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J Ashby

Publications and source records attributed to J Ashby.

At least 271 records · Page 15Linked to original sources
PubMed1987

Lack of UDS activity in the livers of mice and rats exposed to dichloromethane.

Dichloromethane (DCM) has been evaluated for its ability to initiate unscheduled DNA synthesis (UDS) in the livers of male mice and rats in vivo. Two types of experiment were conducted. In the first, Alpk:AP rats were exposed by oral gavage to 100, 500, or 1,000 mg/kg DCM and hepatocytes assessed for UDS via autoradiography 4 and 12 hours later. In the second, Fischer F344 rats or B6C3F1 mice were exposed by inhalation to either 2,000 or 4,000 ppm of DCM for either 2 or 6 hours, and hepatocytes assessed for UDS immediately after exposure. The dose levels and strains of rodent employed in the latter protocol correspond to those employed in a recent cancer bioassay of DCM conducted by the U.S. National Toxicology Program. DCM failed to induce UDS in any of the experiments. These data are discussed within the context of other evidence indicating DCM to be nongenotoxic in vivo, despite its reported carcinogenicity in the mouse.

Administration, Inhalation↗
PubMed1987

Re-evaluation of the need for multiple sampling times in the mouse bone marrow micronucleus assay: results for DMBA.

7,12-dimethylbenzanthracene (DMBA) is confirmed as active in the mouse bone marrow micronucleus assay 24 hr after dosing as a corn-oil homogenate via either oral gavage or intraperitoneal (ip) injection. These data are consistent with recent observations made by several investigators. However, when dosed via ip injection as a solution in DMSO, peak activity was evident 48 hr after dosing and a dramatic reduction in erythropoiesis was observed. The latter results are consistent with early observations made by Salamone and Heddle. The early observations of Salamone and Heddle were highlighted in the Gene-Tox review of this assay and led the OECD to recommend the use of 3 sampling times for this assay (between 12 and 72 hr). The present data indicate that this advice should be reviewed. In particular, it suggested that a maximum of two sampling times is adequate and that, as a consequence, the number of animals employed in the conduct of the test could be reduced with no loss of sensitivity. The present data also suggest that the use of a corn-oil homogenate of insoluble test agents may provide an efficient replacement for the use of ground suspensions or solutions in DMSO.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Re-evaluation of 1,2-dimethylhydrazine in the mouse bone marrow micronucleus assay: observation of a positive response.

1,2-Dimethylhydrazine showed dose-related clastogenic activity in the mouse bone marrow micronucleus assay following intubation of an aqueous solution of the dihydrocholoride salt (10 and 50 mg/kg, 24 h sampling). These data counter earlier reports of the inactivity of this material in a rat and a mouse micronucleus assay, following its intraperitoneal injection. In the present study, 2,000 polychromatic erythrocytes were assessed per animal. However, had only 300 cells been assessed for micronucleated polychromatic erythrocytes, it is shown that a negative result could have been recorded. This may explain the earlier and negative results.

1,2-Dimethylhydrazine↗
PubMed1987

Relative distribution of mature erythrocytes, polychromatic erythrocytes (PE) and micronucleated PE on mouse bone-marrow smears: control observations.

Maps are presented showing the distribution of normal erythrocytes (NE), polychromatic erythrocytes (PE) and micronucleated PE (MPE) on 3 mouse bone-marrow smears. Adjacent areas of each slide were assessed along their whole length, and it was found that both the incidence of MPE and the ratio of PE:NE varied between different regions of the slide. These two variables were essentially independent of each other. The maps give the impression of clusters or islands of MPE on the slide, but these become less significant when the number of erythrocytes in those areas is taken into account. The present data confirm our previous conclusion that the resolving power of the bone-marrow micronucleus assay is related to the number of PE assessed for MPE per slide. Our data also illustrate that in instances where small departures from control values are observed, clarification/confirmation of the result can be obtained by extending the assessment of slides for MPE. It is proposed that the present recognition of the inherent sensitivity contained within this assay necessitates careful examination of the criteria for a positive response. The selection of PE suitable for assessment is discussed, and our recent 24-h oral corn oil control data are analysed.

Administration, Oral↗
PubMed1987

A protocol and guide for the in vitro rat hepatocyte DNA-repair assay.

The in vitro rat-hepatocyte DNA-repair assay is a valuable tool in assessing the genotoxic activity of chemical agents. An advantage of the assay is that the target cells themselves are metabolically competent, so that the patterns of metabolic activation and detoxification closely reflect those in the whole animal. This article provides a typical procedure and guidelines for conducting the rat in vitro hepatocyte DNA-repair assay.

Animals↗
PubMed1987

A protocol and guide for the in vivo rat hepatocyte DNA-repair assay.

The in vivo rat hepatocyte DNA-repair assay is a valuable tool in assessing the genotoxic activity of chemical agents. An advantage of the system is that it reflects the complex patterns of uptake, distribution, metabolism, detoxification and excretion that actually occur in the whole animal. This article provides a typical procedure and guidelines for conducting the rat in vivo hepatocyte DNA-repair assay.

Animals↗
PubMed1987

N-chloropiperidine and calcium hypochlorite: possible examples of toxicity-dependent clastogenicity in vitro.

N-Chloropiperidine (NCP) has been reported to be both toxic and mutagenic in a wide range of in vitro and in vivo genotoxicity assays, however, few experimental details or numerical data have been presented to support these claims. The latter facts, together with the lack of any clear structural precedent for the mutagenicity of this agent, led us to re-evaluate it using the Salmonella mutation assay and the mouse bone marrow micronucleus test. The absence of mutagenic activity observed in both of these systems indicates that the genotoxicity of NCP and related chloramines remains to be unequivocally established. In particular, the potent clastogenicity to CHO cells reported for NCP may be related solely to oxidative denaturation of cellular proteins induced by hypochlorous acid, a hydrolysis product of NCP. Separate reports indicate that calcium hypochlorite (bleaching powder) is also clastogenic in vitro but not in vivo. We therefore suggest that N-chloropiperidine may prove of value as a model compound for studies designed to distinguish genotoxic clastogenicity (specifically DNA-reactive) from general toxicity-mediated clastogenicity.

Animals↗
PubMed1987

The effect of imipenem on strains of Enterobacteriaceae expressing Richmond & Sykes class I beta-lactamases.

Fourteen strains of Enterobacteriaceae producing Richmond & Sykes Class I beta-lactamase were studied. The ability of cefoxitin and imipenem to induce beta-lactamase production (reversible derepression) and to select stably derepressed mutants in these strains was assessed. beta-Lactamase induction by cefoxitin and imipenem was demonstrated by the disc diffusion technique in all strains. Cefoxitin selected stably derepressed mutants for all strains in broth cultures, but in an identical experiment imipenem did not. The susceptibility of each strain and its stably derepressed mutant (selected with cefoxitin) to a range of beta-lactam antibiotics was then ascertained. The stably derepressed mutants exhibited decreased susceptibility to all antibiotics tested except imipenem. The decrease in susceptibility varied between strains and between antibiotics but reached a maximum of a 256-fold decrease. The beta-lactamase activity of selected stably derepressed mutant strains showed at least a 600-fold increase in activity. Imipenem would therefore seem an appropriate choice for therapy of infections caused by this group of organisms, as it is active against derepressed mutants and unlikely to select any such strains during therapy.

Anti-Bacterial Agents↗
PubMed1987

The activity of MNNG in the mouse bone marrow micronucleus assay.

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is established herein as reproducibly active in the mouse bone marrow micronucleus assay. Activity was evident in two strains of mice, using suspensions in water or corn oil, and using two routes of exposure (oral gavage and i.p. injection). Activity was greatest when using the i.p. injection route, but a weak positive response was evident following oral gavage dosing of MNNG as an homogenate in corn oil. The latter weak response was statistically significant and was confirmed by both extended assessment of the slides and by re-analysis of selected slides in an independent laboratory. However, only some of the animals responded, as observed by others earlier. It is concluded that several earlier literature reports of the inactivity of this agent in this assay must be due either to the hydrolysis of MNNG prior to dosing, or to inadequate methods of data acquisition.

Administration, Oral↗
PubMed1987

Positive and negative control observations for the in vivo/in vitro rat liver assay for unscheduled DNA synthesis (UDS).

Positive and negative control data are shown for greater than 50 experiments conducted using the in vivo/in vitro rat liver unscheduled DNA synthesis (UDS) assay. In this assay, animals are dosed with the test agent and the liver is subsequently assessed for UDS by autoradiography and grain counting. The combined corn-oil negative control gave a value of -2.54 +/- 1.4 net gains (NG +/- SD; n = 77) and the positive control agent 6-p-dimethylaminophenylazobenzothiazole (6BT, dosed in vivo, animals sampled at 12 h) gave a value of +28.3 +/- 16.0 NG (+/- SD; n = 51). These data are briefly discussed, as are the reasons why this laboratory employs an in vivo (as opposed to an in vitro) positive control in each experiment.

Animals↗
PubMed1987

Pharmacokinetics and tissue penetration of Ro 23-6240, a new trifluoroquinolone.

A 400-mg dose of the trifluorinated quinolone Ro 23-6240 was administered orally to each of six healthy male volunteers, after which the concentrations of this agent in serum and cantharidin-induced inflammatory fluid were measured. Absorption was rapid, with a mean peak level in serum of 6.1 micrograms/ml, which was attained 0.71 h after administration. The elimination half-life in serum was 11.95 h. The agent penetrated the inflammatory fluid rapidly; the percent penetration was 89.7%. Urinary recovery of Ro 23-6240 was 58.6% by 72 h.

Administration, Oral↗
PubMed1987

Pharmacokinetics and tissue penetration of roxithromycin after multiple dosing.

The pharmacokinetics of the macrolide roxithromycin (RU 28965) were studied during and after administration of 150 mg every 12 h for 3 days (five doses) in six volunteers. The concentrations in serum, blister fluid, and urine were measured. Mean levels in serum taken at 1.5 h after the morning dose increased from 4.4 micrograms/ml on day 1 to 5.9 micrograms/ml on day 2 and 7.4 micrograms/ml on day 3. The mean serum and blister fluid elimination half-lives on day 3 were 13.2 and 12.5 h, respectively. Roxithromycin penetrated blister fluid well; the mean percent penetration (as measured by the ratio of areas under the curve) was 85%. After the final dose, a mean of 10.5% of that dose was recovered in 12 h as microbiologically active compound.

Adult↗