The activity of the lysosomal enzymes of rat liver after a single intraperitoneal injection of methylmercuric chloride (5.0mg/kg) was enhanced in the nuclear fraction during early post-injection (2hr to 7 days), while it decreased in the mitochondrial fraction and increased in the lysosomal fraction during late post-injection (14 days). Rat brain activity, however, was reduced in the nuclear, mitochondrial and lysosomal fractions during late post-injection (14 days). A high accumulation of total mercury was observed in the liver during early post-injection (36 hr and 7 days) while similar accumulation in the brain occured during late post-injection (7 days and 14 days). Both the mercury burdens and the enzyme activities of the rat liver and brain returned to normal levels within 30 days.
The toxicity of xanthene dyes were studied by various interaction between the dyes and the components in vital body. (1) An increase in the amount of Rose Bengale adsorbed on the gill of fish was followed by the increase in red corpuscle number, and it was assumed that the death of fish in xanthene dye solution was due to anoxemia. (2) Binding capacity of xanthene dyes with bovine serum albumin decreased in the following ; Rose Bengale, Phloxine, Erythrosine, Eosine and Uranine. This order was quite coincident with the toxicity compared by TLm values. (3) From the results of recassay test by use of Bacillus subtilis, it was confirmed that Phloxine and Rose Bengale had DNA-damaging capacity related to the mutagenecity.
2, 4-Dinitrotoluene (2, 4-DNT) was incorporated at the level of 0.5% in a standard commercial diet and fed ad lib. to male rats for 6 months. Significant changes were noted in the body weight, organ weight, behavior, mortality, and biochemical analysis of blood and serum of rats ingesting 2, 4-DNT. Furthermore, it was found that the ingestion of 2, 4-DNT affected on the activities of drug metabolizing enzymes in liver microsomes.
Male and female beagle dogs, aged 17-21 months, were administered orally M 73101 (0, 60, 120 and 240 mg/kg/day), a new analgesic and antiinflammatory drug, for 27 weeks, and following recovery test was carried out for 5 weeks. Dead animals were not found throughout the experimental period. Body weight gain, and food and water consumption were not affected due to M73101 administration. Except for a slight increase of vomitting in the highest dose, there were no abnormal symptoms. Biochemical examination showed the slight increase in serum alkaline phosphatase activity and free cholesterol level. Pathological examination revealed a dose-dependent increase of liver weight and hypertrophy of hepatocytes due to proliferation of smooth endoplasmic reticulum. In addition, mitochondria became irregularly large in the highest dose. There were no abnomal findings in the gastro-intestinal tracts except for an erosion of gastric mucosa, which was noted in a female dog treated 240 mg/kg/day of M 73101. From these results, it was suggested that the maximum non-toxic dose was 60 mg/kg/day or less, and the greatest safety dose was 120 mg/kg/day in beagle dogs.
Chronic toxicity and recovery tests of M73101, a new analgesic and antiinflammatory agent, were carried out using male and female JCL:SD rats. The drug was orally administered in doses of 0, 10, 30, 100, 300 and 1000mg/kg body weight/day for six months. A decrease of spontaneous activity in the group given 1000mg/kg and salivation in the groups given higher doses than 100mg/kg were observed during the administration period. In the 1000mg/kg group, inhibitions of body weight gain and of food efficiency were induced. An increased intake of water and a slight increase in urine volume and in urinary outputs of sodium, potassium and chloride were also observed in the highest dose group. No abnormality was observed in hematological findings in all groups tested. As to the biochemical findings of serum, the high dose groups showed an increase in total cholesterol, free cholesterol and triglyceride in females. Histopathological examination revealed a dose-dependent increase in liver weight and a hypertrophy of hepatocytes due to proliferation of smooth endplasmic reticulum. These changes were more intense in females than in males, suggesting the presence of a sex difference in the effect of M73101. A slight increase in kidney weight was also noted in the male groups given higher doses than 100mg/kg. A swelling and vacuolation of proximal tubular epithelial cells were observed in both sexes, and a single cell degeneration or necrosis was found electron-microscopically in the high dose groups. A change occuring in the gastro-intestinal tracts was ulcer formation due to swelling and subsequent desquemation of mucous epithelial cells. However the ulcer did not develop beyond lamina muscularis mucosae (grade I ulcer or erosion). In the recovery test, the symptoms and pathological changes mentioned above almost disappeared 4 to 8 weeks after the cessation of drug administration, except that a hypertrophy of hepatocytes still remained histologically to some extent in the highest dose groups. It was concluded that the target organs of M73101 were regarded virtually to be the liver, kidneys and gastro-intestinal tracts. The largest non-toxic dose of M73101 was considered to be about 30mg/kg body weight/day in male and female rats. Futhermore, it was suggested that the greatest safety dose was 100mg/kg body weight/day in male and female rats.