摘要:

Abstract2‐ethyl‐1‐hexanol (2‐EH) was nominated for carcinogenicity testing by the National Toxicology Program because it is a high‐volume chemical and a major metabolite of di(2‐ethylhexyl)phthalate, a known hepatocarcinogen and a known contaminant in blood storage bags. In addition to uses as an intermediate in the manufacture of plasticizers, 2‐EH is also used as a solvent, a lubricant and as a finishing compound for paper and textiles. The preferred route of administration for the carcinogenicity studies was oral via the diet. However, feed blends containing neat 2‐EH were not sufficiently stable for feed studies. Dosed feed blends prepared with neat 2EH retained only 86% of the theoretical concentration after blending, and 46% of theoretical after storage for 2 days in a rat cage environment. Feed blends containing microencapsulated 2‐EH were sufficiently stable for toxicity studies: no losses of 2‐EH were observed after blending, feed blends stored for 7 days in a rat cage retained 99% of the theoretical concentration and blends stored in sealed containers at room temperature for 21 days retained 97% of the theoretical concentration. These studies demonstrate the potential for microencapsulation technology to eliminate dose formulation problems associated with

ISSN:0260-437X    

DOI:10.1002/jat.2550150103

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractEndothelium‐intact rat aortic rings were incubated with palytoxin (PTX, 10−11–10−9M, 10 min) in oxygenated (O295%, CO25%) baths. Phenylephrine (PE)‐contracted vascular rings demonstrated decreasing relaxation to acetylcholine (ACh), depending upon PTX incubation in a dose‐dependent manner; however, sodium nitroprusside (NaNP) persisted in returning the ring to its pre‐PE tension. After incubation with PTX, relaxation to the receptor‐independent, endothelium‐dependent relaxant A23187 was also attenuated. Thus, endothelium‐dependent mechanism(s) normally responsive to both ACh and A23187, stimulators of nitric oxide (NO) release, were disrupted. Following incubation with PTX, endothelium‐independent relaxation to NaNP remained intact but relaxation to atriopeptin II (APII) decreased. Electron microscopy demonstrated microvesiculation of endothelial cell cytoplasm and an irregular luminal surface following incubation with PTX. The intact response to NaNP, despite the loss of relaxation to ACh, indicated that soluble guanylate cyclase was not affected by PTX. However, loss of relaxation to AP‐II, involving particulate guanylate cyclase of vascular smooth muscle (VSM), was inhibited by PTX pre‐incubation. Determination of the site(s) of action of P

ISSN:0260-437X    

DOI:10.1002/jat.2550150104

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe use of a newly developed head dome system has allowed measurement of pulmonary function in conscious monkeys. Such information is often desired, so that pharmacological or toxicological effects of administered compounds can be measured in the absence of effects from anesthetic agents. The current study was conducted to gain experience with this method and to allow the determination of the effects of sodium pentobarbital anesthesia (30 mg kg−1i.v.) on the bronchoconstriction seen during i.v. infusion of methacholine in rhesus monkeys. Bronchoconstriction was measured as changes in respiratory resistance using a Buxco LS20 pulmonary mechanics computer. Four male rhesus monkeys (4.2–5.1 kg) were used. For the anesthetized exposures, the animals were intubated with a 4.0‐mm cuffed endotracheal tube attached to a size ‘O’ Fleisch pneumotachograph. For the conscious exposures, the animals sat in restraining chairs with a custom‐built head dome attached to the same pneumotachograph. In both cases, transthoracic pressure was monitored with an intrapleural catheter. Each monkey was infused with methacholine in stepwise doses, while anesthetized and conscious, until a 75% increase in respiratory resistance was seen. The ed50values of 0.134 and 0.180 mg ml−1methacholine were not significantly different in anesthetized vs conscious monkeys,

ISSN:0260-437X    

DOI:10.1002/jat.2550150105

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe haemopoietic and immunostimulatory properties of recombinant human interleukin 6 (rhIL‐6) might be used clinically in cancer patients. For the preclinical assessment of the safety of such a therapy, we chose the primate marmoset (Callithrix jacchus) and Wistar rats.Recombinant hIL‐6 given to marmosets at doses of up to 1000 μg kg−1day−1over 4 and 9 weeks did not induce fever and was very well tolerated. Haematological alterations included a sustained two‐ to threefold increase of thrombocyte counts, peaking at 4 weeks, as well as an increase in neutrophils and basophils. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased, but the ploidy grade was augmented. An acute‐phase protein response was observed within 24 h after the first IL‐6 administration, which reached a maximum after 1 week. The acute‐phase protein response was not accompanied by functional or morphological signs of hepatocellular damage. Increased immunoglobulin and soluble IL‐2 receptor in the serum levels reflected systemic immunostimulation.Recombinant hIL‐6 was also given to rats at 500 μg kg−1day−1s.c. for 4 weeks, where it induced a stimulation of thrombopoiesis associated with increased platelet counts within 1 week. Furthermore, rhIL‐6‐treated rats had signs of immunostimulation and increased acute‐phase reactants in serum, as in marmosets. There was no evidence of renal glomerular or hepatic pathology.In conclusion, despite the pleiotrophic effects of IL‐6 observedin vitro, prolonged administration of rhIL‐6 induced quite a selective stimulation of thrombopoiesis and the immune system, which were not associated with any major adverse effect in the two animal species. Since neutralizing antibodies developed against rhIL‐6 in both species within 2–4 weeks, which abolished the biological effect of IL‐6, the conductance of long‐term studies with rhIL‐6—especially on poss

ISSN:0260-437X    

DOI:10.1002/jat.2550150106

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractAsbestos is known to cause lung diseases in occupationally exposed workers. These properties have restricted its use. Industries have been exploring the possibility of other mineral fibres to replace the asbestos. In this direction, wollastonite has gained great attention owing to its high thermal resistance. In the present paper, the toxicity of three samples of Indian wollastonite was compared to that of chrysotile. Dust suspensions were added to the red blood cell suspensions to obtain a final dust concentration of 1.0–5.0 mg ml−1in the system. The wollastonite varieties were found to have smaller haemolytic potential in human red blood cells than that of chrysotilein vitro. Chrysotile also was more effective in inducting peroxidative damage of polyunsaturated fatty acid (PUFA) than wollastonites in the present system. The peroxidative damage of PUFA and the haemolysis were both time and dose dependent. A higher value of malonaldehyde (a lipid peroxidation product) formation in low‐speed supernatant of haemolysate was observed than in the intact cells. As the free‐radical scavengers vitamin E and reduced glutathione prevent haemolysis and lipid peroxidation, these data are consistent with the involvement of lipid peroxidation in the haemolytic

ISSN:0260-437X    

DOI:10.1002/jat.2550150107

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractUrinary selenium excretion was studied in 21 mercury vapour (Hg°)‐exposed workers involved in the demolition of a chloralkali plant. The subjects had no known previous occupational exposure to mercury. Their mean pre‐exposure urinary mercury concentration, determined on average 1.2 days prior to the exposure, was 0.8 nmol mmol−1creatinine (range 0.3–1.9). Their last mean urinary mercury concentration, determined on average after 51.4 days (range 19–103) of exposure, was 4.8 nmol mmol−1creatinine (range 1.2–10.0). The exposure ceased on average 4.1 days after the last determined urinary mercury concentration. The corresponding concentrations of urinary selenium decreased from an average of 39.1 nmol mmol−1creatinine (range 13.9–89.5) to 29.0 nmol mmol−1creatinine (range 10.1–52.9) (P= 0.002). This finding may indicate that even a low to moderate work‐related exposure to Hg° may reduce the urinary selenium concentration in humans in a manner th

ISSN:0260-437X    

DOI:10.1002/jat.2550150108

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractRicin, a toxic lectin from castor beans, reduces blood pressure. The current studies determined the effect of ricin on contractions in response to norepinephrine (NE) of rabbit central ear artery, endothelium‐dependent relaxations to methacholine and ATP of aorta rings and endothelium‐independent relaxations to papaverine in central ear artery and aorta rings. Rabbits were given 0.11 or 0.22 μg kg−1ricin i.v. and 18 h, 4 days, or 7 days later the arteries were removed and tested. Maximal contractions to NE were increased by 8–23% (P>0.05) with ricin treatment. The EC50was increased in five of six ricin‐treated groups, although only significantly so at 18 h after a minimum lethal dose of ricin. Maximum relaxations to methacholine were increased by 20–57% (P>0.05) at 18 h following both ricin doses but returned to control values at later time points. Relaxations in response to ATP were significantly enhanced in all ricin‐treated groups (95–205%) except in the 18 h and 4‐day 0.11 μg kg−1dose groups where the increase was 0–46%. Relaxations in response to papaverine were not altered in either artery. Thus, ricin decreases the sensitivity of the rabbit central ear artery to NE and increases endothelial‐dependent relaxations of the rabbit aorta. Therefore, decreased blood pressure following ricin administration may be due to vasodilation caused by decreased vascular contractions and increased endothelial‐de

ISSN:0260-437X    

DOI:10.1002/jat.2550150109

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractOur experiments suggest that in the development of plant dust‐induced fibrosing alveobronchiolitis—Scadding's fibrosing alveolitis—the cellulose content of plant dusts has a decisive aetiological role. Namely, the wood dust (pine) and the cellulose induced morphologically identical granulomatous inflammation and fibrosis, whereas the fibre‐free extract of wood dust did not cause pathological changes in the lungs. The induction of H2O2and superoxide anion production, shownin vitroin leucocytes, probably has an important role in the development of f

ISSN:0260-437X    

DOI:10.1002/jat.2550150110

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractThe aim of this work was to study if colchicine protects against CCl4‐induced changes in hepatic biochemical parameters by reducing cytochrome P‐450, by comparing the effects of colchicine and SKF 525‐A, a well‐known inhibitor of cytochrome P‐450. Our results show that both drugs reduced the cytochrome P‐450 content andp‐nitroanisoleo‐demethylase activity to the same extent. However, colchicine afforded a total protection from markers of liver injury, while SKF 525‐A protected only partially. The difference in the hepatoprotective activity of both drugs indicates that the beneficial effect of colchicine cannot be attributed solely to the inhibition of the activation of CCl4. Other actions, perhaps at the level of the propagation of lipid peroxidation or a ‘membrane‐stabilizing’ eff

ISSN:0260-437X    

DOI:10.1002/jat.2550150111

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY

摘要:

AbstractExposure to hyperoxia causes alveolar macrophage (AM) injury. The present study investigates the roles of intracellular antioxidant enzymes and of glutathione in the protection of AMs against hyperoxia in a biphasic cell culture system in aerobiosis. The effect of normoxia or hyperoxia on the integrity of AMs was related to indices of cell injury (ATP cell content and lactate dehydrogenase release into culture medium) and cell mass (protein content of AMs). Antioxidant activities were measured in guinea‐pig AMs exposed to 95% O2or to normoxia (control cells) for 3 days. A 3‐day AM culture in normoxia showed a significant decrease in protein and catalase, whereas ATP cell content, superoxide dismutase (SOD) (both Cu, Zn‐SOD and Mn‐SOD) and glutathione peroxidase (GPx) activities significantly increased. The content of reduced glutathione (GSH) did not change. Using the ATP content in AMs expressed as a cell injury index (CII), AM injury increased with increasing O2exposure time (1 day: 13 ± 4.4%; 2 days: 34 ± 3.8%; 3 days: 40 ± 4.1%; 4 days: 55 ± 7.3%; 6 days: 87.5 ± 5.4%). Exposure to 95% O2for 3 days was associated with a significant decrease in ATP cell content, protein, catalase and GSH to the total glutathione ratio, whereas SOD, GSH and total glutathione did not change significantly. The GPx activities increased significantly. There was no significant correlation between the AM CII and SOD or GPx content. In contrast, a significant correlation was observed between hyperoxia‐induced AM CII and catalase content (r= 0.71) and glutathione content (r= 0.71). Incubation of AMs with buthionine sulphoximine, a specific inhibitor of glutathione synthesis, significantly decreased the GSH content, whereas the ATP content and antioxidant enzyme activities in the AMs did not change. Reduction of intracellular GSH increased hyperoxia (50% O2)‐induced AM injury from 2.2 ± 6% to 53 ± 10.2%. Our results support the concept that regulation of cell GSH is an important mechanism of protection agains

ISSN:0260-437X    

DOI:10.1002/jat.2550150112

出版商:John Wiley&Sons, Ltd.    

年代:1995

数据来源: WILEY