Francis L. Earl

Teratogenic action of carbaryl in beagle dogs

Abstract Carbaryl (1-naphthyl- N -methyl carbamate; Sevin), a reversible cholinesterase-inhibiting insecticide, was incorporated into the feed of pregnant beagle dogs and fed throughout the gestational period at levels of 50, 25, 12.5, 6.25, and 3.125 mg/kg body weight daily. Effects observed included an unexplained number of animals with dystocia (difficult births) due to atonic uterine musculature, an apparent contraceptive effect at the highest dose level, and a teratogenic action of carbaryl seen at all but the lowest dose level. The teratism was seen in 21 of a total of 181 pups born, or 11.6%. The characterization of the fetal abnormalities included abdominalthoracic fissures with varying degrees of intestinal agenesis and displacement, varying degrees of brachygnathia, ecaudate pups, failure of skeletal formation, and superfluous phalanges. Several of the pups exhibited multiple defects that were difficult to categorize. It is concluded that carbaryl produces teratogenic and toxic effects in the pregnant beagle dog.

Acute cardiomyopathy induced by the vasodilating antihypertensive agent minoxidil

Abstract Minoxidil, a vasodilating antihypertensive drug, was given orally in doses of 0.5, 1.0, or 3.0 mg/kg to adult Beagle dogs on 2 consecutive days. Within 2 hr of administration, each of these doses produced hypotension and a marked tachycardia which persisted for as long as 24 hr after the second dose of minoxidil. Necropsies performed 24 hr after the second dose revealed focal, superficial areas of epicardial or endocardial hemorrhage in dogs given each of the three dose levels. Hemorrhage was associated with a mild inflammatory reaction and was not limited to the right atrium. Focal arteritis, characterized by extravasation of blood and by focal accumulation of erythrocytes and fibrin-like material in the walls of small coronary arteries, occurred in three hearts from the 3-mg/kg dose group. Myocardial necrosis was noted in one of eight dogs given the minimal pharmacologic dose of 0.5 mg/kg, and in five of eight dogs in each of the groups given 1 or 3 mg/kg. Necrosis was most frequent in the left ventricular papillary muscles, particularly the posterior one. An ischemic origin of the necrosis is suggested by the localization of the lesions and by the pharmacologic effects of minoxidil.

Endothelial lesions in the aorta of egg yolk-fed miniature swine: A study by scanning and transmission electron microscopy

Abstract Evidence has been accumulating which suggests that atherosclerotic lesions are preceded by endothelial cell damage. Ten miniature swine (FDA, Beltsville, Md.) were maintained on an egg yolk diet (six animals) or on a control diet (four animals) beginning at 5 weeks of age. All animals were sacrificed at 52 weeks of age by intracardiac perfusion of glutaraldehyde. Segments of the aortae were excised and prepared for scanning (SEM) and transmission (TEM) electron microscopy. SEM examination of the aortae of egg yolk-fed animals revealed crater-like defects in the endothelial surface associated with marked cellular deformation and disruption. With TEM there were areas of focal disruption of the luminal plasma membrane and exposure of subendothelial tissues. These alterations were found most commonly on or near the leading or following lip or lateral to branch orifices. Similar endothelial lesions (crater-like defects) have been found in monkey and rabbit arteries following ischemia and in rabbit arteries following cholesterol feeding, epinephrine injection, mechanical trauma, and delayed fixation. It is believed that these alterations are a nonspecific reaction of endothelial cells to injury and may represent the initial morphological abnormality in the pathogenesis of atherosclerosis.

Diazinon toxicity—Comparative studies in dogs and miniature swine☆

Abstract Beagle dogs and Hormel-Hanford swine survived single oral doses of 300 or 500 mg/kg of diazinon. In addition, 4 daily doses of 50 mg/kg/day were tolerated. Dogs survived as long as 15 days and swine up to 30 days at doses of 25 mg/kg/day, although 2 female pigs died after 2 and 3 similar daily doses. In a chronic study, 30 beagle dogs and 30 Hormel-Hanford swine were distributed into 5 groups of 6 animals each. Diazinon, dissolved in corn oil, was given by capsule to the dogs at doses of 0, 2.5, 5.0, 10.0, and 20 mg/kg/day and to the swine at doses of 0, 1.25, 2.5, 5.0, and 10 mg/kg/day for 8 months. Consistent cholinergic signs were observed, primarily in the high-dose groups of both species. No marked changes in hematologic values were noted in these animals when measured at monthly intervals. Among the blood chemistry determinations made, increases with respect to control values were observed in the serum levels of amylase, lactic dehydrogenase, and ornithine carbamyl transferase. These responses were not sex-related. In the dose-range studies, gross pathologic findings included hemorrhages of the heart and congestion or hemorrhage of the gastrointestinal tract, along with marked edematous thickening of the duodenum and jejunum in some animals. In the chronic studies, thickening and occasional rupture of the intestinal wall were observed. In swine, ulcers were found in the duodenum and the livers were firm, gritty, and hard to cut. Histopathologically, slight cirrhotic changes of the liver and hemorrhage of the intestinal tract were seen most frequently. In 2 of the 3 male dogs in the high-dose group, testicular atrophy was observed. Myeloid:erythroid (M/E) ratios in excess of 100 1 were found in dogs which received 20 mg/kg/day of diazinon and died during the first 30 days of the experiment. Three of four pigs receiving 10 mg/kg/day of diazinon died in the same period and had and M/E ratio of 3.4 1 or more. Reticulocytopenia was found in both species, although classical aplasttic anemia was not produced in either species.

The cardiotoxic effects of pressurized aerosol isoproterenol in the dog

Abstract A pressurized aerosol isoproterenol sulfate was administered through a face mask or through an endotracheal tube to conscious beagle dogs. Tachycardia was elicited by both methods of dosing; however, depression of the ST segment of the EKG and arrhythmia was elicited only by the latter technique. Twenty to 80 sprays given endotracheally at the rate of 5 sprays per minute during inhalation on 2 consecutive days caused EKG changes and focal myocardial necrosis of dose-related severity. The left and right ventricular papillary muscles were the primary sites of the lesion. The presence of induced myocardial necrosis or ACTH pretreatment did not sensitize the heart to isoproterenol. Endotracheal dosing with such a product appears to be a suitable route for the detection of adverse cardiac effects in the dog.

Ornithine carbamyl transferase as a liver function test comparative studies in the dog, swine, and man☆

Abstract Selective tissue damage was induced in groups of dogs and swine, either chemically by the nephrotoxic agent uranyl nitrate or the hepatoxic agent carbon tetrachloride, or surgically by biliary duct or coronary artery ligation. Human cases with myocardial infarction, pulmonary edema, myositis, viral and toxic hepatitis were included in this study. The following blood assays were monitored throughout the study: Cell counts, hemoglobin, hematocrit, coagulation tests, blood urea nitrogen, fasting blood sugar, isocitric dehydrogenase, lactic dehydrogenase, alkaline phosphatase, ornithine carbamyl transferase, glutamic oxaloacetic and glutamic pyruvic transaminase. Our data show that ornithine carbamyl transferase became elevated only when the hepatic parenchyma was damaged, and that this elevation became evident just as early and was much higher than that of the other enzymes assayed.

Elevation of serum cholesterol and increased fatty streaking in egg yolk:lard fed castrated miniature pigs.

The effects of feeding an experimental diet containing 16.25% (w/w) dry powdered egg yolk and 30.8% total fat (20% from lard) were compared with an isocaloric amount of control (stock) diet in castrated (N = 11 each) and sham-operated (N = 8 each) male miniature pigs of Hormel origin. Piglets were castrated at 2 weeks of age. The experimental diet was fed from 9 weeks of age and serum lipids (cholesterol and triglycerides) and plasma testosterone were determined at 5-week intervals up to 52 weeks of age. At 52 weeks of age, the animals were sacrificed and the aortas evaluated for fatty streaking after Sudan IV staining. Castration was accompanied by significantly (P <= 0.02) elevated serum cholesterol (castrated 84 ± 4 mgm/dl vs. sham, 67 ± 5 mgm/dl; mean ± SEM) within 5 weeks after feeding the stock diet and throughout the duration of the expriment. Except for the initial cholesterol concentration (castrated, 118 mgm/dl vs. sham, 88 mgm/dl), both castrated and sham-operated animals on egg yolk had significantly higher (P <= 0.05) serum cholesterol than their littermate controls. At 52 weeks of age, the serum cholesterol of sham-operated and castrated animals on experimental diet were 152 ± 29 and 292 ± 41 mgm/dl as compared with 68 ± 5 and 96 ± 4 mgm/dl for their littermates on stock diet respectively. No correlation was found between the concentrations of plasma testosterone and serum cholesterol. Consistent with the elevation of serum cholesterol, the castrated animals on egg yolk diet had significantly greater area of the aorta covered with fatty streaking than did the sham-operated group. These data show that castration and feeding of egg yolk: lard diet resulted in hypercholesterolemia and increased fatty streaking.

Cardiotoxicity studies with diazoxide, reserpine, guanethidine, and combinations of diazoxide and propranolol in dogs

Abstract Diazoxide, a vasodilating antihypertensive drug, caused tachycardia when given to dogs as iv doses of 10–40 mg/kg. Doses of 20–40 mg/kg, given on 2 or 3 consecutive days, caused myocardial necroses similar to that produced by hydralazine. The papillary muscles were the primary sites of the lesion. The lesion is considered to be of ischemic origin, brought about by the exaggerated pharmacological effects. Reserpine and guanethidine, given orally in sublethal doses for 2 or 3 days, did not cause such a lesion. Propranolol, given orally in doses of 3 mg/kg two or three times daily concurrently with diazoxide, decreased the cardiotoxic effect of diazoxide but did not diminish the hypotensive effect.

The toxicity of brominated sesame oil and brominated soybean oil in miniature swine

Miniature swine were fed brominated sesame oil at dietary levels of 0, 5, 25, 50 or 500 mg/kg of body weight for 17 weeks and brominated soybean oil at levels of 0, 5, 50 or 500 mg/kg of body weight for 28 weeks. Growth rate and food intake were decreased only at the high dose level in the brominated sesame oil study. In both studies, signs of lethargy and ataxia occurred in pigs fed the highest dose, and were probably due to a dose-related increase in serum bromine concentrations. Marked elevations in lactic dehydrogenase (LDH), serum glutamic-oxalacetic transaminase (SGOT) and serum glutamicpyruvic transaminase (SGPT) values were seen at the highest dose level with both substances and these enzyme activities were increased at the 50 mg/kg dose level in the brominated sesame oil study. Histopathologic lesions were confined to animals given the highest dose level of either oil. Marked fatty degeneration of the hepatic plate cells and renal tubular epithelial cells were seen in both studies. In the brominated sesame oil study, neutral fat was moderately increased in the myocardium of the pigs fed 500 mg/kg. However, marked diffuse accumulation of LDH, marked diffuse fatty degeneration and focal degeneration, and/or necrosis of individual or small groups of cardiac muscle fibers were seen in the group fed brominated soybean oil at 500 mg/kg. A moderate to marked testicular atrophy was also observed in this group. A dose-related accumulation of total and hexane-soluble bromine was observed in all tissues examined in both studies; the highest concentrations occurred in adipose tissue of the pigs given the highest dose level. Kidneys, livers, hearts and thyroids of these groups also contained large amounts of bromine. In pigs given the 50 mg/kg dose level, total and hexane-soluble bromine concentrations were higher in the brominated sesame oil study than in the longer brominated soybean oil study and may be responsible for the elevations in LDH, SGPT and SGOT activities in this group.

The effect of lindane and phenobarbital on microsomal enzyme induction in dogs and miniature swine.

Abstract The enzymic activities of 9000g supernatant fractions obtained from the livers of normal beagle dogs and miniature swine and of dogs and swine treated with lindane and phenobarbital are presented. No significant sex differences in activities were noted in control dogs. Preparations from dogs of both sexes fed lindane at 7.5 and 15.0 mg/kg exhibited a significant loss in codeine demethylase activity while nitroreductase activity was increased twofold. Phenobarbital pretreatment of dogs and swine stimulated all microsomal systems tested. Addition of lindane to the diet of these induced dogs caused a significant and rapid decline in the values after only two feedings. Enzymes induced to a greater extent in dogs by phenobarbital were inhibited to a greater extent by lindane; i.e., as a class, demethylases were affected by both lindane and phenobarbital to a greater extent than aromatic hydroxylases. In contrast, administration of lindane to phenobarbitaltreated swine caused an actual further increase in demethylase activities. A decrease in the induced state was observed in aromatic hydroxylation, azo-reduction, and nitro-reduction reactions, although the activities of these enzymes were still higher than the values from control swine.