95Nb, 59Fe, 144ce, 89Sr, 60Co, 65Zn, 54Mn, 45Ca, 51Cr and 91Y, which are listed in decreasing order in respect to amount bound. The labelled cells were killed by heating them 120 min at 60 degrees C, without loss of immunologic properties. Owing to the amount and strength of binding, 144Ce labelled Candida, together with 14C labelled cells was used in animal kinetic study. A rapid disappearance of the labelled cells from blood, interrupted by a small peak, was paralleled by a transient uptake in lungs and followed by a long lasting accumulation in the liver. The kidneys and spleen revealed only small uptakes of the labelled material.     

Distribution and histologic effects of intravenously administered amorphous nanosilica particles in the testes of mice

Amorphous nanosilica particles (nSP) are being utilized in an increasing number of applications such as medicine, cosmetics, and foods. The reduction of the particle size to the nanoscale not only provides benefits to diverse scientific fields but also poses potential risks. Several reports have described the in vivo and in vitro toxicity of nSP, but few studies have examined their effects on the male reproductive system. The aim of this study was to evaluate the testicular distribution and histologic effects of systemically administered nSP. Mice were injected intravenously with nSP with diameters of 70 nm (nSP70) or conventional microsilica particles with diameters of 300 nm (nSP300) on two consecutive days. The intratesticular distribution of these particles 24h after the second injection was analyzed by transmission electron microscopy. nSP70 were detected within sertoli cells and spermatocytes, including in the nuclei of spermatocytes. No nSP300 were observed in the testis. Next, mice were injected intravenously with 0.4 or 0.8 mg nSP70 every other day for a total of four administrations. Testes were harvested 48 h and 1 week after the last injection and stained with hematoxylin-eosin for histologic analysis. Histologic findings in the testes of nSP70-treated mice did not differ from those of control mice. Taken together, our results suggest that nSP70 can penetrate the blood-testis barrier and the nuclear membranes of spermatocytes without producing apparent testicular injury.     

Toxicity of ultrasound in mice: Neonatal studies

Summary Pregnant mice were exposed to ultrasound (continuous wave, 2 MHz) on Day 8 of gestation to determine effects on the progeny. The most significant finding was a decrease in mean uterine weight of the female progeny. The thresholds for this effect were 140 s at 0.5 W/cm² and 60 s at 1 W/cm², which were below the thresholds previously reported for other effects in mice. We suggest that this indicates a delay or impairment of maturation of the mice exposed in utero.Exposure of the dams to spatial average intensity of 1 W/cm² for 40 and 60 s had no effect on body weight of the progeny, compared with sham-treated controls. In this experiment the body weights of progeny from sham-treated controls were significantly lower than those from untreated controls on Days 10, 17, and 25 of age. After exposure in utero to 0.5 W/cm² for 180 s, statistically significant decreases in mean body weights of the neonates were observed, but only on Day 25 of age, in both sexes compared with sham-treated controls. At necropsy at Day 25 of age, neonatal organ weights relative to body weights were not significantly affected for the thymus in either sex or for the seminal vesicles and testes in comparison with sham-treated controls.