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Biomedical subjects

M R Elwell

Publications and source records attributed to M R Elwell.

15 recordsLinked to original sources
PubMed1992

Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water.

Barium Chloride dihydrate (BaCl2.2H2O) was given for 92 days to B6C3F1 mice and Fischer 344/N rats in their drinking water at levels of 0, 125, 500, 1000, 2000, and 4000 ppm. The no-effect level for this study was 2000 ppm BaCl2.2H2O in the drinking water. At 4000 ppm, daily consumption for mice was 436 to 562 mg/kg barium, up to four times more chemical than rats. Mortality ranged from 60 to 70% in mice and from 10 to 30% in rats in the 4000 ppm groups. Deaths in mice were associated with a treatment-related renal toxicity. Renal lesions in rats were much less severe than in mice and did not contribute to the treatment-related deaths seen in the high dose group. Body weights of both species and sexes in the 4000 ppm groups were lower than controls at 92 days. Male and female rats in treated groups exhibited higher serum phosphorus than controls. Serum sodium, potassium, and calcium levels in rats were unchanged by barium treatment, as were hematological values. In both species at 4000 ppm, motor activity, grip strength, and thermal sensitivity were marginally affected. These effects were probably secondary changes resulting from BaCl2 toxicity observed at this dose level. In a mating trial, no anatomical effects on offspring of rats or mice were seen. Rats receiving 4000 ppm exhibited marginal reductions in pup weights. No effects were seen on reproductive indices.

Animals↗
PubMed1992

Application of molecular encapsulation for toxicology studies: comparative toxicity of p-Chloro-alpha, alpha, alpha-trifluorotoluene in alpha-cyclodextrin vehicle versus corn oil vehicle in male and female Fischer 344 rats and B6C3F1 mice.

The application of alpha-cyclodextrin (alpha-CD) as an alternative vehicle for water insoluble and volatile chemicals was investigated in toxicity studies of p-chloro-alpha, alpha, alpha-trifluorotoluene (CTFT). Groups of F344 rats and B6C3F1 mice of each sex were administered CTFT (97% pure) by gavage in either corn oil or alpha-CD aqueous formulations daily for 14 consecutive days. The dose levels used were 10 (mice only), 50, 400, and 1000 mg/kg for corn oil vehicle and 10, 50, and 400 mg/kg (maximum achievable dose at gavage volume of 5 ml/kg) for alpha-CD vehicle. With both vehicles CTFT and alpha 2u-globulin were found to accumulate in the male rat kidney after 14 days of exposure and a dose-related toxic nephropathy was observed at dose of 50 mg/kg or higher. The hepatocellular hypertrophy and cytoplasmic vacuolation of the adrenal cortex which appeared in dosed male and female rats were also found to be independent of vehicle. Clinical pathology findings suggested a mild anemia and cholestasis in rats. With both vehicles no tissue bioaccumulation of CTFT was found in male or female mice. Vehicle-independent hepatocellular hypertrophy and cholestasis were also observed in mice at doses of 400 and 1000 mg/kg. In conclusion, the alpha-CD vehicle does not affect the toxic responses of CTFT in both sexes of both species. The results of the studies suggest that alpha-CD may be an appropriate alternative vehicle for toxicity studies.

Alpha-Globulins↗
PubMed1992

Subchronic (13-week) toxicity studies of oral phenolphthalein in Fischer 344 rats and B6C3F1 mice.

Phenolphthalein is a cathartic agent that is widely used in over-the-counter laxatives. Thirteen-week toxicity studies of phenolphthalein were performed using F344/N rats and B6C3F1 mice. Rats and mice were fed ad libitum with a NIH 07 diet containing 0; 3000; 6000; 12,000; 25,000; or 50,000 ppm phenolphthalein. On a milligram per kilogram body weight basis, rats and mice fed 50,000 ppm phenolphthalein ingested more drug than would be expected during human laxative abuse. Phenolphthalein produced little evidence of toxicity in rats. There was slightly lower weight gain among the 25,000 and 50,000 ppm groups. Treated rats showed elevated relative kidney weights (males only) and elevated absolute and relative liver weights at 12,000-50,000 ppm phenolphthalein. Rat serum bile acids were depressed early (Days 5 and 6) by phenolphthalein treatment. Several treatment-related toxic effects, however, were identified in mice who received more phenolphthalein per unit body weight than rats. Although there were no effects on body weight gain, elevated liver weights were noted in female mice receiving 6000-50,000 ppm phenolphthalein. The primary treatment-related findings that occurred during the mouse studies involved the reproductive and hematopoietic systems. Reproductive changes including depressed testis and right epididymal weights and sperm density, an elevated production of abnormal sperm, and morphologic alterations in seminiferous tubules occurred at all levels of exposure (3000-50,000 ppm). Hematopoietic changes included bone marrow hypoplasia (12,000-50,000 ppm), increased splenic hematopoiesis (males only; 25,000 and 50,000 ppm), and an elevated incidence of micronucleated erythrocytes (6000-50,000 ppm).

Animals↗
PubMed1991

Evidence that toxic injury is not always associated with induction of chemical carcinogenesis.

Long-term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty-one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty-two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity. Although cellular proliferation does play an intrinsic role in neoplastic processes, the responses associated with chronic toxicity in these studies were not always sufficient to induce neoplasia. Regardless of their mutagenic potential, 19 carcinogens induced toxic effects at sites that did not show neoplastic changes; similar toxic lesions were also seen among the mutagenic and nonmutagenic noncarcinogens. Although many nonmutagens induced neoplasia at sites that showed toxic effects, some of the same chemicals also exhibited toxicity at other sites that showed no neoplastic effect. These results suggest that for some chemicals, properties other than mutagenicity or toxicity may be responsible for their carcinogenic potential.

Animals↗
PubMed1991

Carcinogenicity of p-chloroaniline in rats and mice.

p-Chloroaniline (PCA), a dye intermediate, was evaluated for potential long-term toxicity and carcinogenicity. Groups of 50 F344/N rats of each sex were given by gavage PCA hydrochloride in deionized water at doses of 0, 2, 6 or 18 mg/kg body weight, 5 days/wk for 103 wk. Groups of 50 male and female B6C3F1 mice of each sex were given 0, 3, 10 or 30 mg/kg on the same schedule. In general, body weights and survival were unaffected by PCA administration. In rats the group given 18 mg/kg had mild haemolytic anaemia and slight increases in methaemoglobin at various times during the study. Fibrosis of the spleen was significantly increased in all PCA-treated groups of male rats and in the 18-mg/kg group of female rats. Sarcomas of the spleen occurred in male rats, their incidence being 0/49, 1/50, 3/50 and 38/50 in control low-, mid- and high-dose groups, respectively. There was a slightly increased incidence of pheochromocytomas of the adrenal gland in both male and female rats. Dosed groups of male mice had increased incidences of hepatocellular adenomas or carcinomas (11/50, 21/49, 20/50 and 21/50 in controls, low- mid- and high-dose groups, respectively). Haemangiosarcomas of the liver or spleen were also increased in the high-dose group (incidences of 4/50, 4/49, 1/50 and 10/50 in controls, low-, mid- and high-dose groups, respectively). In conclusion, PCA was carcinogenic in male rats and male mice.

Adenoma↗
PubMed1991

Comparative toxicity and tissue distribution of antimony potassium tartrate in rats and mice dosed by drinking water or intraperitoneal injection.

Antimony potassium tartrate (APT) is a complex salt that until recently was used worldwide as an antischistosomal drug. Treatment was efficacious only if APT was administered intravenously to humans at a near lethal total dose of 36 mg/kg. Because unconfirmed epidemiologic studies suggested there might be an association between APT treatment and bladder cancer, we initiated prechronic toxicity studies with the drug to select a route of administration and doses in the event that chronic studies of APT were needed. The toxicity and concentration of tissue antimony levels were compared in 14-d studies with F344 rats and B6C3F1 mice administered APT in the drinking water or by ip injection to determine the most appropriate route for longer term studies. Drinking water doses estimated by water consumption were 0, 16, 28, 59, 94 and 168 mg/kg in rats and 0, 59, 98, 174, 273, and 407 mg/kg in mice. APT was poorly absorbed and relatively nontoxic orally, whereas ip administration of the drug caused mortality, body weight decrements, and lesions in the liver and kidney at doses about one order of magnitude below those in drinking water. Because of these data and the dose-related accumulation of antimony in the target organs, an ip dose regimen was selected for subsequent studies. Both sexes of F344 rats and B6C3F1 mice were given 0, 1.5, 3, 6, 12, and 24 mg/kg doses of APT every other day for 90 d by ip injection. There were no clinical signs of toxicity nor gross or microscopic lesions in mice that could be attributed to toxicity of APT, although elevated concentrations of antimony were detected in the liver and spleen of mice. Rats were more sensitive than mice to the toxic effects of APT, exhibiting dose-related mortality, body weight decrements, and hepatotoxicity. The concentrations of antimony measured in liver, blood, kidney, spleen, and heart of rats were proportional to dose, but there were no biochemical changes indicative of toxicity except in the liver. Hepatocellular degeneration and necrosis occurred in association with dose-related elevations in activities of the liver-specific serum enzymes sorbitol dehydrogenase and alanine aminotransferase. By alternating the site of abdominal injection and the days of treatment, mesenteric inflammation at the site of administration was minimized in the rats and mice, indicating that the ip route would be suitable for chronic studies.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1978

Virulence alterations of tacaribe virus infection in adult mice: lethal model for encephalitis.

Selection of population of Tacaribe virus strain 11573 lethal for mice was carried out by serial intracerebral passage of the virus in adult mice. Viral populations have been characterized by determination of virulence for suckling, weanling, and adult mice, and by histopathologic changes observed in brains of adult mice after intracerebral inoculation. Some of the virus preparations produced 80 to 90 per cent mortality after two or three intracerebral passages in adult mice and maintained this virulence for 1 to 3 passages, after which the virulence rapidly declined with subsequent passages. Clinical signs of infection in adult mice were manifested by a rough hair-coat, ventriflexed posture, diminished activity, increased excitability, flaccid hind-limb extension with progressive paralysis and death. Histologic examination revealed meningoencephalitis.

Age Factors↗
PubMed1977

Possible endotoxemia in rabbits after intravenous injection of Staphylococcus aureus enterotoxin B.

Staphylococcus aureus enterotoxin B (SEB) administered intravenously may exert its toxicity by damaging capillary endothelium in the large intestine and, thereby, permit absorption of endotoxin into the circulation. To investigate this possibility, we measured an index of the level of plasma endotoxin. This index was the ability of plasma to cause gelation of limulus amebocyte lysate (GLAL), before and after intravenous administration of SEB (800-1,000 microng/kg of body weight) to 13 rabbits. All samples taken before administration of SEB were negative for GLAL, but GLAL activity was detectable in the plasma of 10 of the rabbits 12 hr after SEB was injected. Only rabbits that developed GLAL activity died; the levels of GLAL in plasma were comparable to those detected by other workers after administration of an intravenous, lethal dose of endotoxin to rabbits.

Animals↗
PubMed1977

Pathogenesis of respiratory Klebsiella pneumoniae infection in rats: bacteriological and histological findings and metabolic alterations.

Gram-negative bacterial pneumonias have been increasingly important as nosocomial infections. The following model was developed to study the pathogenesis and evaluate therapy of such infections. Intranasal instillation of rats with a suspension of 5 x 10(6) Klebsiella pneumoniae caused bronchopneumonia with 24 h. Bacteria were isolated from the lungs in large numbers (greater than 10(5) colony-forming units [CFU] for at least 13 days after inoculation. Thereafter, the viable concentration decreased to about 10(3) CFU at 21 days but increased to 10(4) CFU at 25 days. Mortality rarely exceeded 25%. Plasma zinc concentration decreased, and plasma seromucoid, lysozyme, and alpha2-macrofetoprotein increased during respiratory K. pneumoniae infection in rats. There seemed to be a linear relationship between seromucoid concentration and the concentration of K. pneumoniae in the lung expressed in log10 units. Plasma zinc, alpha2-macrofetoprtoein, or lysozyme levels, however, did not change until the concentration of bacteria retrieved fron lungs exceeded 4 to 5 logs, Analysis of blood samples obtained serially from the orbital sinuses revealed that rats that succumbed to infection had significantly higher levels of seromucoid, alpha2-macrofetoprotein, and lysozyme and lower levels of plasma zinc than infected rats that survived. Progressive increases in seromucoid and particularly in lysozyme and alpha2-macrofetoprotein appeared to be predicative of death. It is postulated that the threshold effect observed for alpha2-macrofetoprotein and lysozyme reflect significant damage to lung tissue, and thus these two variables are good indexes of the severity of this infection. We propose that this model may be of value in elucidating the pathogenesis of respiratory K. pneumoniae as well as in assessing various models of therapy.

Animals↗
PubMed1977

Fibrosarcoma in a white-tailed deer.

A large, rapidly growing subcutaneous fibrosarcoma was observed on the head of an aged male white-tailed deer (Odocoileus virginianus) from Frederick County, Maryland. Although there was no evidence of distant metastasis, the large neoplastic mass had extensively invaded the osseous supraorbital process, and had several small satellite nodules nearby.

Animals↗
PubMed1976

Oral fructose tolerance, gastric emptying and absorption: a compartmental model.

Gastric emptying and intestinal absorption regulate transfer of ingested fructose from stomach to plasma. Using conscious rhesus monkeys we have developed a compartmental model which describes this system. Fructose tolerance tests were performed in groups of monkeys by intragastrically administering 2 g/kg of 10.5% D-fructose solution; fructose concentration in arterial plasma, [fructose], and intragastric volume were measured at intervals afterward. One group was pretreated with atropine; stomachs imptied with a time constant, tau, of 67 min. Another group received fructose solution with trisodium citrate added; tau was 18 min. Another group received only fructose; tau was 30 min. Using these constants, a model was developed to describe the [fructose] data. In this model k1 related amount of fructose in intestine to absorption rate and Ae represented absorption efficiency. K1 = 0.03 and Ae = 89% provided a good fit for data from the atropinized group. k1 = 0.018 and Ae = 56% provided a good fit for data from the other groups. Differences were explained by considering effects of atropine on gastrointestinal secretion. The model adequately describes our [fructose] data and may be adapted for tests utilizing other substances.

Animals↗
PubMed1975

Changes in blood pH in rats after infection with Streptococcus pneumoniae.

Acid-base alterations in Streptococcus pneumoniae infection were studied in 80 male albino rats. Hematocrit and concentrations of plasma electrolytes, glucose, and total protein were also measured. At 3-h intervals throughout a 27-h study, four control and four infected rats were anesthetized with ether, and blood samples were taken. Arterial blood pH, Po2, and hematocrit increased in the infected group, whereas arterial Pco2, HCO3-, and venous Po2 decreased. Plasma K+ concentration increased slightly and glucose levels decreased in the infected rats as the sepsis progressed. No significant changes were observed in venous blood pH, HCO3-, and Pco2. Plasma Na+, Cl-, and total protein remained unchanged. The increase in arterial blood pH and decrease in arterial Pco2 and HCO3- indicated respiratory alkalosis, which was present in rats infected with S. pneumoniae.

Acid-Base Equilibrium↗
PubMed1975

Mechanisms of oral staphylococcal enterotoxin B-induced emesis in the monkey (38553).

Vomition is the most consistent response to oral SEB challenge in the monkey. The technique of cross-circulation clearly differentiates local neural phenomenon from humoral mechanisms. Our results support the theory that SED-induced vomition follows stimulation of local neural receptors in the gut. The evidence indicates no significant amount of enterotoxin absorption or stimulation of vomition by any centrally acting humoral mechanism.

Administration, Oral↗