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Biomedical subjects

J Ashby

Publications and source records attributed to J Ashby.

At least 235 records · Page 13Linked to original sources
PubMed1990

Cell replication and unscheduled DNA synthesis (UDS) activity of low molecular weight chlorinated paraffins in the rat liver in vivo.

The rodent carcinogen C12-chlorinated paraffin (C12-CP) has been evaluated for unscheduled DNA synthesis (UDS) activity in the rat liver in vivo. Evidence of cell proliferation was also assessed by measuring cells undergoing semi-conservative DNA activity (S phase). No evidence of UDS was observed at doses up to 2 g/kg at either 2 or 12 h after dosing. Concomitant positive UDS responses were observed for the liver genotoxins N-nitrosodimethylamine, 4-aminobiphenyl, methyl methanesulphonate, 2-acetylaminofluorene, benzidine and 6-dimethylaminophenylazobenzthiazole. A strong positive response was observed in the cell proliferation assay for the test agent and the positive control agents quinoline and 4-acetylaminofluorene. These observations are discussed within the context of the rodent carcinogenicity reported for the same sample of C12-CPs as studied by the US National Toxicology Program.

Animals↗
PubMed1990

Will a breast screening programme change the workload and referral practice of general practitioners?

STUDY OBJECTIVE: The aim of the study was to consider possible changes in the clinical activities of general practitioners whose patients are registered in a breast cancer screening programme. DESIGN: The study was a survey based on completion of forms recording breast consultations carried out by participating general practitioners during a four week period. SETTING: One of three intervention centres and one of three comparison centres in the national trial of early detection of breast cancer was selected. The intervention centre was in Guildford; the comparison centre in Stoke on Trent. PARTICIPANTS: The participants were general practitioners in the selected centres. In Guildford, 64 of 99 general practitioners approached took part (65%); in Stoke on Trent, 81 of 177 took part (46%). The proportion of male and female participants in the two centres was similar. Doctors in Stoke on Trent were older and worked in smaller practices than in Guildford. RESULTS: A comparison of workloads showed that in the screening centre there was less demand for doctor consultations from those in the screened age group, but those excluded from screening made more use of the general practitioners' services. A difference in referral practice was also apparent, with doctors in the screening centre referring more frequently for specialist advice. CONCLUSIONS: The evidence suggests that no significant change in the overall use of general practice resources can be expected with the introduction of national screening, but there may be greater pressure on assessment services.

Adult↗
PubMed1990

Lack of effect of vitamin B-6 supplementation on the lipoprotein profile of post-menopausal chronic hemodialysis patients.

This study was designed to analyze the effect of vitamin B-6 supplementation on the lipoprotein profile of chronic hemodialysis patients. Individuals on chronic hemodialysis experience an acceleration of atherosclerosis, which is often accompanied by abnormal lipid metabolism. Although total plasma cholesterol is usually normal, high-density-lipoprotein (HDL) cholesterol is often low. Recently, it has been suggested that the development of atherosclerotic lesions in chronic hemodialysis patients may be the result of a decreased plasma concentration of pyridoxal 5'-phosphate (PLP) and concomitant alterations in plasma amino acid and/or lipoprotein profiles. All subjects in this study were supplemented with 0.97 mmol (200 mg) pyridoxine hydrochloride per day for 28 days; then, concentrations of PLP, total cholesterol, and lipoprotein cholesterol fractions were determined in the plasma. No significant difference was noted in PLP concentration between Group 1 (five post-menopausal women with a history of atherosclerosis who were undergoing maintenance hemodialysis therapy) and Group 2 (six subjects who were non-symptomatic). However, both groups had significant increases in PLP concentrations between the pre- and post-supplementation periods (p less than .01). In contrast, there was a statistically significant difference in total plasma cholesterol and very-low-density- and low-density-lipoprotein (VLDL and LDL) cholesterol concentrations between groups, but no significant changes in total cholesterol or VLDL and LDL cholesterol content were found during vitamin B-6 supplementation. No statistically significant differences in HDL, HDL2, and HDL3 cholesterol concentrations were observed between Group 1 and Group 2 subjects or within either group during vitamin B-6 supplementation.

Aged↗
PubMed1989

Quinoline: unscheduled DNA synthesis and mitogenesis data from the rat liver in vivo.

Quinoline is a specific and potent carcinogen to the rat and mouse liver. Studies are described here in which it was evaluated for its ability to initiate unscheduled DNA synthesis (UDS) in the rat liver in vivo. Although some individual animals showed indications of a marginal response the absence of clear group positive responses and the lack of an obvious dose relationship precluded the classification of quinoline as positive. The analogous NTP non-carcinogen 8-hydroxyquinoline was shown also to be devoid of UDS activity. Quinoline did, however, induce a potent mitogenic response in the rat liver between 24 and 48 hr after oral dosing of 200-500 mg/kg. Under similar conditions of test, 8-hydroxyquinoline was essentially inactive. These data represent a further instance in which mitogenicity in the liver appears to correlate better with carcinogenicity than does genotoxicity; but it may not be that simple, as discussed in the text. A single dose of quinoline was shown to act as a replacement for surgical partial hepatectomy in the liver micronucleus assay described by Tates, consistent with its potent mitogenicity.

Animals↗
PubMed1989

The present lack of evidence for unique rodent germ-cell mutagens.

Six chemicals, diethylhexyl phthalate (DEHP), ethanol, cyclohexylamine (CHA), sodium saccharin (NaS), cadmium chloride (CdCl2) and triflupromazine (TFP), were suggested to be unique germ-cell mutagens (Auletta and Ashby, 1988) by the GeneTox Workgroups of the U.S. Environmental Protection Agency (EPA). If this is a correct classification it would have major consequences when screening for mutagenicity and when labelling genotoxic substances. However, our re-evaluation of the GeneTox literature, including some more recent publications, has failed to find substantive evidence that any of these chemicals have been unequivocally established as having unique mutagenic activity in germ cells. For DEHP, NaS and TFP the evidence for genotoxic/mutagenic effects is questionable, in both germinal and somatic cells. Ethanol and CdCl2 showed clastogenic activity, but it was not restricted to germ cells. Both, ethanol and cadmium salts, appear to induce aneuploidy. The unconfirmed clastogenic effect of CHA was restricted to rats, but it occurred in both bone marrow and spermatogonia. Therefore, the general observation that rodent germ-cell mutagens are also genotoxic in somatic cells in vivo (Brusick, 1980; Holden, 1982) remains valid.

Animals↗
PubMed1989

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicity by the U.S. National Toxicology Program.

This paper is an extension and update of an earlier review published in this journal (Ashby and Tennant, 1988). A summary of the rodent carcinogenicity bioassay data on a further 42 chemicals tested by the U.S. National Toxicology Program (NTP) is presented. An evaluation of each chemical for structural alerts to DNA-reactivity is also provided, together with a summary of its mutagenicity to Salmonella. The 42 chemicals were numbered and evaluated as an extension of the earlier analysis of 222 NTP chemicals. The activity patterns and conclusions derived from the earlier study remain unchanged for the larger group of 264 chemicals. Based on the extended database of 264 NTP chemicals, the sensitivity of the Salmonella assay for rodent carcinogens is 58% and the specificity for the non-carcinogens is 73%. A total of 32 chemicals were defined as equivocal for carcinogenicity and, of these, 11 (34%) are mutagenic to Salmonella. An evaluation is made of instances where predictions of carcinogenicity, based on structural alerts, disagree with the Salmonella mutagenicity result (12% of the database). The majority of the disagreements are for structural alerts on non-mutagens, and that places these alerts as a sensitive primary screen with a specificity lower than that of the Salmonella assay. That analysis indicates some need for assays complementary to the Salmonella test when screening for potential genotoxic carcinogens. It also reveals that the correlation between structural alerts and mutagenicity to Salmonella is probably greater than 90%. Chemicals predicted to show Michael-type alkylating activity (i.e., CH2 = CHX; where X = an electron-withdrawing group, e.g. acrylamide) have been confirmed as a structural alert, and the halomethanes (624 are possible) have been classified as structurally-alerting. To this end an extended carcinogen-alert model structure is presented. Among the 138 NTP carcinogens now reviewed, 45 (33%) are non-mutagenic to Salmonella and possess a chemical structure that does not alert to DNA-reactivity. These carcinogens therefore either illustrate the need for complementary genetic screening tests to the Salmonella assay, or they represent the group of non-genotoxic carcinogens referred to most specifically by Weisburger and Williams (1981); the latter concept is favoured.

Animals↗
PubMed1989

The rat-liver carcinogen N-nitrosomorpholine initiates unscheduled DNA synthesis and induces micronuclei in the rat liver in vivo.

Alkylation of DNA is generally accepted as the primary event in the carcinogenicity of nitrosamines. However, the cyclic nitrosamine N-nitrosomorpholine (NMOR), a potent rat hepatocarcinogen, has been reported as binding at very low levels to the liver DNA of treated rats. This led us to investigate the activity of NMOR in two in vivo rat-liver genotoxicity assays--for the induction of unscheduled DNA synthesis (UDS) and the production of micronucleated hepatocytes in the liver micronucleus assay (LMN). Rats treated with oral doses of NMOR (10-200 mg/kg) gave a positive liver UDS response either 2.5 h or 12 h after dosing. Similarly, treatment with oral doses of NMOR (10 or 100 mg/kg) followed by mitogenic stimulation with 4-acetylaminofluorene (4AAF) resulted in high incidences of micronucleated hepatocytes in the LMN assay. These data confirm that the genotoxicity reported for NMOR in vitro can be reproduced in vivo and that NMOR interacts with liver DNA of treated rats. Earlier reports of only very weak binding of radiolabelled NMOR to rat liver DNA in vivo are discussed within the context of these data.

Animals↗
PubMed1989

Effect of aspartame on plasma amino acid profiles of diabetic patients with chronic renal failure.

A randomized, double-blind study was conducted to determine the possible effects of aspartame on the plasma amino acid profiles of 23 diabetic patients with renal failure who were undergoing maintenance hemodialysis. Subjects were given a single dose of 10 mg aspartame/kg (approximately equivalent to 25 packets of Equal [NutraSweet Consumer Products, Inc, Chicago, IL] or the amount of phenylalanine in a 300-mL glass of milk) or a placebo in a crossover study design. Three postdialysis blood samples were drawn just before and 1 and 2 h after aspartame or placebo consumption. After aspartame consumption statistically significant increases in only two amino acids, phenylalanine and tyrosine, were noted at 1 and 2 h when compared with placebo values. The increases in phenylalanine were within the normal postprandial range for healthy subjects; no other increases in essential or nonessential amino acids, except for tyrosine, were detected. This study supports the view that aspartame is safe for diabetic subjects with chronic renal failure.

Amino Acids↗
PubMed1989

Evaluation of dichloromethane as an inducer of DNA synthesis in the B6C3F1 mouse liver.

The potential of the mouse hepatocarcinogen dichloromethane (DCM) to induce hepatocellular division, as monitored by increased DNA synthesis, has been evaluated using B6C3F1 mice--the strain in which it is carcinogenic but not apparently genotoxic. Male mice were exposed to DCM either by oral gavage in corn oil (1000 mg/kg) or by inhalation of an atmosphere containing 4000 p.p.m. DCM for 2 h. Cells undergoing DNA synthesis (S-phase) were radiolabelled by means of four consecutive i.p. injections of tritiated thymidine at hourly intervals prior to killing. No evidence of S-phase activity was observed in the gavage studies. The inhalation studies resulted in some weak, but statistically significant increases in S-phase incidence, but the biological significance was unclear due to similar increases being observed in some control groups. It is concluded that DCM does not share the mitogenic properties of such presumed non-genotoxic mouse liver carcinogens as trichloroethylene, polybrominated biphenyls and carbon tetrachloride, and as such its carcinogenicity to the mouse liver remains mechanistically obscure.

Administration, Inhalation↗
PubMed1989

Comparison of acridine orange and Giemsa stains in several mouse bone marrow micronucleus assays--including a triple dose study.

Data from four mouse bone marrow micronucleus assays are presented in which sister slides were stained with Giemsa or Acridine Orange (AO). These data are used to support our decision to change from Giemsa stain to AO when conducting rodent bone marrow micronucleus assays. The AO method leads to definitive assessments of the incidence of micronucleated polychromatic erythrocytes on a slide, and in so doing, it saves reading time and increases confidence in data. Preliminary experiments with DMBA using the triple-dose/single sample protocol of MacGregor are also described, and it is concluded that this protocol shows great promise.

Acridine Orange↗