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Biomedical subjects

P W Mellick

Publications and source records attributed to P W Mellick.

At least 19 recordsLinked to original sources
PubMed2002

Mutagenicity and carcinogenicity in relation to DNA adduct formation in rats fed leucomalachite green.

Leucomalachite green is a persistent and prevalent metabolite of malachite green, a triphenylmethane dye that has been used widely as an antifungal agent in the fish industry. Concern over the use of malachite green is due to the potential for consumer exposure, evidence suggestive of tumor promotion in rodent liver, and suspicion of carcinogenicity based on structure-activity relationships. Our previous study indicated that feeding rodents malachite or leucomalachite green resulted in a dose-related increase in liver DNA adducts, and that, in general, exposure to leucomalachite green caused an increase in the number and severity of changes greater than was observed following exposure to malachite green. To characterize better the genotoxicity of leucomalachite green, female Big Blue rats were fed leucomalachite green at doses of 0, 9, 27, 91, 272, or 543 ppm for up to 32 weeks. The livers were analyzed for lacI mutations at 4, 16, and 32 weeks and DNA adducts at 4 weeks. Using a 32P-postlabeling assay, we observed a dose-related DNA adduct in the livers of rats fed 91, 272, and 543 ppm leucomalachite green. A approximately 3-fold increase in lacI mutant frequency was found in the livers of rats fed 543 ppm leucomalachite green for 16 weeks, but significant increases in mutant frequencies were not found for any of the other doses or time points assayed. We also conducted 2-year tumorigenesis bioassays in female and male F344 rats using 0, 91, 272, and 543 ppm leucomalachite green. Preliminary results indicate an increasing dose trend in lung adenomas in male rats treated with leucomalachite green, but no increase in the incidence of liver tumors in either sex of rat. These results suggest that the DNA adduct formed in the livers of rats fed leucomalachite green has little mutagenic or carcinogenic consequence.

Adenoma↗
PubMed1999

Inhalation toxicity and carcinogenicity studies of cobalt sulfate.

Cobalt sulfate is a water-soluble cobalt salt with a variety of industrial and agricultural uses. Several cobalt compounds have induced sarcomas at injection sites in animals, and reports have suggested that exposure to cobalt-containing materials may cause lung cancer in humans. The present studies were done because no adequate rodent carcinogenicity studies had been performed with a soluble cobalt salt using a route relevant to occupational exposures. Groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate hexahydrate, 6 h/day, 5 days/week, for 104 weeks. Survival and body weights of exposed rats and mice were generally unaffected by the exposures. In rats, proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were observed in the lung in all exposed groups. Nonneoplastic lesions of the nose and larynx were also attributed to exposure to all concentrations of cobalt sulfate. In 3.0 mg/m3 male rats and in female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were increased over those in the control groups. Lung tumors occurred with significant positive trends in both sexes. The incidences of adrenal pheochromocytoma in 1.0 mg/m3 male rats and in 3.0 mg/m3 female rats were increased. Nonneoplastic lesions of the respiratory tract were less severe in mice than in rats. In mice, alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were greater than those in the controls, and lung tumors occurred with significantly positive trends. Male mice had liver lesions consistent with a Helicobacter hepaticus infection. Incidences of liver hemangiosarcomas were increased in exposed groups of male mice; however, because of the infection, no conclusion could be reached concerning an association between liver hemangiosarcomas and cobalt sulfate. In summary, exposure to cobalt sulfate by inhalation resulted in increased incidence of alveolar/bronchiolar neoplasms and a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tracts of male and female rats and mice. Adrenal pheochromocytomas were increased in female rats, and possibly in male rats.

Administration, Inhalation↗
PubMed1996

Subchronic toxicity evaluation of lewisite in rats.

Health and exposure criteria have not been established for lewisite [dichloro(2-chlorovinyl)arsine], a potent toxic vesicant that reacts with the sulfhydryl groups of proteins through its arsenic group. Sixty Sprague-Dawley rats of each sex, 6-7 wk old, were divided into 6 groups (10/group/sex) and gavaged with either 0, 0.01, 0.1, 0.5, 1.0, or 2.0 mg/kg of lewisite in sesame oil 5 d/wk for 13 wk. No significant dose-related change in body weight was observed. At the high dose, serum protein, creatinine, SGOT, and SGPT were decreased in males; lymphocytes and platelets were increased in females. A treatment-related lesion was detected in the forestomach of both sexes at 2.0 mg/kg. These lesions were characterized by necrosis of the stratified squamous epithelium accompanied by infiltration of neutrophils and macrophages, proliferation of neocapillaries, hemorrhage, edema, and fibroblast proliferation. Mild acute inflammation of the glandular stomach was also observed in some cases at 1.0 and 2.0 mg/kg. Early deaths were attributed to severe inflammation of the upper and/or lower respiratory tract, possibly from deposition or reflux of test material into the pharynx. Estimated dose range for NOEL appears to be >0.5 and <1.0 mg/kg when administered orally.

Animals↗
PubMed1995

Bronchiolarized metaplasia and interstitial fibrosis in rat lungs chronically exposed to high ambient levels of ozone.

The cellular and tissue changes in the lungs of rats were studied using electron microscopy following 20 months exposure to a range of ozone levels from 0.12 to 1.0 ppm. Male and female Fischer 344 rats were exposed and morphometric methods were used to determine the volume, surface area, and cellular changes observed in bronchiole-alveolar duct regions following chronic ozone exposure. No major gender-related effects were observed in response to chronic inhalation of ozone nor were significant effects of ozone exposure found in either terminal bronchioles or the proximal alveolar regions in animals chronically exposed to 0.12 ppm ozone. The proximal alveolar regions of animals exposed for 20 months to 0.5 and 1.0 ppm ozone were significantly altered with exposure. The high-dose, long-term exposure to ozone resulted in a pronounced increase in volume of both the interstitium and epithelium in the proximal alveolar regions. The thickening of the epithelium was due to a change in tissue type from the normal squamous epithelium to a cuboidal epithelium similar, but not identical, to that found in terminal bronchioles. This bronchiolar epithelial metaplasia of proximal alveolar ducts, which was dose related, was composed of differentiated ciliated and Clara cells similar to those found in terminal bronchioles. In addition, unique cells which contained morphologic features of many different cell types were observed. These cells, which may represent stem cells or differentiated but transformed cells, were found associated with the bronchiolar metaplasia of alveolar ducts. In conjunction with the epithelial changes, cellular and matrix components in the interstitium were increased with chronic exposure to 0.5 and 1.0 ppm ozone. All matrix components were increased including collagen, elastin, and basement membrane, as well as other acellular spaces which did not contain identifiable structures. The total volume of interstitial fibroblasts was also increased in the high-dose exposure group. Alveolar macrophages were increased only in the 1.0 ppm exposed animals. The cell and tissue changes in the terminal bronchioles were less pronounced indicating a relative resistance of this tissue to ozone and mainly consisted of a change in cell type from ciliated to Clara cells in the 1.0 ppm exposed animals. The relative resistance of bronchiolar tissue to high concentration ozone exposure and the extensive bronchiolar epithelial metaplasia may be an adaptive mechanism following chronic ozone exposure.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Histopathology and cell replication responses in the respiratory tract of rats and mice exposed by inhalation to glutaraldehyde for up to 13 weeks.

In addition to being a respiratory tract irritant and cross-linking agent, glutaraldehyde has a number of properties in common with the rodent nasal carcinogen, formaldehyde. The acute and subchronic responses to glutaraldehyde in the respiratory tract of rats and mice were characterized using histopathology and epithelial cell labeling index as end points. Male and female F344 rats and B6C3F1 mice were whole-body exposed for 1 day, 4 days, 6 weeks, or 13 weeks to 0, 62.5, 125, 250, 500, or 1000 ppb glutaraldehyde using a recycling inhalation chamber. The respiratory tract, with special reference to the nose, was examined by light microscopy and histoautoradiography. Unit length labeling index (ULLI) was determined by nuclear thymidine labeling for selected sites, chosen on the basis of histopathology. A small number of animals exposed to 1000 ppb (rats and mice) or 500 ppb (mice) died before the 6-week time point; these deaths were attributed to glutaraldehyde exposure-associated occlusion of the external nares. Treatment-induced lesions, including epithelial erosions, inflammation, and squamous metaplasia, were confined to the anterior third of the nose and were present in both sexes and species. No histopathological evidence of glutaraldehyde-induced responses was observed in the trachea, central airways, or lungs, while the larynx showed minimal changes. There were clear increases in ULLI in association with acute and subacute cytotoxic responses, with similar concentration-response relationships. Neutrophilic infiltration of the squamous epithelium of the nasal vestibule, present in both rats and mice, became progressively more severe with increasing exposure time and was associated with increased ULLI. The latter responses were generally most severe at the higher glutaraldehyde exposure concentrations, while in female mice they were present at all concentrations of glutaraldehyde studied. Lesions induced by glutaraldehyde were more anterior in the nose than those reported for formaldehyde, they differed in character, and no evidence of "pre-neoplastic" lesions or karyomegaly, reported for formaldehyde, was observed with glutaraldehyde.

Administration, Inhalation↗
PubMed1993

Differentiated bronchiolar epithelium in alveolar ducts of rats exposed to ozone for 20 months.

The effects of exposure to 1.0 ppm of ozone for twenty months were studied in male Fischer 344 rats. Light microscopic, morphometric, and immunohistological approaches were used to determine the distribution and degree of differentiation of ciliated and nonciliated bronchiolar epithelial (Clara) cells lining alveolar ducts of the central acinus, a primary target of ozone-induced lung injury. Alveolar duct pathways extending beyond the level of the most proximal alveolar outpocketing of terminal bronchioles were isolated in longitudinal profile. The distance that ciliated and nonciliated bronchiolar epithelial (Clara) cells projected down each alveolar duct pathway was determined by placing concentric arcs radiating outward from a single reference point at the level of the first alveolar outpocketing. A high degree of heterogeneity in the magnitude of bronchiolar epithelial cell extension into alveolar ducts was noted for each isolation and animal. Age-matched control animals also demonstrated variation in the degree of bronchiolar epithelial cell extension down alveolar ducts. In animals exposed to ozone, a striking similarity was noted by scanning electron microscopy in the surface characteristics of cells lining both terminal bronchioles and alveolar ducts. The presence of Clara cell secretory protein in cells of bronchioles and alveolar ducts was also detected immunohistochemically and visualized using confocal laser scanning microscopy in the reflectance mode. Well-differentiated ciliated and nonciliated bronchiolar epithelial cells were found lining alveolar septal tips and alveoli up to a depth of 1,000 mu into the pulmonary acinus after 20 months of exposure to ozone. No evidence of inflammation was present in alveolar ducts, suggesting that epithelial cell transformations in alveolar ducts is a natural consequence of lifetime exposures to oxidant gases.

Animals↗
PubMed1992

Histologic methods and interspecies variations in the laryngeal histology of F344/N rats and B6C3F1 mice.

The relatively high incidence and variety of lesions induced in the upper respiratory tract of rodents by inhalation of xenobiotics has resulted in considerable attention given to the microscopic anatomy of this area. Specific areas of the rodent laryngeal mucosa appear to be more sensitive to inhaled materials and more likely to contain cellular changes in response to injury. These include the epithelium covering the base of the epiglottis, ventral pouch, and the medial surfaces of the vocal processes of the arytenoid cartilages. There are few good landmarks for trimming rodent larynges to get consistent and accurate sections through these target areas. We have obtained consistently reproducible results by cutting transversely through the easily palpable cricothyroid notch and embedding the entire larynx anterior to this in paraffin with the cut surface against the face of the block. Multiple sections are cut from the caudal larynx toward the epiglottis, unstained sections examined microscopically for orientation, and sections from target areas selected for staining and histopathologic examination. Routine use of these methods for preparation and microscopic examination of sections of the larynx has revealed some variations in normal laryngeal anatomy between Fischer 344 (F344/N) rats and B6C3F1 mice.

Aging↗
PubMed1988

Antigenic variation of wild and vaccine rabies strains of Egypt.

Nineteen street rabies virus strains, isolated in Egypt from humans (two), dogs (nine), cats (two), farm animals (two), gerbils (three), and a jackal were antigenically analyzed. The Pasteur strain used for the preparation of human rabies vaccine, the Flury high and low egg passage stains (HEP, LEP) used for animal vaccines, and the challenge virus standard (CVS) strain were also assayed. All were examined by the indirect fluorescent antibody test, using a panel of 20 monoclonal antibodies against the nucleocapsid of rabies and rabies-related viruses. The rabies isolates demonstrated patterns of reactivity with the antinucleocapsid panel different from those of the Pasteur, HEP, and CVS strains. Representative human, dog, and rodent isolates were analyzed by neutralization tests in mice, with a second panel of 19 monoclonal antibodies against rabies and Mokola envelope glycoproteins. With this panel, the isolates demonstrated patterns of reactivity different from the vaccine strains. These data indicate antigenic variation between wild virus and vaccine strains.

Animals↗
PubMed1982

Perfused rat hindlimb wound model: lambda-carrageenan induced.

We established an isolated perfused rat hindlimb wound model using intramuscular injections of lambda-carrageenan. Wound and control hindlimbs of 24-h fasting anesthetized (phenobarbital sodium, 5 mg/100 g body wt) rats were perfused for 60 min (10 ml/min) with media containing 10 mM glucose and physiological levels of amino acids. Analysis of perfusate showed a significant increase in glucose clearance and lactate production from the wounded hindlimb but no significant difference in tissue adenine nucleotide levels. Alterations in net amino acid release were measured over a 60-min period; all amino acids were released in greater concentration from wounded hindlimbs. Comparison of amino acid release, normalized for phenylalanine concentration, suggested the following alterations in amino acid metabolism by the wounded tissue: depressed threonine, glycine serine and alanine release, and increased release of the branched chain amino acids (BCAA), leucine, isoleucine, and valine. The increased release and intracellular concentration of BCAA was supported by decreased BCAA transaminase activity in the wounded muscle tissue. This result may explain the decreased alanine release from the wounded hindlimbs.

Adenine Nucleotides↗
PubMed1981

Influence of dietary iron deficiency on hemoglobin, myoglobin, their respective reductases, and skeletal muscle mitochondrial respiration.

Male weanling rats were fed a control diet (46 ppm iron) or an iron-deficient diet (11 ppm iron) for 7 wk to determine the influence of iron deficiency on heme proteins and skeletal muscle mitochondrial respiration. At the end of 7 wk, the hemoglobin in the blood of the iron deficient rats was 35% less and skeletal muscle myoglobin was 20 to 37% less than in the control animals. The concentration of myoglobin in the heart was not appreciably diminished by iron deficiency. Cytochrome c concentration was 20% less in the heart and 35% less in the mixed-fiber gastrocnemius in the iron-deficient animals. Iron deficiency did not influence the activity of metmyoglobin reductase in either heart or skeletal muscle. There was about 30% more methemoglobin reductase activity in the red blood cells of the iron-deficient animals, which resulted in methemoglobin levels that were so low as to be virtually unmeasurable. In the iron-deficient rats, skeletal muscle mitochondrial respiration with either pyruvate-malate or palmitylcarnitine as substrate was 17 to 20% less than in the control animals. This study demonstrates that dietary iron deficiency of sufficient severity to reduce blood Hb and skeletal muscle myoglobin or cytochrome c also results in an impaired skeletal muscle oxidative capacity. The study also illustrates the preferential utilization of iron, not only between tissues, but within tissues, and tissue specific adaptive responses to iron deficiency.

Animals↗
PubMed1980

Massive exchange transfusions with crystalline hemoglobin solution and subsequent replacement of hemoglobin and blood volume.

Crystalline hemoglobin solution was used to exchange transfuse rats to 75 per cent blood replacement. At three hour intervals after transfusion, the rats received bolus injections of hemoglobin solution to replace plasma hemoglobin and intravascular volume lost during each time interval. At 12 and 24 hours after termination of exchange transfusion, the livers of five of six rats exhibited normal hepatic structure. One rat had centrilobular hepatic neurosis similar to that reported for rats given a single transfusion. Plasma hemoglobin, packed cell volume, plasma oncotic pressure and oxygen-carrying capacity of the intravascular fluid were monitored; the data demonstrate that changes observed in these parameters are rectified by the bolus injection which brought their values to the levels observed after transfusion. No hepatic lesions or other abnormalities were observed in the rats in the control group exchange transfused isovolemically with pooled rat blood or subjected to surgical procedures only. Serial bolus injections of hemoglobin solution, by rapidly restoring blood volume and hemoglobin concentration, appear to prevent the hepatic necrosis observed in rats a few hours after a single transfusion, as reported in previous studies.

Animals↗
PubMed1977

Short term morphologic effects of high ambient levels of ozone on lungs of rhesus monkeys.

Groups of laboratory-reared, young adult rhesus monkeys were exposed to 0.8 p.p.m. or 0.5 p.p.m. of ozone for 8 hours a day on 7 consecutive days. Lesions were studied using correlated techniques which permitted examination of specified levels of airways and adjacent lung parenchyma by light microscopy, scanning electron microscopy, and transmission electron microscopy. Lesions were observed in the trachea and lungs of all exposed animals. The extent and severity of damage, but not its nature, varied with exposure concentration. Damage was most severe in respiratory bronchioles and more distal parenchymal regions were unaffected. Major features of the response within respiratory bronchioles were hyperplasia and hypertrophy of nonciliated bronchiolar epithelial cells and intraluminal accumulations of macrophages. Replacement of type 1 epithelium in alveoli by type 2 cells and forms intermediate between types 1 and 2 were also observed. In large conducting airways, damage to ciliated cells was observed but mlcus-producing cells were morphologically unaltered. Two gradients in severity of ozone-induced lesions were appreciable in the trachea and lungs. The most obvious gradient was in respiratory bronchioles where the degree of damage was most severe in proximal locations. A second gradient in severity was noted in conducting airways in which more severe and extensive lesions occurred in the trachea and major bronchi than in small bronchi and terminal bronchioles.

Air Pollutants↗