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J Ashby

Publications and source records attributed to J Ashby.

At least 253 records · Page 14Linked to original sources
PubMed1988

Clastogenicity of tritiated thymidine to the mouse bone marrow.

Tritiated thymidine (3HTdR; 120 microCi/mouse) increases the incidence of micronucleated polychromatic erythrocytes (MPE) in bone marrow PE of both B6CF1 and CBA male mice. This effect observed in vivo reflects, the clastogenicity reported by other investigators for 3HTdR in vitro. Thymidine itself was concluded to be inactive in the assay at a dose-level 100 times greater than that required to show activity for 3HTdR. These observations are of relevance to those employing 3HTdR to monitor the mitogenic activity and the genotoxicity of chemicals.

Animals↗
PubMed1988

Weak and unexpected mutagenicity to Salmonella of the rat hepatocarcinogen methapyrilene.

The rat liver carcinogen methapyrilene is shown to be a selective mutagen to strain TA1535 of Salmonella typhimurium when tested in the absence of S9 mix and using the standard plate-incorporation assay protocol. The activity observed was weak but was reproducible for a range of samples on many occasions of test and was not due to impurities. These data contrast with six earlier reports of the inactivity of this chemical in the Salmonella mutation assay.

Aminopyridines↗
PubMed1988

Mutagenicity to bacteria, cultured cells, and rodents of the human carcinogen chlornaphazine.

The human carcinogen and nitrogen mustard chlornaphazine (CN) has been confirmed to be mutagenic to Salmonella and, unexpectedly, the more so when evaluated in the presence of liver S9 mix. It also has been established as clastogenic to Chinese hamster lung cells exposed in vitro to dose levels greater than 2.5 micrograms/ml. Chlornaphazine subdued mice at doses of 5 g/kg, but only the occasional death occurred during the 4 days following oral administration of this dose in corn oil. Consequently, a median lethal dose level was not established. Nonetheless, dose levels of 500 mg/kg or greater gave a clear positive response in both the mouse and the rat bone marrow micronucleus assay. Although depression of erythropoeisis was observed in mice, a clastogenic response still was observed in the bone marrow 24 hr after dosing. The positive response in the rat was greater than that observed in the mouse. The present data provide a further instance of an established human carcinogen being readily detected by standard in vitro and in vivo mutagenicity assays.

Animals↗
PubMed1988

DNA-binding studies with 6BT and 5I: implications for DNA-binding/carcinogenicity and DNA-binding/mutagenicity correlations.

The divergent activities of a reported carcinogen/noncarcinogen pair of monoazo dyes related to the hepatocarcinogen Butter Yellow (DAB) are currently under investigation in our laboratories. As part of these studies we have determined (a) target organ distribution after oral dosing to rats and (b) covalent binding of 14C-labelled compound to DNA. In DNA-binding studies, 3 rat liver-metabolising systems were employed: in vivo (whole liver), isolated intact hepatocytes, and liver subcellular fractions. Distribution studies revealed that comparable levels of both compounds were detected in the liver at similar times after dosing, and these in vivo tissue concentrations were used for in vitro DNA-binding studies. At this 'in vivo equivalent dose', the carcinogen was consistently bound to DNA more effectively, and the difference (ratio of DNA binding) between the 2 compounds was far greater in vivo. In subsequent studies, covalent DNA binding to bacterial (Salmonella) DNA was assessed at the in vivo equivalent dose. In contrast to the afore-mentioned findings in mammalian systems, the carcinogen was bound less effectively to DNA, and gave fewer revertant counts/plate when the 2 compounds were bound to an equivalent extent. These data are discussed in view of their implications for DNA-binding/carcinogenicity correlations, and with respect to the relationship between DNA binding and mutagenicity in the Salmonella assay.

Animals↗
PubMed1988

A non-invasive micronucleus assay in the rat liver.

The potent rat-liver mitogen 4-acetylaminofluorene (4AAF) is shown here to provide an effective replacement for the surgical procedure of 2/3 partial hepatectomy (2/3PH) in the in vivo rat-liver micronucleus assay described by Tates and his colleagues. This protocol modification enables the assay to be conducted on a routine basis. Control observations for both 2/3PH and 4AAF-treated rats are presented, together with evidence indicating 4AAF itself to be without activity in the assay, irrespective of the mitogenic stimulus. The activities of the rat carcinogens DMN, 2AAF, DMH and 6BT, and of the non-carcinogens 4AAF and 4N are demonstrated. Recommendations for the conduct of the modified assay are made.

2-Acetylaminofluorene↗
PubMed1988

Assessment of the potential germ cell mutagenicity of industrial and plant protection chemicals as part of an integrated study of genotoxicity in vitro and in vivo.

An approach is described that enables the germ cell mutagenicity of chemicals to be assessed as part of an integrated assessment of genotoxic potential. It is recommended, first, that the genotoxicity of a chemical be defined by appropriate studies in vitro. This should involve use of the Salmonella mutation assay and an assay for the induction of chromosomal aberrations, but supplementary assays may be indicated in specific instances. If negative results are obtained from these 2 tests there is no need for the conduct of additional tests. Agents considered to be genotoxic in vitro should then be assessed for genotoxicity to rodents. This will usually involve the conduct of a bone marrow cytogenetic assay, and in the case of negative results, a genotoxicity test in an independent tissue. Agents found to be non-genotoxic in vivo are regarded as having no potential for germ cell mutagenicity. Agents found to be genotoxic in vivo may either be assumed to have potential as germ cell mutagens, or their status in this respect may be defined by appropriate germ cell mutagenicity studies. The basis of the approach, which is supported by the available experimental data, is that germ cell mutagens will be evident as somatic cell genotoxins in vivo, and that these will be detected as genotoxins in vitro given appropriate experimentation. The conduct of appropriate and adequate studies is suggested to be of more value than the conduct of a rigid set of prescribed tests.

Animals↗
PubMed1988

Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP.

A survey has been conducted of 222 chemicals evaluated for carcinogenicity in mice and rats by the United States NCI/NTP. The structure of each chemical has been assessed for potential electrophilic (DNA-reactive) sites, its mutagenicity to Salmonella recorded, and the level of its carcinogenicity to rodents tabulated. Correlations among these 3 parameters were then sought. A strong association exists among chemical structure (S/A), mutagenicity to Salmonella (Salm.) and the extent and sites of rodent tumorigenicity among the 222 compounds. Thus, a approximately 90% correlation exists between S/A and Salm. across the 115 carcinogens, the 24 equivocal carcinogens and the 83 non-carcinogens. This indicates the Salmonella assay to be a sensitive method of detecting intrinsic genotoxicity in a chemical. Concordance between S/A and Salm. have therefore been employed as an index of genotoxicity, and use of this index reveals two groups of carcinogens within the database, genotoxic and putatively non-genotoxic. These two broad groups are characterized by different overall carcinogenicity profiles. Thus, 16 tissues were subject to carcinogenesis only by genotoxins, chief among which were the stomach, Zymbal's glands, lung, subcutaneous tissue and circulatory system. Conclusions of carcinogenicity in these 16 tissues comprised 31% of the individual chemical/tissue reports of carcinogenicity. In contrast, both genotoxins and non-genotoxins were active in the remaining 13 tissues, chief among which was the mouse liver which accounted for 24% of all chemical/tissue reports of carcinogenicity. Further, the group of 70 carcinogens reported to be active in both species and/or in 2 or more tissues contained a higher proportion of Salmonella mutagens (70%) than observed for the group of 45 single-species/single-tissue carcinogens (39%). 30% of the 83 non-carcinogens were mutagenic to Salmonella. This confirms earlier observations that a significant proportion of in vitro genotoxins are non-carcinogenic, probably due to their non-absorption or preferential detoxification in vivo. Also, only 30% of the mouse liver-specific carcinogens were mutagenic to Salmonella. This is consistent with tumors being induced in this tissue (and to a lesser extent in other tissues of the mouse and rat) by mechanisms not dependent upon direct interaction of the test chemical with DNA. Detection of 103 of the 115 carcinogens could be achieved by use of only male rats and female mice.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Species-specific response to the rodent carcinogens 1,2-dimethylhydrazine and 1,2-dibromo-3-chloropropane in rodent bone-marrow micronucleus assays.

1,2-Dimethylhydrazine is confirmed as active in the mouse bone-marrow micronucleus assay when administered as an aqueous solution via oral gavage to three different strains of mice. It is also shown to be inactive in a corresponding rat assay under similar conditions of test. The observations were independently repeated in two laboratories. In contrast, 1,2-dibromo-3-chloropropane showed the reverse profile, being active in the rat bone-marrow assay but inactive in the mouse; the latter observations were also made in two laboratories. The carcinogen procarbazine was active in both species. These findings are discussed within the context of the present GeneTox revision of the standard test protocol of the rodent bone-marrow micronucleus assay.

1,2-Dimethylhydrazine↗
PubMed1988

UDS activity in the rat liver of the human carcinogens benzidine and 4-aminobiphenyl, and the rodent carcinogens 3,3'-dichlorobenzidine and direct black 38.

The activity of benzidine and three structurally related carcinogens in an in vivo/in vitro rat liver assay for unscheduled DNA synthesis is described. The first three of these chemicals, benzidine, 4-aminobiphenyl (4AB) and Direct Black 38 have been reported as positive in this assay by other investigators, albeit the data reported for 4AB were limited. The fourth compound, 3,3'-dichlorobenzidine has not been studied in this assay before. Each compound gave a clear positive response under conditions of routine testing.

3,3'-Dichlorobenzidine↗
PubMed1988

Activity of the human carcinogens benzidine and 2-naphthylamine in male mouse bone marrow micronucleus assays.

Conflicting reports exist in the literature regarding the activity of the human bladder carcinogens benzidine and 2-naphthylamine in the rodent bone marrow micronucleus assay. These chemicals have therefore been re-evaluated in mouse bone marrow micronucleus assays, and each gave a clear positive response in male mice 24 h after oral dosing of approximately 20% of the 4-day median lethal dose level. Experiments were repeated.

2-Naphthylamine↗