摘要:

Thirty‐four chemicals‐diverse in structure, postulated mechanisms of action, and primary target organs‐were tested for cytotoxic response in isolated hepatocyte suspensions from young male Sprague‐Dawley rats. Hepatocytes were incubated in the presence and absence of the test chemicals in closed vessels fitted with side arms for serial sampling for up to 5 h at 37°C with gentle shaking under an O2:CO2(95:5) atmosphere. The parameters evaluated were glutamate‐oxaloacetate transaminase and lactate dehydrogenase release from the cells, Trypan blue exclusion, cell count, urea synthesis capability, and steady‐state ATP levels. All chemicals cytotoxic in animals following single or short‐term repeated exposures caused statistically significant changes in one or more of these parameters in the 0.01–70‐mM concentration range. Dimethylnitrosamine and thioacetamide were not as potent in the isolated cell system as expected from their in vivo hepatotoxicity, and the quantitative changes produced with thioacetamide in the hepatocytes were marginal, even at 10 mM. The solvents tested‐ethanol, acetone, dimethyl sulfoxide (DMSO), and propylene glycol—were without effect. These results indicate that isolated hepatocyte suspensions are useful for the identification of cytotoxins in general and hepatotoxins in particular, but that their capability for yielding a quantitative index of cytotoxic potential for diverse chemical species remains to be demonstrated.

ISSN:0098-4108    

DOI:10.1080/15287398309530362

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Benzo[a]pyrene (BaP), a ubiquitous potent carcinogen, has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. A detailed knowledge of the rate and pattern of metabolite formation and factors affecting their formation is essential for understanding the mechanism of action of BaP in the lung. An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a crude airborne particuiate mixture on the metabolism of BaP. [14C]BaP with and without crude air particuiate (CAP) was administered intratracheally to an isolated perfused lung (IPL) preparation after intratracheal pretreatment of the whole animal with CAP and/or BaP, or intra‐peritoneal pretreatment of the whole animal with BaP. BaP and its metabolites were extracted from perfusing blood at 6 time points up to 180 min after administration of [14C/BaP to the IPL. BaP and its metabolites were also extracted from lung tissue, washout fluid, aveolar macrophages, and trachea bronchi at the end of the perfusion at 180 min. Patterns of BaP metabolites were determined by chromatographic techniques and liquid scintillation counting.

ISSN:0098-4108    

DOI:10.1080/15287398309530363

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Rats malnourished since birth and fed a protein‐free diet for 2 wk showed almost un‐detectable levels of liver microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase. Treatment with benzo[a]pyrene rapidly enhanced this activity to levels higher than those observed with untreated normal rats. The carbon‐monoxide‐reduced cytochrome P‐450 spectral peak was shifted from 452 nm in malnourished untreated rats to 448 nm in malnourished benzo[a]pyrene‐injected rats and resulted in increases in the intensity of several microsomal protein bands (MW range 46,000–60,000) separated by gel electrophoresis. Malnourished rats then fed with a protein diet exhibited an important increase in aryl hydrocarbon hydroxylase activity, an increase in the intensity of microsomal protein electrophoretic bands (MW range 46,000–60,000), and a shift of the carbon‐monoxide‐reduced cytochrome P‐450 spectral peak from 452 nm to 450 nm. These results suggest that alterations in cytochrome P‐450 species related to benzo[a]pyrene metabolism might explain the modulation of this activity by nutritional effects.

ISSN:0098-4108    

DOI:10.1080/15287398309530364

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Thein vitrocytotoxicity of amosite asbestos and its silanized and bovine serum albumin conjugated derivatives were studied in two cell lines. The overall cytotoxicity of amosite towards Chinese hamster lung cells (V79–4) was not affected by derivatization, although the rate of cell‐particle interaction was reduced. Protein derivatization virtually abolished the cytolytic action of amosite to the macrophage‐like cell line (P388D1), although this derivatized material still induced the release of arachidonate. These results confirm that thein vitrocytotoxic effect of fibrous particulates toward V79–4 cells is mainly dependent on fiber size, while the response of macrophage‐like cells is more sensitive to alterations in surface chemistry. The relationship between these results and the pathogenicity of asbestos is discussed.

ISSN:0098-4108    

DOI:10.1080/15287398309530365

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

We were interested in whether ozone (O3) could stimulate the migration of mast cells into the tracheal lumen. To test this we determined the effect of an acute O3exposure on the types and relative numbers of cells recovered by tracheal lavage. Seven conscious sheep were intubated with an elongated nasotracheal tube. The trachea between the larynx and the cuff of the tracheal tube (15–20 cm) was lavaged repeatedly with 10–15‐ml aliquots (total 350 ml) of 0.9% buffered (pH 7.4 saline, which contained the mast cell‐stabilizer disodium cromoglycate (10 μg/ml). One hour after a baseline lavage, the sheep were exposed on separate occasions to either air (control) or 0.5 ppm O3for 2 h. Lavages were repeated 24 h later. Cells were recovered from the lavage effluent by centrifugation across a saline/Ficoll Paque gradient. From part of this material we estimated total cells and total viable cells (with Trypan blue). The rest of the material was recentrifuged at 400 × g for 5 min, and cytological slides were made from the cell pellet. Slides were stained with Poli‐chrome and Wright‐Giemsa, and were analyzed by light microscopy. The percentages of epithelial cells, macrophages, lymphocytes, and mast cells were determined from a total count of 500 cells/slide. Differences in cell percentages between pre‐and postexposure were calculated both for air and O3exposures, and these differences were compared. Exposure to O3resulted in an increased number of mast cells and lymphocytes when compared to the changes observed with air. It seems likely that the increase in number of luminal mast cells and lymphocytes following O3exposure signals an enhanced inflammatory response and that these changes could contribute to O3‐induced increased nonspecific airway hyperresponsiveness and susceptibility to allergic IgE‐mediated airway reactions.

ISSN:0098-4108    

DOI:10.1080/15287398309530366

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

The covalent binding to hepatic RNA, DNA, and protein of a highly genotoxic dinitrotoluene (DNT) isomer (2,6‐DNT) was compared with that of a less genotoxic DNT isomer (2,4‐DNT) after oral administration to male Fischer‐344 rats. Covalent binding to each macromolecular species was proportional to dose (10 or 35 mg/kg) for each isomer, but that due to 2,6‐DNT was always 2–5‐fold higher than that due to 2,4‐DNT. There was no selectivity of either isomer for any macromolecule. The time course of appearance and disappearance of covalently bound material was similar regardless of isomer or dose administered. Little covalently bound material was present until 8 h after the dose. Covalent binding peaked between 12 and 24 h and then slowly declined. The half‐lives of covalently bound material were independent of the isomer administered, ranging from 2.9 to 5.0 d for RNA and protein and from 5.1 to 7.9 d for DNA. Both isomers disappeared from the small intestine rapidly, and covalent binding to hepatic macromolecules became significant only after the isomeric dinitrobenzyl alcohol glucuronides had appeared in the small intestine. The concentration of alcohol glucuronides in the intestine declined prior to peak covalent binding in the liver. The data suggest that covalent binding to hepatic macromolecules qualitatively reflects the differences in genotoxicities between the two isomers. The time course of intestinal disposition of the two isomers supports previous reports that suggest that activation of both isomers requires oxidation to the corresponding benzyl alcohol, glucuronidation, excretion in the bile, deconjugation, and further metabolism by intestinal microorganisms, followed by reabsorption.

ISSN:0098-4108    

DOI:10.1080/15287398309530367

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Mice were exposed via inhalation to high concentrations of either dichloromethane (168 mg/l) or carbon tetrachloride (134.3 mg/l). The mice were tested for learning ability using a passive‐avoidance conditioning task. Exposed animals were found to have a significantly decreased ability to learn when compared with controls. The 3‐wk‐old mice were more affected than the 5‐wk‐old and the 8‐wk‐old mice. The exposed animals were indistinguishable from controls in terms of motor activity, weight gain, and absence of analgesia.

ISSN:0098-4108    

DOI:10.1080/15287398309530368

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Thirty‐two pregnant Long‐Evans rats were divided into 10 groups of 3 or 4 pregnant rats, and each rat was given a single dose of 4 ml ethanol/kg (20 ml/kg of a 20% solution) between d 6 and 15 of gestation. An 11th group of 50 pregnant rats received distilled water and served as controls. Offspring body weights were decreased in groups of rats given ethanol as compared to controls (3.0–3.6 g, versus 3.9 g for controls). Total litter weight was decreased in dams given ethanoi on d 6. Skeletal variants were seen in 13–78% of the offspring given ethanoi, compared to 0.6% of the controls. Variations may be considered as additional signs of embryotoxicity. Malformations such as hydronephrosis, pelvic kidney, microcephalus, cranioschisis, and microphthalmia occurred in 72–100% of the ethanoi treated offspring, as compared to 12% of controls. Hydronephrosis was most frequent on d 9 or 14, pelvic kidney on d 8 and 11, and microphthalmia from d 10–12. Cranioschisis was maximal on d 7, 11, and 15, and microcephalic offspring were most frequently born to dams given ethanol on d 7 or 14. Skeletal defects were usually single entities, while soft‐tissue anomalies occurred in a consistent pattern. These results suggest that ethanoi is a stage‐specific teratogen in the rat at comparable exposure levels attained by many humans.

ISSN:0098-4108    

DOI:10.1080/15287398309530369

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Existing Syrian hamster embryo (SHE) cell‐transformation assay methods were modified to allow the assay of complex synfuel mixtures. A shale oil, high‐molecular‐weight, high‐boiling distillates from two different solvent‐refined coal (SRC) processes, and two crude petroleum samples caused transformation of SHE cells. Chemical fractionation of SRC‐II heavy distillate and assay of resultant fractions allowed detection of significant transforming activity in chemical fractions, where such activity had not previously been observed. The polyaromatic‐hydrocarbon‐enriched fraction, neutral aliphatic hydrocarbon fraction, and neutral tar fraction all showed a positive response in the SHE assay. In addition, we confirmed earlier data showing that both the tar fractions (basic and neutral) and the soluble basic fractions from both SRC processes and shale oil contained genetically active materials.

ISSN:0098-4108    

DOI:10.1080/15287398309530370

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor

摘要:

Approximately 1000 urine samples were collected from the general adult U.S. population and were analyzed for cadmium, beta2‐microglobulin, specific gravity, and creatinine. The distributions of urinary cadmium and beta2‐microglobulin levels were quantified for use as benchmarks against which the effects of environmental cadmium exposure may be measured. Urinary cadmium is significantly higher in females than males, and increases significantly with age. Urinary beta2‐microglobulin is significantly higher in males than females, is probably related to age, and does not significantly increase with increased urinary cadmium (at the levels found). Since urinary creatinine is lower in females than males and is a function of age, specific gravity is concluded to be the most straightforward and practical parameter to use in data adjustment for urine concentration.

ISSN:0098-4108    

DOI:10.1080/15287398309530371

出版商:Taylor & Francis Group    

年代:1983

数据来源: Taylor