Nulliparous female mice were injected subcutaneously with CrCl3 9 times every other day from the 0 day to the 16th day of gestation and the placental transfer of Cr and its effects on fetal growth were examined (Experiment I). In addition, pregnant mice were given a single intraperitoneal injection of CrCl3 on the 7th, 8th or 9th day of gestation to examine teratogenic potentials of Cr (Experiment II-1). Furthermore, in order to examine a possible dose-response relationship, pregnant mice were injected with 4 dose levels on the 8th day of gestation (Experiment II-2). In these experiments the mothers were killed on the 18th day of gestation and their uteri were examined for implantation and resorption sites; each fetus was weighed and examined for both external and skeletal anomalies. Concentration of Cr in fetal tissues was negligible and trace. A significant decrease of weight gain was observed among fetuses in Exp. I. In case of group injected on the 8th day (Exp. II-1), external malformations were obseved at the highest rate. In Exp. II-2, together with a significant decrease of weight gain, notable increase in the incidence of both external and skeletal anomalies occurred also and among them the incidences of exencephalies (including acephalies) and rib fusions were the most frequent. The positive dose-response relationship between amounts of CrCl3 injected to pregnant mice and the incidences of both external and skeletal anomalies was demonstrated. It is concluded that trivalent chromium has apparent teratogenic effects and inhibits growth in mice.
Acute toxicity of Na-adenosine 3', 5'-cyclic monophosphate (Na-cAMP) was studied in mice. LD50 values (in g/kg) in males (m.) and females (f.) by three routes were as follows : p. o. : m. 14.3, f. 15.2 ; i. p. : m. 1.14, f. 0.395 ; i. v. : m. 1.57, f. 0.645. After a depression following the Na-cAMP administration (i. p. and i.v.) wore off, a delayed, progressive severe ataxia (just like a curare-induced ataxia) was noted 10-30 hr after the administration especially in females. If the ataxia once appeared, animals died in 2-3 hr without exception, seemingly from respiratory paralysis. The females given with highest doses and most of males died earlier in an extreme depression. In the ataxic animals, the twitch tension development of the hind limb induced by sciatic nerve stimulationin in situ was strongly suppressed as compared with that induced by direct stimulation. On the basis of the results and also of those of some electrophysiological studies in vitro, it is suggested that some disturbance of the motor nerve terminals may be a main cause of the ataxia. The question whether this ataxia is the primary toxic effect of cAMP or a secondary effect is now under investigation.
When the Japanese encephalitis (JE) virus infected mice were given methyl mercuric chloride (MMC) intraperitoneally, the mercury retention was increased in the blood and tissues of the JE mice compared to the control mice. However, the rate of mercury excretion was nearly the same in the both. In spite of the increased mercury concentrations in the liver of the JE mice, the total amount of mercury in the liver was about the same as the control mice, because of the reduced organ weight. Mercury content was actually increased only in the brain of the JE mice. In mice surviving after the JE virus infection, the rate of increase of mercury concentration in tissues was nearly proportional to the rate of maximum body weight loss. The consumption, due to the JE virus infection was presumed to be the major cause for the increased mercury retention.
The results of toxicity studies on sulbenicillin (SB-PC) in rats, dogs and monkeys as well as distribution and excretion patterns in these animals and humans were reviewed and, taking into account the results of its clinical trials in 6376 patients, the following conclusion was obtained. 1. There was marked species difference in excretion and distribution of SB-PC. In dogs, unlike other animals including humans, excretion of SB-PC into bile was larger than that into urine, and its distribution in the liver at an extraordinarily high concentration was observed. When SB-PC was intravenously injected to dogs at various dosages, transient but dose-related hepatotoxic signs appeared, and a few animals died at 1500 mg/kg/day. 2. There were no abnormalities in rats treated intramuscularly with 2500 mg/kg/day of SB-PC for 6 months except for a local irritation at the injection site. The excretion pattern of SB-PC in cynomolgus monkeys was quite similar to that in humans, and they tolerated daily intravenous injections at 1500 mg/kg/day for one month well. None of the animals showed any significant changes in hematological, biochemical and histological examinations. 3. In clinical trials of SB-PC, intravenous infusion at 30 g (15 gx 2)/day/man did not affect the normal function of the liver and kidneys in the patients. The above results were compared with those reported for carbenicillin (CB-PC) and it was indicated that SB-PC is less toxic than CB-PC in humans.