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J Ashby

Publications and source records attributed to J Ashby.

At least 181 records · Page 10Linked to original sources
PubMed1993

Mechanistic relationship among mutagenicity, skin sensitization, and skin carcinogenicity.

Twenty organic Salmonella mutagens, seven of which (including benzo[a]pyrene) are established skin carcinogens, and one of which (2-chloroethanol) is a well-defined noncarcinogen to skin, have been evaluated for skin-sensitizing activity using the local lymph node assay. The relative mutagenicity of the agents to Salmonella was also established. Fourteen of the chemicals were positive in the local lymph node assay, including the seven skin carcinogens. 2-Chloroethanol was inactive as a sensitizing agent. We suggest that a variety of factors contributes to the lack of sensitizing activity of the remaining six bacterial mutagens: extremes of intrinsic chemical reactivity, high water solubility reducing dermal translocation, and inappropriate dermal metabolism. Two reference skin-sensitizing agents (an oxazolinone and fluorescein isothiocyanate) were established as in vitro clastogens after their recognition as nonmutagens to Salmonella. These data imply that mutagenicity, rather than simply activity in the Salmonella assay, is a primary stimulus for electrophilic sensitization and carcinogenic initiation in the skin. We conclude that genotoxicity data for an agent can provide indications of the agent's potential to induce skin sensitization and that genotoxins which are skin-sensitizing agents have an enhanced potential to initiate skin carcinogenesis. We suggest that common, albeit individually distinct, structure-activity relationships underpin genotoxicity, skin sensitization, and the initiation of skin carcinogenesis. These relationships should simplify the hazard evaluation of chemicals and contribute to a reduction in animal usage. Several predictions of skin carcinogenicity are made based on the data presented.

Animals↗
PubMed1993

The influence of chemical structure on the extent and sites of carcinogenesis for 522 rodent carcinogens and 55 different human carcinogen exposures.

Gold and her colleagues have tabulated the results of rodent bioassays on 522 chemicals and have analysed the data. The present study complements those analyses by providing a perspective from the viewpoint of the chemical structure of the carcinogens. The chemical structure of each of the carcinogens is displayed and the Gold database is represented with the test agents as the primary variable. The carcinogens are gathered into six chemical classes and each chemical is assessed for structural alerts to DNA reactivity. The database is then analysed using an integration of the following parameters: bioassay in rat, mouse or both; structural alert status; chemical class; sites and multiplicity of carcinogenesis, and trans-species carcinogenicity. A series of Figures is presented that enables rapid acquaintance with what represents the core database of rodent carcinogenicity. The several analyses presented combine in endorsing the reality of two broad classes of rodent carcinogen--presumed DNA-reactive and others (putative genotoxic and non-genotoxic carcinogens, but semantics have been largely avoided). Vainio and his colleagues have tabulated 55 situations in which humans have succumbed to chemically induced cancer, and have listed the tissues affected. This database of human carcinogens has been analysed in the present study as done for the rodent carcinogen database, and comparisons made between the two. The predominance of putative genotoxic carcinogens in the human database was confirmed, as was the reality of putative non-genotoxic carcinogenicity in humans. It is concluded that putative genotoxic rodent carcinogenesis can be correlated both with chemical structure and the extent and nature of the induced effect, and that it is of clear relevance to humans. In contrast, it is concluded that putative non-genotoxic rodent carcinogenesis is more closely related to the test species than to the test chemical, and that it is essentially unpredictable in the absence of mechanistic models. In the absence of such models nongenotoxic carcinogenic effects should be extrapolated to humans with caution. Progress in the accurate prediction and extrapolation of rodent carcinogenicity will be helped by a common, if only temporary, enabling acceptance that not all carcinogens are intrinsically genotoxic.

Alkylating Agents↗
PubMed1993

Mutagenicity to Salmonella, Drosophila and the mouse bone marrow of the human antineoplastic agent fotemustine: prediction of carcinogenic potency.

The antineoplastic agent fotemustine is shown to be a base-pair mutagen to Salmonella. Activity is more marked in the uvrB-proficient strain G46 than in the repair-deficient strain TA1535. This is consistent with its ability to cross-link DNA. Potent activity as a somatic and germ-cell mutagen to Drosophila was also observed. A potent clastogenic response was given by fotemustine in the mouse bone marrow following either oral gavage or intraperitoneal injection of a single dose of 5 mg/kg. In each of these respects it is shown to be indistinguishable from the structurally related antineoplastic agent and human carcinogen MeCCNU. It is concluded that fotemustine should be regarded as having clear potential to induce cancer in humans. Based on these data, including the preponderance of chromosome breakages over recessive lethal mutations in Drosophila, an estimated rodent carcinogenic potency (TD50) of between 15-150 mg/kg is suggested for fotemustine.

Animals↗
PubMed1993

Correlation of carcinogenic potency with mouse-skin 32P-postlabeling and muta-Rmouse lac Z- mutation data for DMBA and its K-region sulphur isostere: comparison with activities observed in standard genotoxicity assays.

The genotoxicities in vitro and in vivo of the mouse-skin carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) have been compared with those of its weakly carcinogenic 4,5-sulphur analogue, 6,11-dimethylbenzo[b]naphtho-[2,3-d]thiophene (S-DMBA). The only datasets that correlated with the relative carcinogenicity of these agents to the skin were those conducted using topically exposed mouse skin. Thus, both chemicals induced lacZ- mutations in the skin of lacZ+ transgenic mice, and both produced DNA adducts on mouse-skin DNA as assessed using the 32P-postlabeling technique. In each case, DMBA gave a stronger response than did S-DMBA. In contrast to these responses, only DMBA was active in the mouse bone-marrow micronucleus assay and in the C3H10T1/2 in vitro cell transformation assay. Both chemicals were mutagenic to Salmonella and of approximately equal potency. The molecular geometry of DMBA and S-DMBA are compared, and divergent CASE predictions of activity in the Salmonella assay and skin-painting bioassay are discussed. The importance of conducting predictive genotoxicity assays in systems close to those in which carcinogenicity is to be assessed is emphasized by these data.

Aniline Compounds↗
PubMed1993

2,4,6-Trichlorophenol (TCP) induces chromosome breakage and aneuploidy in vitro.

2,4,6-Trichlorophenol (2,4,6-TCP), a non-mutagen to Salmonella, was reportedly negative in tests for chromosome breakage in vitro, but did produce numerical chromosome changes and micronuclei in V79 cells (Jansson and Jansson, 1992). This apparent specific ability to induce aneuploidy is of interest since aneuploidy testing is not part of routine genotoxicity test procedures. Here we show 2,4,6-TCP clearly induces structural chromosome aberrations in CHO cells and in V79 cells using a 3-h treatment and 20-h sampling time (17-h recovery). The isomers 2,4,5- and 2,3,6-TCP were also clastogenic in this protocol. There was no increase in aberrations when we used the protocol of Jansson and Jansson (1992), i.e., a 24-h treatment with sampling either immediately, or with a 24-h recovery period. However, positive results were obtained when a recovery time of 4-12 h was allowed after the 24-h treatment with 2,4,6-TCP. Previous negative aberration tests of 2,4,6-TCP (Galloway et al., 1987; Ishidate, 1988) are also likely due to inappropriate protocols. All these results were obtained without S9 metabolic activation. We also found positive results in CHO cells when 2,4,6-TCP was tested with S9. The present study demonstrates that 2,4,6-TCP induces both structural and numerical aberrations, and underscores the importance of protocol design, in particular the appropriate recovery time after treatment, for detecting clastogenic activity in vitro.

Aneuploidy↗
PubMed1993

Genotoxic activity of 1-chloromethylpyrene in stomach epithelium in vivo: insensitivity of the stomach scintillation UDS assay.

An acknowledged weakness of current testing programmes for genotoxic hazard has been the potential insensitivity of the established mouse bone marrow micronucleus test and rat liver unscheduled DNA synthesis (UDS) assays to direct-acting or short-lived mutagens, which may be consumed at the site of initial contact. In such cases, in vivo test systems sampling tissues such as the skin or the stomach would provide valuable data. To test these principles a stomach UDS assay was evaluated using the potent locally active mutagen 1-chloromethylpyrene (1-CMP). Contrary to expectations, no UDS response was observed 16 h following 1-CMP dosage by oral gavage. To confirm the integrity of the 1-CMP used for the stomach UDS assay, a sample of the stored chemical was re-evaluated in vitro and shown to be still strongly positive in the Ames assay and to have alkylating activity at least 15 min after incubation at stomach acid pH. No UDS response was observed when test dose levels were reduced or when earlier sampling times were used. Other genotoxic endpoints were examined in stomach. 32P-Postlabelling analysis revealed high levels of adduct formation in gastric DNA. An assay utilizing electrophoresis of DNA (the comet assay) showed the occurrence of DNA damage following dosing with 1-CMP in vivo. These positive results confirmed that 1-CMP should be regarded as a potential in vivo genotoxin. The failure to detect a UDS response to 1-CMP in stomach was investigated; a strong UDS response was observed in an in vitro hepatocyte UDS assay of 1-CMP indicating that the rat was capable of repairing 1-CMP-derived DNA adducts. Pretreatment of rats with hydroxyurea depressed the level of incorporation of thymidine into DNA both in negative and positive [methyl-N-nitrosoguanidine (MNNG)] controls. The results of these studies indicated that the protease digestion method employed did not selectively or efficiently sample those cells with any UDS response to 1-CMP or MNNG, and the activity seen for the latter was most likely due to the presence of S phase cells within the digests. As a result of the finding that UDS responses were not demonstrated for the potent direct-acting mutagens 1-CMP and MNNG, the protease digestion/scintillation method for stomach UDS does not appear to have general value in a screening programme for locally active genotoxic agents.

Administration, Oral↗
PubMed1993

Clastogenicity of chlorambucil to the mouse bone marrow: consideration in relation to its genetic specificity of action in some assays.

The human carcinogen and mouse germ cell mutagen chlorambucil is reported here to give a strong positive response in the mouse bone marrow micronucleus assay (4 mg/kg; single intraperitoneal injection). An increased incidence of micronucleated bone marrow white cells was also observed. It is concluded that chlorambucil is a broad spectrum mutagen that possesses subtle and specific mutagenic activities in some assay systems.

Animals↗
PubMed1993

Failure of N-acetylcysteine to protect the mouse bone marrow against the clastogenicity of 7,12-dimethylbenzanthracene.

De Flora et al. (1991a) have demonstrated a marked protective effect afforded by N-acetylcysteine (NAC) to the liver and lung of rats exposed to benzo[a]pyrene (BP) by intratracheal injection. Due to the protocol used by De Flora et al., BP was inactive in the bone marrow micronucleus assay and, consequently, the possible protective effect of NAC in this tissue could not be assessed. In the present study, three daily administrations of 7,12-dimethylbenzanthracene (DMBA; 15 or 25 mg/kg/day via oral gavage) resulted in the expected increased in micronucleated polychromatic erythrocytes (MPE) in the bone marrow of male C57BL/6 mice 24 h after the final dose. Pretreatment of similar groups of mice with NAC (1 g/kg/day via oral gavage) 5 h before each administration of DMBA had no effect on MPE frequencies. It is concluded that NAC does not have a protective effect on the mouse bone marrow.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Mitogenesis, micronuclei, and carcinogenesis in the rat liver: some basic inconsistencies.

The rodent liver carcinogen, mitogen, and peroxisome proliferator, methylclofenapate (MCP), has been investigated as a chemical mitogen for use in the rat liver micronucleus assay. A series of experiments comparing MCP with the potent mitogen 4-acetylaminofluorene (4AAF) and with 2/3 partial hepatectomy showed unexpected differences between the three treatment regimes as monitored by the expression of micronucleated hepatocytes (MH) in livers initiated with N-nitrosodimethylamine (NDMA). These differences were observed in both the profile of MH induction, as a function of time after mitogenic stimulation, and in the magnitude of response. There was no correlation between the magnitude of MH induction and the degree of mitogenesis triggering the MH induction. It is concluded that the yield of MH observed in a rat liver micronucleus assay is not a simple function of the level of DNA damage induced by the initiating agent (here NDMA). This indicates the need for caution in the interpretation of data obtained in the liver micronucleus assay for chemicals of unknown carcinogenicity. The use of acridine orange as a fluorescent stain for use with isolated hepatocytes is described.

2-Acetylaminofluorene↗
PubMed1992

Mitogenic activity of quinoline to the rat, mouse, and guinea pig liver: empirical correlations with hepatic carcinogenicity.

Previous studies have shown that the rat liver carcinogen quinoline is essentially nongenotoxic to the rat liver in vivo. Those studies also established it as a potent mitogen to rat liver. The present experiments have established quinoline as a mitogen to the mouse liver, a tissue in which it is also reported to be carcinogenic. In contrast, quinoline is reported to be noncarcinogenic to the guinea pig liver, and the present data establish it to be essentially nonmitogenic to the guinea pig liver. It is concluded that the mitogenicity of quinoline correlates better with its hepatocarcinogenic properties than does its genotoxicity in vivo.

2-Acetylaminofluorene↗