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The gelatin-starch syrup microencapsulation method was applied to subacute toxicity studies of tribromomethane (TBM), dibromochloromethane (DBCM) and bromodichloromethane (BDCM). Groups of Wistar rats (7 males and 7 females) both sexes were given diet containing microcapsules of each of these trihalomethanes (THMs) at the following concentrations: TBM, 0.068, 0.204 and 0.612% in males, and 0.072, 0.217 and 0.651% in females; DBCM, 0.020, 0.062 and 0.185% in males, and 0.038, 0.113 and 0.338% in females; BDCM, 0.024, 0.072 and 0.215% in males, and 0.024, 0.076 and 0.227% in females. Suppression of body weight gain was seen in each high-dose males fed TBM or BDCM and females fed DBCM or BDCM. Histopathologically, hepatic lesions such as vacuolization and swelling of liver cells were significantly noted in both sexes of all groups fed TBM, in both sexes of the middle- and high-dose groups fed DBCM, and in males of the high-dose group and in females of the middle- and high-dose groups fed BDCM. In addition, single cell necroses were observed in males and females fed DBCM and in males fed BDCM. Hepatic cord abnormalities were also noted in males of the high-dose group fed BDCM. Although no increases in serum transaminase activities (ASAT, ALAT) were evident in either sex fed any of the THMs, decreases in triglyceride content, cholinesterase and lactate dehydrogenase activity were observed. Renal lesions reported to occur in gavage studies were not found in the present feeding study. Lowest-observed-adverse-effect-level (LOAEL) of TBM and no-observed-adverse-effect-level (NOAEL) of DBCM and BDCM were determined to be 56.4 mg/kg, 18.3 mg/kg and 20.6 mg/kg, respectively, under the present experimental conditions.

A chronic feeding study was carried out in Wistar rats using microencapsulated bromodichloromethane. The test substance was administered in the diet at doses of 0, 0.014, 0.055 and 0.22% for 24 months. Rats were sacrificed after 6, 12, 18 and 24 months of continuous dosing. The results showed a suppression of body weight gain in the 0.22% group for both males and females. Dose related changes were clearly observed in the liver with histopathological findings including fatty degeneration in the 0.014% or higher dose male groups, and fatty degeneration and granuloma in the 0.055 and 0.22% group females, as well as bile duct proliferation and cholangiofibrosis in the 0.22% group for both males and females. No significant differences in incidences or numbers of neoplastic changes were seen between control and any of the treatment groups. There were no dose-related non-neoplastic lesions in the kidneys of either sex. Lowest-observed-adverse-effect-level was determined to be 6.1 mg/kg/day under the present experimental conditions.

Acute oral toxicity test of glutaraldehyde (GA) was carried out in young (5-6W) and old (57-60W) Wistar/ST rats. Experiment 1: Various doses of GA were administered by gavage. After 30 minutes, the rats showed abnormal gait, then took an abdominal or lateral position after 4 hours. Gross erosion, discoloration and thickening of the glandular stomach mucosa and hyperemia of the liver, intestine and lung were observed in the dead rats. The LD50 values were 283 mg/kg for young rats and 141 mg/kg for old rats. Experiment 2: One half of the LD50 doses (140 mg/kg and 70 mg/kg of GA) were administered to young and old rats by gavage, respectively. Both groups showed a similar toxicity. Organ weights were not changed. In gross findings, erosion, discoloration and thickening of the glandular stomach mucosa were observed on day 1-7, but these damages were recovered by day 14. Histopathologically, atrophy, degeneration, necrosis, hemorrhage, edema and cell infiltration of the glandular stomach mucosa were found on day 1. Recovery from these changes was observed from day 3. Changes in several serum enzyme activities were observed on day 1-3. Therefore, susceptibility to the acute toxic effect of GA was higher in old rats than in young rats. However, no apparent differences were observed in the toxic profiles by GA between young and old rats.

Tris(2-chloroethyl)phosphate (TCEP), a widely used flame retardant, was tested for its skin chronic toxicity/carcinogenicity using female Slc: ddY mice. TCEP (5 and 50%) dissolved in ethanol was applied to the shaved skin twice a week for 79 weeks. The control group received ethanol under similar condition. In addition, 5 animals in each group were killed at 6 and 12 months and used for the chronic toxicity study. In body weight, food consumption and survival rate, there was no significant difference between the control and treated groups. Spleen weight was decreased in the 50% group. No significant difference in the incidence of tumors and other non-neoplastic lesions of the skin and other organs was found between the control and treated groups. The results indicate that under the conditions of the present study, TCEP has no carcinogenicity and toxicity for the skin.

The effects of changes in distal resistance on stenotic resistance were studied in vitro. Physiological saline was passed through the left carotid artery obtained from the dog, flexible rubber tubing, or through solid polyethylene tubing with a constant perfusion pressure or with a constant flow rate. Various stenotic resistances were established using a screw type constrictor and the distal resistance was varied by allowing physiological saline to pass through either a 23 gauge hypodermic needle (high peripheral resistance) or 23 and 20 gauge needles (low peripheral resistance ). For arteries with anatomically fixed stenosis, the calculated resistance was increased in association with reduction of the distal resistance. The stenotic resistance in the flexible rubber tubing changed in the same manner as that of the carotid artery, while the solid polyethylene tubing showed no significant stenotic resistance changes due to altering the distal resistance. These findings suggest that the stenotic resistance change of the artery correlates with the elasticity of the vessel wall and also indicate that resistance values were of little usefulness for evaluating the effects of vasodilating stimuli on the vessel segment with a significant stenosis.

The effects of intravenous infusion of isoproterenol on stenosis resistance were studied in the anesthetized open-chest dog. The circumflex coronary artery (LCx) was isolated near its origin and an electromagnetic flow transducer was placed around the vessel for measuring coronary flow. A polyethylene catheter was inserted into the small branch of LCx for monitoring distal coronary pressure. LCx was constricted with a thick cotton string to a degree of obstruction that eliminated reactive hyperemia following a 20-second coronary occlusion. The coronary resistance across the stenotic segment (RL) was calculated as the pressure gradient across the stenosis divided by coronary flow. Isoproterenol was infused intravenously in a dose to keep the heart rate at a level 25-30% above the control with and without coronary constriction. For maintaining the ascending aortic pressure at the pre-isoproterenol level, the descending thoracic aorta was constricted with a tape. In the absence of coronary constriction, the vascular resistance of large coronary arteries was not affected by isoproterenol with a significant increase in coronary flow. In the presence of coronary stenosis, isoproterenol markedly increased RI regardless of additional aortic constriction. The magnitude of the increase in RL during aortic constriction varied directly with the percent increase in the pressure gradient across the coronary stenosis. Pacing-tachycardia essentially did not affect RL. These results suggest that isoproterenol increased the vascular resistance of the stenotic segment with fixed caliber.

Doppler ultrasound detection of the blood flow associated with liver tumours was studied in primary hepatocellular carcinoma as well as in metastatic liver cancer and haemangioma. Doppler signals were detected from 48 of 55 hepatocellular carcinomas (87.3%), seven of 25 metastatic liver cancers (28.0%) and four of 30 haemangiomas (13.3%). The waveforms of Doppler signals were divided into two types: the pulsatile wave, which was detected from hepatocellular carcinoma (in 35 of the 48 with Doppler signals) and metastatic liver cancer (in all seven with positive signals), and the continuous wave, which was seen from hepatocellular carcinoma (41 out of 48) and haemangioma (in all four with signals). In six patients with hepatocellular carcinoma who underwent transcatheter arterial embolization, the pulsatile wave detected before therapy disappeared immediately thereafter and it is possible that this type of wave originates from tumour vessels. In the study of small, hypoechoic, mass lesions appearing in liver cirrhosis, such signals were also demonstrated, even in eight of 10 small hepatocellular carcinomas less than 2 cm in diameter, whilst they were not detected from nine regenerative nodules related to cirrhotic change. In conclusion, the Doppler ultrasound method may be a useful technique in detecting blood flow within liver tumours and may offer the possibility of a differential diagnosis of small tumours.

In the open-chest dog constriction of the descending thoracic aorta, which raises central aortic pressure by 30-80 mmHg, increases cardiac oxygen usage (MVO2) and coronary blood flow (CBF) but reduces heart rate and myocardial oxygen extraction [(A-V)O2]. Pacing tachycardia superimposed on aortic constriction further increases MVO2 and CBF but does not alter (A-V)O2. Atropine or vagotomy abolishes the effect of aortic constriction on (A-V)O2, whereas vagal stimulation in the presence of alpha- and beta-adrenergic blockade reduces (A-V)O2. L-propranolol and phenoxybenzamine fail to modify the effect of aortic constriction on (A-V)O2. These results indicate that aortic constriction reduces (A-V)O2 by eliciting parasympathetically-mediated coronary vasodilation.

Automatic blood cell analyzer "MICROX" was examined for possible applicability to the differential count of white blood cell in the rabbit, rat and mouse. Spun blood smear slides prepared from 37 rabbits were treated with Wright-Giemsa stain, and those from 49 rats and 46 mice were stained with Wright's dye. Totals of 4272 white blood cells of rabbit, 5484 cells of rat and 5329 cells of mouse were counted, respectively. The identification rate of MICROX was checked by the cell-by-cell counting method. Analysis of the data was made to examine correlation between the results with a MICROX and those of visual counting by optical microscopy on the same slides. 1) Corrected identification rates were 98.0%, 98.2% and 97.8% respectively in rabbits, rats and mice. 2) A high degree of correlation was observed between the results by MICROX and by optical microscopy in respect of segmented neutrophils and lymphocytes. 3) There were an average of 13.2 cells counted as unknown cells in rabbit blood, 10.5 in rat blood and 13.6 in mouse blood per 100 cells, respectively. Of the unknown cells about 30 to 40% were closely disposed leukocytes within the same counting squares. Almost all of atypical lymphocytes and erythroblasts were also counted as unknown cells on the analyzer. The data support the feasibility of the use of MICROX for the differential count of white blood cells of normal rabbits, rats and mice as well as monkeys and dogs.

Comparative effects of heart rate and aortic blood pressure on myocardial oxygen consumption (MVO2) were studied in anesthetized open-chest dogs. The left coronary artery was perfused through the external shunt with blood from the left common carotid artery. Heart rate was changed with the left atrial pacing and the constriction of the descending thoracic aorta was utilized to elevate the proximal aortic blood pressure (BP). The left ventricular enddiastolic pressure was insignificantly changed with the atrial pacing and with the aortic constriction. With the constant BP (100 +/- 5 mmHg), and unit increase in heart rate per minute augmented MVO2 by 0.027 ml/min/100 Gm of left ventricular muscle, while one mmHg elevation of BP caused 0.15 ml increment in MVO2 per minute per 100 Gm of left ventricular muscle under the constant heart rate (115 +/- 5 beats/min). Therefore an unit change in BP caused five- to six-fold greater increase in MVO2 compared with that in heart rate, indicating extremely important roles of BP in MVO2.

Effects of coronary constriction on the flow reserve of regional myocardium were studied in the anesthetized open-chest dogs. Regional myocardial blood flow (RMBF) was continuously measured using heated crossthermocouple method. Left circumflex coronary artery (LCX) was constricted gradually with a screw type constrictor. The coronary constriction decreased subendocardial myocardial blood flow, while subepicardial myocardial blood flow was not affected until reactive hyperemia in LCX nearly disappeared. Recovery and arrival to peak flow rate of RMBF following the release of 15-second's occlusion of LCX were progressively delayed with an increase in the constriction, especially in the subendocardial myocardium. Repayment of flow debt, however, was remained relatively well since the duration of reactive hyperemia in RMBF was prolonged by an increment of the constriction. From these findings, it might be concluded that in the heart with coronary stenosis recovery from ischemia was caused by prolonged duration of reactive hyperemia, and is suggested that the time required for recovery from ischemia or ischemic abnormalities after the cessation of stress might be an important marker for the severity of coronary insufficiency.

Changes in the stenotic resistance of a coronary artery following brief coronary occlusion were studied in the anesthetized open-chest dog. A critical coronary stenosis was constructed by tying a thick string around the circumflex coronary artery (LCx) near its origin. The LCx was occluded for 5, 10, 15, 20 and 30 seconds with and without coronary stenosis then the reactive hyperemia was observed. In the absence of the stenosis, resistance of the segment of the large coronary artery remained unchanged during the reactive hyperemia independent of the duration of occlusion. In the presence of the stenosis, however, stenotic resistance increased for a certain time after the release of occlusion. This increased resistance lasted longer with more severe stenosis and with longer duration of coronary occlusion. These results suggest that stenotic resistance can increase dynamically, and that the duration of increased resistance may reflect the severity of the stenosis.

A comparison of blood flow and myocardial O2 consumption (MVO2) in the right and left ventricles was made in 21 open-chest dogs. Simultaneous measurements were made of left anterior descending (LAD) and right coronary arterial blood flow and of O2 saturation in the coronary sinus and in from one to four anterior cardiac veins. Blood flow was greater in the LAD than in the right coronary artery, 87 +/- 5 vs. 46 +/- 3 ml.min-1.100 g-1. Similarly, the O2 saturation was 51 +/- 3% in the anterior cardiac veins and 40 +/- 1% in the coronary sinus. In a subset of seven dogs, the O2 saturation in blood from anterior cardiac veins varied substantially from vein to vein. The mean MVO2 was greater for the left than for the right ventricle, 8.6 +/- 1.4 vs. 4.0 +/- 0.3 ml O2.min-1,100 g-1. Increases in LAD flow with no increase in O2 extraction accounted for enhanced MVO2 of the left ventricle due to pacing, isoproterenol, or methoxamine. In contrast, pacing, isoproterenol, or constriction of the pulmonary artery increased MVO2 of the right ventricle by both augmented O2 extraction and a rise in right coronary blood flow. We conclude that right coronary arterial blood flow is lower per 100 g tissue and is less dependent on MVO2 than is LAD blood flow. The heterogeneity of O2 saturation in anterior cardiac veins suggests that regional differences in MVO2 may exist.

Spontaneous hyperglycemia, glycosuria, hypoinsulinemia, and glucose intolerance were observed in some WBN/Kob rats, at about 9 months of age, and in all at the age of 17 months. Females did not present this pathology. Histopathologic examination of the pancreas revealed severe changes in male rats at the age of 3 months. Between 3 and 6 months of age a distinct infiltration of inflammatory cells was found around islets and among adjacent acinar cells. At the same time, marked fibrosis was seen around the pancreatic ducts and blood vessels. With advancing age the fibrous tissue gradually invaded extensive areas of the pancreas where also the islets became involved in fibrotic degeneration. At 17 months of age and later, an obvious decrease in islet number and size (less than 50 mu in diameter) was observed, even in relatively unaffected areas of the organ. Frequent bilateral cataracts began to appear at about 15 months of age. Opacities were first observed in the periphery of the lens, then increased rapidly in intensity and extended centripetally. Nineteen-month-old male rats were hypersensitive to exogenous insulin, but showed no significant decrease in blood glucose level when treated with oral tolbutamide. These results suggest that these rats suffered from a decreased insulinogenic response.