The course of the sleeping time response after a single injection of p, p'-DDE was investigated in rats. The concentrations of p, p'-DDE in tissues after the sleeping time respense had returned to the original control level were also determined. Sleeping time response were somewhat dependent on p, p'-DDE dose level. Considerable amounts of p, p'-DDE were found in fat, liver and serum even after sleeping time response had returned to the control level. Using the experimental data, the biological half lives of p, p'-DDE in tissues was estimated. The concentrations of p, p'-DDE in liver, fat and serum just after the sleeping time had returned to the control level were also estimated.
Di-(2-ethylhexyl) phthalate (DEHP) was mixed into diet and given to Wistar male rats for 16 days. A significant and dose-dependent increase in the relative liver weight (RLW) was observed in the rats fed DEHP at dietary levels greater than 0.1%. The RLW increased progressively with the duration of the treatment, reaching its maximun in two weeks. Biochemical analysis of the principal hepatic components has shown that the increase in RLW induced by DEHP was due to an increase in the total amounts of protein, water, lipid, and nucleic acids. The increase in protein was most marked and was due mainly to the increase in non-collagen protein. The total amounts of glycogen and collagen did not change. However, most of these components were found to be unchanged or reduced in their contents per liver weight, except that of protein. The increase in RLW is caused equally by the increase in cell number and in the cell volume, the nuclear DNA content being unaffected. The content of cytochrome P-450 in microsomes increased in the rats of both sex fed a 0.5% DEHP-diet for 16 days. However, the activities per mg of microsomal protein or per g of liver of aminopyrine N-demethylase and aniline hydroxylase decreased in male rats but increased in female rats. Total activities of these enzymes increased markedly in both sex of animals. Glucose 6-phosphatase, acid phosphatase and cytochrome c oxidase were reduced significantly in their activities per liver weight but glucose 6-phosphate dehydrogenase was unchanged. The significance of the liver enlargement induced by DEHP is discussed in relation to the physiological response of liver and to possible pathological changes of liver.
Treatment of animals with a potent hepatotoxin carbon tetrachloride (CCl4) was found to decrease drastically the enzymatic activity of the hepatic microsomal ethanol oxidizing system (MEOS). CCl4 treatment, however, appeared to have no effect on ethanol metabolism in vivo, as estimated from the elimination rate of blood ethanol in rabbits and rats, or from the disappearance rate of ethanol from the whole body in mice. In contrast to the reduced MEOS activity, the cytoplasmic alcohol dehydrogenase (ADH) activity was not influenced by CCl4 treatment. In confirmation of other reports, it is concluded that the elimination rate of ethanol from the blood is not an adequate index for the liver damage and the hepatic microsomes do not play a significant role in ethanol metabolism in vivo.
The electrophysiological basis of pharmacological actions of halothane on canine cardiac fibers was examined to elucidate the mechanism of the induction of the arrhythmia by the combination of anesthetic and epinephrine. The pacemaker activity of the right bundle branch (RBB) was compared with that of the sinus node under the influence of halothane and epinephrine. In the spontaneously active fiber of RBB, halothane (1.3% v/v) caused remarkable increase in the slope of pacemaker potential and in the rate of firing in most preparations. In contrast, halothane produced a profound depression in pacemaker activity of the sinus node in half number of preparations, but the remaining preparations were not affected significantly. The positive chronotropic action of epinephrine was augmented by halothane in RBB preparations, while the enhancement was not observed in atrial preparations. These effects might result in an enhanced liability to arrhythmia.
Histopathological examinations were performed in attempting to explore the mechanisms of the toxic effect of a large amounts of exogenous adenosine 3', 5'-cyclic monophosphate sodium salt in mice previously reported by us : death preceded by ataxia which rapidly developed appearing about 20 hr after the injection of high doses of Na cyclic AMP. Degenerations of tubular epithelium of the kidney could be noticed as early as 1-2 hr after the injection of 330 and 660 mg/kg. When the ataxia progressed, the kidney showed extensive degeneration and necrosis of the tubular epithelium, while changes of the glomerulus were minimal. A remarkable increase in serum urea nitrogen was observed. Serum Ca level was decreased and serum Mg level was increased. Serum cyclic AMP level returned to normal range about 4 hr after the administration. A renal failure was suggested to be the main cause of death, and the ataxia, a typical intoxication symptom, was assumed to be a secondary consequence of this failure. The pathogenesis of the renal degeneration is discussed.
Chronic toxicity of carbamate pesticide (1-Naphthyl-N-methyl carbamate : Sevin) was studied in four wister male rats and the results were compared with four controls treated by saline in the same route of administration. Both treated and controls were feeded and kept under the same environmental condition. The drug was orally administrated (3 mg/rat/week) for one year. Total doses of administration were approximately 750 mg/kg per rat. Histopathological study of endocrinological organs of pancreas, adrenal gland and testis were made. Conventional hematoxylin and eosin staining were made after sacrifice by cervical dislocation at the termination of the administration. In order to quantitate the ratio between the area of Langerhans islets and all pancreatic tissue, histometry by means of a newly developed image-analyzer with built in computer (Imagelyzer) was used. At least, four different cross sections at the tail of pancreas in each animal were examined and they were photorapghed and analyzed. Significant reduction of the area of Langerhans islets to the total area of the tissue was noted in two of four treated animals when compared with the controls. In two out of four treated rats, in adrenal cortex, broadona reticularis with occasional vacuolated cells between zona fasciculata and zona reticularis were the major changes. The reduction in the number of spermatogonia and spermatozoa was noted in seminifercus tubules of the testes of the treated animals. These were not seen in the controls. The results indicated that Sevin involved rat's endocrine organs when chronically treated.