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J Ashby

Publications and source records attributed to J Ashby.

At least 307 records · Page 17Linked to original sources
PubMed1985

Weak mutagenicity to Salmonella of the formaldehyde-releasing anti-tumour agent hexamethylmelamine.

Hexamethylmelamine (HEMLA) is a metabolism-dependent formaldehyde-releasing agent related in structure to hexamethylphosphoramide (HMPA). Both compounds are known to be mutagenic to Drosophila. HMPA, in common with the other formaldehyde-releasing agents studied, is non-mutagenic to Salmonella. The present paper describes the mutagenicity of HEMLA to strain TA100 of Salmonella typhimurium. Activity is dependent upon both the use of a pre-incubation assay protocol and on high concentrations of Aroclor-induced rat liver in the S9 mix. HMPA was inactive under similar conditions of test.

Altretamine↗
PubMed1985

Genetic toxicology in industry: perspectives and initiatives.

Recent studies support the view that, incidents apart, synthetic chemicals in general present only an industrial hygiene problem. It is also apparent that, if performed well, the Salmonella assay plus a genetically independent eukaryotic assay will be sufficient to detect genotoxins in vitro, while the in vivo micronucleus assay, linked to a liver genotoxicity assay, will alert to significant carcinogens. Some 'carcinogens' are not genotoxic, are weak and are usually species/organ specific in their action; they should be recognized as different and treated separately. Cancer bioassays could probably be discontinued except in special cases. Current protocols for such assays often yield misleading data and are unnecessarily expensive. When seeking significant environmental carcinogens and mutagens it would be profitable to turn away from industrial chemicals, despite the fact that they are readily available. In summary, it is suggested that there now exist short-term methods from the results of which it is possible to decide, with a high level of certainty, whether a compound will be a rodent carcinogen at dose levels that may be relevant to man.

Animals↗
PubMed1985

Studies in vivo to investigate the status of 4-N-pyrrolidinylazobenzene as a pure cancer initiating agent to the rat liver.

4-N-Pyrrolidinylazobenzene (4N) has been described sequentially as a potential rat hepatocarcinogen, a non-hepatocarcinogen to the rat, a possible pure initiating agent to the rat liver and as unlikely to be either a rat hepatocarcinogen or a cancer initiating agent. Given the importance of defining a pure initiating agent to the rodent liver we have conducted experiments to evaluate the status of 4N in this respect. By histopathological criteria 4N is non-hepatotoxic to the rat liver following daily oral gavage for 6 weeks, but it can be detected unbound in the rat liver following a single exposure via oral gavage and methaemoglobin is evident in peripheral blood. In addition, it fails to bind covalently to hepato-proteins or to initiate unscheduled DNA synthesis in the rat liver following oral dosing. Under similar conditions of bioassay, the rat liver carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'M) gave a positive response on each count. Further, no evidence of histopathological change was observed in the rat liver following daily intraperitoneal injection of 4N for 2 weeks. It is concluded that 4N is both non-toxic and non-genotoxic to the rodent liver in vivo in all respects studied, and that it is therefore very unlikely to possess cancer initiating activity in this tissue.

Animals↗
PubMed1985

Irreversible depression in the ratio of tetraploid:diploid liver nuclei in rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'M).

A reduction in the ratio of tetraploid to diploid liver nuclei has been investigated as an early indicator of hepatocarcinogenesis in the rat using the liver carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'M). In a dose ranging study 3'M was administered by gavage to rats at 5, 12.5 and 25 mg/kg for up to 10 weeks and the following parameters studied: bodyweight gain, dye binding to hepatic protein, nuclear ploidy in liver and histopathology. Significant reduction in bodyweight occurred only with 25 mg/kg; dye binding to protein occurred in a dose-related manner; depression of the percentage of tetraploid nuclei compared with diploids was dose-related and effects were detected even at the lowest dose. These observations were consistent with those from previous studies by other investigators. In a separate experiment 3'M was administered at the maximum tolerated dose (MTD) of 25 mg/kg for 3 weeks, during which time there was a significant reduction in bodyweight gain and a reduction in the ratio of tetraploid:diploid liver nuclei. After cessation of dosing the rate of bodyweight gain returned to normal but there was no corresponding recovery of the ratio of tetraploid:diploid nuclei in the liver. A long-term continuous gavage study at 2.5 mg/kg revealed a time dependent reduction in the ratio of tetraploid:diploid liver hepatocyte nuclei and histopathological changes that included hepatocarcinoma were also observed. There was no correlation between the severity of pathological changes and the change in nuclear ploidy ratio in this experiment and it is concluded that the changes in ploidy ratio are related to the carcinogenic effect of 3'M and are independent of its gross toxicity.

Animals↗
PubMed1985

Use of an in vivo/in vitro rat liver DNA repair assay to predict the relative rodent hepatocarcinogenic potency of 3 new azo mutagens.

The in vivo/in vitro rat liver DNA repair assay described by Mirsalis and Butterworth has been employed to compare the relative genotoxicity to the rat liver of three mutagenic analogues of the potent rat hepatocarcinogen 6-dimethylamino-phenylazobenzthiazole (6BT). The compounds evaluated were 6BT, its monomethyl analogue (6-monomethylamino-phenylazobenzthiazole; MA6BT), an analogue in which the -NMe2 group of 6BT is replaced by a piperidinyl group (6-[4-N-piperidinylphenyl]azobenzene; 6PT) and the N-cyanoethyl analogue of MA6BT (6-[p-(N-beta-cyanoethyl-N-methylamino)-phenylazo]benzthiazole; CNEt6BT). The order of relative carcinogenic potency predicted by the Salmonella mutation data was CNEt6BT much greater than MA6BT = 6BT much greater than 6PT. In contrast, that inferred from the in vivo liver DNA repair data was MA6BT greater than 6BT much greater than CNEt6BT much greater than 6PT. This divergence of predictions is discussed in terms of the differing solution properties of the four test chemicals.

Animals↗
PubMed1985

Pharmacokinetics and tissue penetration of carumonam, a new synthetic monobactam.

The pharmacokinetics of the monobactam carumonam (Ro 17-2301) as derived from serial measurement of the concentrations of this agent in serum, blister fluid, and urine were studied in six male volunteers subsequent to intravenous infusion of a single 2-g dose. Drug levels in serum in excess of 75 micrograms/ml were achieved 0.5 h after the end of infusion, declining to 2.9 micrograms/ml at 8 h. The mean serum and blister fluid elimination half-lives were 1.68 and 1.7 h, respectively. The urinary recovery of the drug by 24 h was 80.6% (range, 68.3 to 91.1%). Carumonam penetrated blister fluid well, the mean percentage penetration (as measured by the ratio of areas under curves) being 101.6%.

Adult↗
PubMed1984

Mutagenicity to Salmonella of the mono methylamino and N-cyanoethyl analogues of 4-dimethylaminoazobenzene (DAB) and 6-dimethylaminophenylazobenzthiazole (6BT).

Replacement of one of the methyl groups of the carcinogens 4-dimethylaminoazobenzene (DAB) and 6-dimethylaminophenylazobenzthiazole (6BT) with a cyanoethyl (-CH2CH2CN) substituent dramatically increases their mutagenic potency to Salmonella (strain TA98). The corresponding monomethylamino derivatives (-NHCH3) are more mutagenic than the parent dimethylamino [-N(CH3)2] compounds, but substantially less mutagenic than the cyanoethyl derivatives. All of these mutagenic activities are liver-S-9-dependent. The very similar dose response curves observed for the two cyanoethyl compounds argues for the formation of a common electrophilic intermediate from each.

Animals↗
PubMed1984

Inhibition of antibody-dependent cellular cytotoxicity and natural cytotoxicity by retinoic acid.

The present study has shown that in vitro antibody-dependent cellular cytotoxicity and natural cytotoxicity of human blood lymphocytes are inhibited by retinoic acid (5 X 10(-4)M). The inhibition of cytotoxicity is due to a specific effect on the effector lymphocytes and not to an effect on the target cells. The reduction of killing is most pronounced with prolonged incubation (20 h) of the killer cells with retinoic acid, recovery of killer and natural killer cell activity occurring with post-treatment incubation (greater than 24 h, 37 degrees C) in medium. Retinoic acid was found to have an antagonistic effect to interferon in modulating in vitro natural killer cell activity. The mechanism of inhibition by retinoic acid was uncertain but modulation of cell membrane receptors appeared to be a likely possibility.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1983

The unique role of rodents in the detection of possible human carcinogens and mutagens.

Some of the probable reasons underlying the observation that not all chemicals shown to be genotoxic in vitro are capable of eliciting tumours in rodents or humans are discussed using appropriate examples. It is suggested that a substantial proportion of the resources currently available for conducting rodent carcinogenicity bioassays should be employed in the short-term evaluation in vivo of some of the many hundreds of chemicals recently defined as genotoxic in vitro, rather than in the protracted evaluation of a few chemicals, often of unknown activity in vitro, for carcinogenicity. A decision tree approach to the evaluation of chemicals for human mutagenic/carcinogenic potential is presented which is at variance with the construction and philosophy of many of the current legislative guidelines. The immediate need for the adoption of one of the available short-term in vivo liver assays, and/or the development of a short-term in vivo rodent assay capable of concomitantly monitoring different genetic end-points in a range of organs or tissues is emphasized.

Animals↗
PubMed1983

The possible role of azoreduction in the bacterial mutagenicity of 4-dimethylaminoazobenzene (DAB) and 2 of its analogues (6BT and 5I).

The extent to which azoreductive cleavage contributes to the bacterial mutagenicity of 3 azo compounds has been investigated. The compounds studied were the rodent-liver carcinogens 4-dimethylaminoazobenzene (DAB) and 6-dimethylaminophenylazobenzthiazole (6BT), and the reported non-carcinogenic isostere 5-dimethylaminophenylazoindoline (5I). Although each of these compounds is mutagenic to Salmonella when evaluated using a pre-incubation protocol and in the presence of an induced rat-liver S9 mix, the constituent amines (cleavage products) were essentially inactive. It is therefore concluded that the mutagenic response reported for DAB, 6BT and 5I is related to metabolic activation of the intact molecules. In addition, the non-mutagenicity of 4'-phenyl-4-dimethylaminoazobenzene (4PhDAB) suggests that azoreductase activity is low in the Salmonella preincubation assay, at least as conducted in this laboratory. In the case of 4PhDAB, less than 1.4% azoreduction would yield sufficient quantities of the derived amine, 4-aminobiphenyl, for a positive mutagenic response to have been observed.

Animals↗
PubMed1983

6-p-Dimethylaminophenylazobenzothiazole: a potent hepatocarcinogen in the rat.

6-p-Dimethylaminophenylazobenzothiazole (6BT) administered at a dose of 10 mg/kg by gavage to Sprague-Dawley and Wistar-derived rats for 2 months produced marked cellular changes in the liver, including proliferation of oval cells and the formation of regenerative/hyperplastic nodules. Cellular change continued after stopping dosing at 2 months such that liver tumours were first observed after only 4 months into the study, and animals examined between 4 months and termination at 6 months showed a 75% and 85% incidence of hepatocellular carcinoma for the Sprague-Dawley and Wistar strains, respectively. This study establishes 6BT as a potent hepatocarcinogen in the rat when administered by gavage, and confirms and extends an initial brief report by Brown and Sanchorawala in 1968 of its carcinogenicity following dietary administration.

Animals↗
PubMed1983

Cyclic amines as less mutagenic replacements for dimethyl amino (--NMe2) substituents on aromatic organic compounds: implications for carcinogenicity and toxicity.

Replacement of the dimethylamino (--NMe2) group of the rodent liver carcinogens 4-dimethylaminoazobenzene (DAB) and 6-dimethylaminophenylazobenzthiazole (6BT) with a pyrrolidinyl group leads to a marked attenuation of their mutagenicity to S. typhimurium in vitro. Replacement with the 6-membered piperidinyl group leads to a virtual loss of mutagenic activity. These results are discussed within the context of a possible, albeit limited correlation between carcinogenic potency to rodents and mutagenic potency to S. typhimurium. Based on these observations, it is suggested that replacement of the --NMe2 group of a toxic/carcinogenic/mutagenic aromatic chemical by a cyclic amine substituent may produce a less toxic (etc.) analogue with similar gross molecular properties. The significance of weak (less than 2-fold increase) mutagenic responses is discussed in relation to potential carcinogenicity.

Azo Compounds↗
PubMed1983

Synthesis of 1,6-diaminopyrene from 1,6-dinitropyrene and its S9 dependent mutagenicity to S. typhimurium.

1,6-Dinitropyrene elicits a potent mutagenic response in a range of microorganisms in the absence of auxiliary metabolism (S9 mix). This activity is considered to be dependent upon nitroreductase enzymes endogenous to the marker organism producing electrophilic species from one or both of the nitro groups. In order to evaluate this suggestion 1,6-diaminopyrene has been synthesised, characterized and found to elicit a mutagenic response in strain TA98 of Salmonella typhimurium, but only when evaluated in the presence of S9 mix. The active dose-range of the diamino compound was 10(4) times higher than that of the parent dinitro compound.

Dose-Response Relationship, Drug↗
PubMed1983

Initiation/promotion versus complete carcinogenicity in the rodent liver.

4-N-Pyrrolidinylazobenzene (4N) is a close structural analog of the rodent liver carcinogen 4-dimethylaminoazobenzene (DAB). This structural similarity led us to evaluate it for genotoxic activity in vitro. We observed activity for 4N and DAB in the BHK cell transformation assay and subsequently in the Salmonella mutation assay of Ames. By a curious chance, Scribner, Miller and Miller, probably prompted by the same structural similarity, had synthesized 4N in the 1960s and found it to be noncarcinogenic to the rodent liver using a bioassay test protocol that detected DAB as carcinogenic. These findings were only described following the publication of our observations made in vitro. The conflict that apparently exists between these data can be interpreted in two separate ways. (a) Scribner et al. have suggested that 4N may be a carcinogenic initiator as opposed to a complete carcinogen like DAB. They also suggested that promotion of 4N-treated rodents with phenobarbitone might lead to the production of liver tumors. (b) We have evaluated the simpler concept that the activities observed for 4N in vitro define a carcinogenic potential that is not realized in vivo due to its rapid detoxification, at least in rodents. The first of these explanations implies that pure carcinogenic initiators may form a separate class of genotoxic agents from complete carcinogens, and perhaps of greater interest, that 4N might provide a valuable model compound for the study of carcinogenic promotion in the rodent liver. The second explanation regards potential carcinogenicity as a single property that can be defined in vitro and which may or may not be expressed in vivo depending on the enzymic environments encountered by the test chemical. It is clearly important to evaluate these different propositions in order to aid progress in the study of carcinogenic promotion, especially in the rodent liver. The presentation will describe our recent studies in vitro and in vivo in this connection.

Animals↗
PubMed1982

Comparisons between carcinogenic potency and mutagenic potency to Salmonella in a series of derivatives of 4-dimethylaminoazobenzene (DAB).

8 derivatives of the rodent liver carcinogen 4-dimethylaminoazobenzene (DAB), all of known carcinogenicity in rodents, have been evaluated in the 3 major variants of the Salmonella mutation assay; the standard plate test of Ames et al., the pre-incubation assay of Yahagi et al. and the fluctuation assay of Gatehouse. Although 4 of these chemicals were reported to be non-carcinogenic, and 4 to be of greater carcinogenic potency than DAB, each was mutagenic in a least 2 of the assays. Further, no quantitative correlation between carcinogenic and mutagenic potency was evident in any of the assay employed. The parent carcinogen DAB, 5-dimethylaminophenylazoindazole (a non-carcinogenic bacterial mutagen) and 6-dimethylaminophenylazobenzthiazole (a carcinogenic bacterial mutagen) were administered to rats via intraperitoneal injection, followed, 26 h later, by a sub-acute dose of [14C] dimethylnitrosamine. The histopathological condition of the livers of the treated animals was assessed together with a determination of the extent and nature of methylation by DMN of the DNA in the livers according to the method of O'Connor. Disturbances in both the pathological and DNA-related parameters were observed for the 2 carcinogens while control levels were seen for the non-carcinogen. Within this context the value of short-term assays conducted in vivo is discussed, especially their potential to identify potent mammalian carcinogens from among a collection of structurally related bacterial mutagens.

Animals↗