摘要:

The ability to predict the biological effect of complex waste mixtures from chemical characterization data was examined by comparing observed mortality to that predicted by a mathematical additivity model with literature LD50 values for the chemicals identified in the mixtures. Male F344 rats were exposed by gavage to 1 of 10 samples of complex industrial waste. Seven of the 10 waste samples caused death within 24 h of administration at dosages ranging from 1 to 5 ml/kg body weight. Two of the 7 lethal waste samples produced 100% mortality at a dosage of 2.5 ml/kg; another 2 waste samples produced 100% mortality at 5 ml/kg. The partial chemical analysis, although providing more extensive information on chemical composition than might normally be available for most complex waste mixtures, was not sufficient to distinguish lethal from nonlethal waste samples or to indicate lethal potency. Possible explanations for the apparent inability to predict readily lethality from the chemical characterization data include the possible inappropriateness of an additivity model due to the presence of interactions, such as synergism or antagonism; the kinetics of chemical absorption, distribution, and elimination, which may be affected by administration of the chemical in a complex matrix; and the presence of unidentified chemicals in the mixture that may have contributed to the observed toxicity.

ISSN:0098-4108    

DOI:10.1080/15287398909531299

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

The multistage model is used by U.S. regulatory agencies to calculate estimates of the carcinogenic potency (ß) of chemicals; the data for these estimates are generally obtained from chronic rodent bioassays. Three quantities characterize each group tested in the chronic bioassay: the dose level, the sample size, and the number responding to the dose. The dose levels tested are fixed by conventional protocols; the typical National Toxicology Program (NTP) experimental design calls for use of the maximum tolerated dose (MTD), one‐half and one‐fourth MTD, plus a control group. Only rarely are doses even one order of magnitude less than the MTD utilized in chronic bioassays. This experimental design constraint on dose selection limits the possible values of ß that can arise from multistage model analyses of chronic bioassay data. Sample size is also constrained by the experimental design of the chronic bioassay; the typical sample size in NTP studies is 50 animals. Occasionally, fewer animals are used, but only rarely are more. Thus, the multistage model which theoretically has three variable quantities with which to estimate carcinogenic potency, has in practice only one: the incidence of treatment‐related response. Even this can vary within only a narrow range determined by sample size, the control incidence, and the level of statistical significance desired. The net result of these design constraints is that carcinogenic potency estimates derived from multistage‐model analyses of chronic bioassay data may vary within only a narrow range surrounding the inverse maximum dose tested. We have illustrated this by calculating the largest possible finite potency estimates that could have arisen from the experimental designs used to test 82 mouse carcinogens in chronic bioassays. On average these maximum potency estimates were within one order of magnitude of the inverse maximum dose tested. We thus conclude that the chronic rodent bioassay, in and of itself, is altogether inadequate as a data source for estimating the risk to humans from exposure to carcinogenic chemicals.

ISSN:0098-4108    

DOI:10.1080/15287398909531300

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Male Sprague‐Dawley rats were exposed toN,N‐dimethylacetamide (DMAC) and mated to untreated virgin females. Mean analytical exposure concentrations were 40, 116, and 386 ppm, respectively. A control group was exposed to air containing no DMAC. A total of 69 d of exposure to DMAC at these levels produced treatment‐related effects of increased liver weights and liver/body weight ratios in the high‐ and medium‐exposure groups of male rats. Reproductive data indicated no treatment‐related effects on copulation efficiency or efficiency in effecting pregnancy, and there were no detectable treatment‐related effects on preimplantation loss, postimplantation loss, embryotoxicity, or fetotoxicity in litters of females mated to males exposed to DMAC at the levels used in this study. The significance of these findings is discussed.

ISSN:0098-4108    

DOI:10.1080/15287398909531301

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

To obtain further information on the negative calcium balance caused by Cd, the factors associated with serum calcium and phosphorus homeostasis other than inhibition of intestinal calcium absorption were studied by using urinary cyclic 3',4'‐adenosine monophosphate (cAMP). In rats exposed to Cd for 30 d, the levels of urinary excretion of cAMP after treatment with parathyroid hormone (PTH), parathyroidectomy (PTX), or 1α‐hydroxycholecalciferol (1α‐OH‐D3) showed almost the same patterns as those of control rats: the response of urinary cAMP to treatment with PTH was not influenced by continuous oral administration of Cd. On the other hand, in rats exposed to Cd for 90 d without the other three treatments, the amount of urinary excretion of cAMP was markedly higher than in control rats. In PTX rats exposed to 90 d of Cd, urinary cAMP was unchanged, but it was markedly increased when the parathyroid was intact, with or without treatment with PTX. This phenomenon indicated hyperparathyroidemia in response to continuous oral administration of Cd for 90 d. The negative calcium balance with hyperparathyroidemia occurred after continuous oral administration of Cd and developed via increased urinary excretion of calcium. Urinary excretion of cAMP in Cd‐exposed rats was unaffected by the administration of 1α‐OH‐D3.

ISSN:0098-4108    

DOI:10.1080/15287398909531302

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Male Sprague‐Dawley rats were exposed daily for 52 wk in a nose‐only exposure system to smoke from the University of Kentucky 2R1 reference cigarettes (SM) or from cigarettes made of cadmium‐enriched tobacco (Cd‐SM). At sacrifice, the animals were evaluated by bronchoalveolar lavage (BAL) for inflammatory cell response in the lungs, and the cells so obtained were analyzed for phagocytosis of particles (latex and IgG‐coated SRBCs) and for their ability to release oxidants upon phagocytic challenge. Additionally, lung tissues were analyzed for Cd levels and lung homogenate fractions were assayed for aryl hydrocarbon hydroxylase (AHH) as well as total and selenium‐dependent glutathione peroxidase (GSH‐Px) activities. BAL cell counts showed a significant influx of inflammatory cells into the lungs of the Cd‐SM group but not the SM group. The proportion of neutrophils in the BAL cells of the Cd‐SM group was elevated to 40 ± 9%, compared with less than 2% in the SM group. Phagocytosis of both types of particles by macrophages from SM and Cd‐SM groups was similar to that of the control groups, except that a greater uptake of latex particles was seen in Cd‐SM macrophages. The release of oxidants (Superoxides and hydrogen peroxide) by the BAL cells was severely impaired in the Cd‐SM group, whereas a slight stimulation was seen in the SM group. Pulmonary CSH‐Px activity was the same in all groups. A significant induction of the pulmonary AHH activity was observed in the SM group only. The Cd levels in the lungs were approximately 8‐ and 200‐fold greater than controls in SM and Cd‐SM groups, respectively. These observations suggest a significant influence of tobacco Cd on the toxicity of cigarette smoke.

ISSN:0098-4108    

DOI:10.1080/15287398909531303

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Carbon monoxide (CO), an environmental pollutant, inhibits the cytochrome P‐450‐mediated metabolism of xenobiotics in vitro. In recent years, the importance of the lung in the metabolic disposition of certain airborne and systemically administered xenobiotics has been demonstrated. The purpose of this investigation was to establish a threshold for the CO‐induced inhibition of cytochrome P‐450‐mediated activities in the isolated perfused rabbit lung and to determine if these reactions are equally sensitive to this toxicant in this model. Neither the mixed‐function oxidase‐mediated hydroxylation nor the acetylation of aniline was altered by exposure to 7.5% CO/20% O2for 2.5 h in the isolated perfused rabbit lung. p‐Nitroanisole O‐demethylation by isolated rabbit lungs ventilated with 7.5% CO/20% O2was significantly decreased (‐37%) in comparison to controls. That these reactions are not similarly influenced by carbon monoxide may indicate that the constitutive isozymes of cytochrome P‐450 in the rabbit lung are differentially sensitive to CO‐induced inhibition.

ISSN:0098-4108    

DOI:10.1080/15287398909531304

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

4‐Ipomeanol is a naturally occurring toxin that induces lesions in the lung following its activation to an alkylating metabolite by the pulmonary cytochrome P‐450 system. The aim of this study was to determine if an environmentally relevant concentration of carbon monoxide could inhibit the activation of 4‐ipomeanol and prevent the associated toxic sequelae in the isolated perfused rabbit lung. The lungs of male New Zealand rabbits were removed and perfused with [14C]‐4‐ipomeanol for 2 h starting with an initial concentration of 0.1 mM. Lungs were ventilated with either air (control) or 7.5% CO/20% O2. 4‐Ipomeanol‐derived covalent binding was identical in the control and carbon monoxide treatment groups. Lungs perfused with 4‐ipomeanol and ventilated with air or 7.5% CO/20% O2both displayed alveolar type II cell hyperplasia and alveolar macrophage infiltration. Surprisingly, there was no histological evidence of Clara cell damage in any of the 4‐ipomeanol‐perfused lungs. These results suggest that the isozymes of pulmonary cytochrome P‐450 that act in concert to metabolize 4‐ipomeanol are relatively insensitive to inhibition by carbon monoxide.

ISSN:0098-4108    

DOI:10.1080/15287398909531305

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

In isolated, hemoglobin‐free perfused livers of fasted rats, formaldehyde at an initial concentration of 10 mmol/l produced toxicity as evidenced by a release of enzymes (GPT, SDH) and of glutathione (mainly GSSG) into the perfusate, an accumulation of calcium in the liver, and a depletion of hepatic glutathione. Formaldehyde also led to an enhanced release of malondialdehyde into the perfusate, indicating peroxidative processes and decreased hepatic oxygen consumption by about 50–70%. The electron microscopic investigation of formaldehyde‐exposed livers showed a destruction of the mitochondria (ruptured membranes, loss of the cristae) and some damage of the rough endoplasmic reticulum.

ISSN:0098-4108    

DOI:10.1080/15287398909531306

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

Bis‐2‐chloroethyl Sulfide‐ (BCES‐) induced DNA cross‐links in confluent, primary cultures of newborn rat cutaneous epidermal keratinocytes were detected using an assay that includes in situ unwinding of the DNA followed by separation of single‐stranded DNA and double‐stranded DNA (DSDNA) with hydroxylapatite. DNA cross‐links in BCES‐challenged cultures were inferred from increases in the percentage of DNA that remained double‐stranded, compared with control cultures, after a 60‐min alkaline unwinding incubation. The amount of DNA cross‐linking after 5 or 10 μMBCES was increased when keratinocytes were first pretreated with 0.05 μMMNNG for 1 h at 8 a.m., 2 p.m., and 8 p.m. for two consecutive days and challenged with BCES the following morning. This increase was statistically significant (p< .05, by ANOVA). For example, after 5 μMBCES challenge, cultures not pretreated with MNNG had 114.14% control DSDNA, whereas MNNG pretreated cultures had 122.78% control DSDNA. The level of BCES‐induced cross‐linking was maximal immediately after 30‐min challenge and decreased during postchallenge incubation. At 24 and 48 h post 5, 10, or 20 μMBCES challenge, the level of DSDNA was actually depressed below unchallenged levels. This postchallenge decrease in the level of DSDNA, indicative of SSB in DNA, suggests repair activity by glycosylases and endonucleases. However, completion of repair (i.e., a return to control levels of DSDNA) was not seen in these experiments. The activity that resulted in decreases in the level of DSDNA during postchallenge incubation response was unaffected by MNNG pretreatment.

ISSN:0098-4108    

DOI:10.1080/15287398909531307

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor

摘要:

The sodium channel blocker saxitoxin (STX) was conjugated to keyhole limpet hemocyanin (KLH) and used to immunize BALB/c mice. Anti‐STX antibodies were detected in serum by an enzyme‐linked immunosorbent assay (ELISA) within a week or two after the first immunization. Spleens from immunized mice were fused with NS‐1 myeloma cells and approximately 7000 resultant hybrids were screened by ELISA for reactivity to STX. Two stable hybrids were isolated, subcloned, and characterized. These hybrids, termed S1A5 and S3E.2, secreted specific anti‐STX antibodies that did not recognize the closely related toxin tetrodotoxin (TDT), as determined by competition ELISA. The S1A5 monoclonal antibody (mAb) was of the lgMkclass and S3E.2 of the IgG‐1ksubclass with affinity constants (Kavalues) of approximately 106M−1. The protective ability of these antibodies was tested by a competitive displacement assay for [3H]STX binding on rat brain membranes. Purified S3E.2 strongly displaced [3H]STX binding, whereas S1A5 weakly inhibited [3H]STX binding to membranes. One nano‐mole of S3E.2 or S1A5 was able to bind 0.03 nmol or 0.005 nmol, respectively, of STX. The S3E.2 mAb offered partial protection against STX‐induced reduction of peripheral nerve action potential in rat tibial nerve when administered in situ at concentrations 10‐ to 30‐fold greater than STX. The S1A5 mAb, despite its ability to inhibit STX binding in vitro, was completely ineffectual in situ. These antibodies, particularly S3E.2, thus represent potentially useful reagents for neurobiologic research, detection of toxin contamination, and diagnosis of poisoning, and may provide protection against the toxicity of STX in vivo.

ISSN:0098-4108    

DOI:10.1080/15287398909531308

出版商:Taylor & Francis Group    

年代:1989

数据来源: Taylor