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J A Styles

Publications and source records attributed to J A Styles.

At least 55 records · Page 3Linked to original sources
PubMed1978

An evaluation of 6 short-term tests for detecting organic chemical carcinogens.

A number of tests have been described which are thought to be capable of identifying carcinogens without using the actual induction of cancer as an endpoint. This study compared the performance of 6 such tests on a selection of 120 organic chemicals. The tests studies were: (1) mutation of Salmonella typhimurium; (2) cell transformation; (3) degranulation of endoplasmic reticulum; (4) sebaceous gland suppression; (5) tetrazolium reduction and (6) subcutaneous implant. A further 4 tests were examined briefly, but were not included in the complete evaluation. The chemicals were classified into carcinogens (58) and non-carcinogens (62) on the basis of published experimental data, and into 1 of 4 broad chemical classes. There was considerable variation between tests in their ability to predict carcinogenicity, with the cell-transformation test and the bacterial-mutation test being the most accurate (94% and 93% accurate respectively). These 2 tests were considered to be of general use in screening, since they were clearly more accurate than the others. Statistical consideration of various combinations of these tests showed that the use of cell transformation and bacterial mutation together, provide an advantage over the use of either test alone. The inclusion of the other 4 tests in a screening battery predictably resulted in a great increase in overall inaccuracy and loss of discrimination, even though the detection of carcinogens is improved. All the tests were shown to generate both false positive and false negative results, a situation which may be controlled by the use, where possible, of appropriate chemical-class controls, to identify the test which is optimal for the class of chemical under test. Structural analogy may have a part to play in the rapid detection of environmental carcinogens, and some general guidelines for its use are given.

Animals↗
PubMed1978

In vitro evaluation of some derivatives of the carcinogen Butter Yellow: implications for environmental screening.

The rat-liver carcinogen 4-dimethylaminoazobenzene (Butter Yellow, DAB) and 12 of its structural analogues have been evaluated in a cell transformation assay. Eight of these analogues have already been tested for carcinogenicity in rats, whilst the remaining 4 are new or hitherto untested. Benzidine and its 3,3'-disulphonic acid derivative have also been evaluated. The in vitro results agree with long-term animal data for 8 compounds but disagree in finding DAB-4'-sulphonic acid, 4-trifluoromethyl-DAB and 4-diethylaminoazo-benzene positive. Possible reasons for these divergencies are discussed. It is concluded that 9-phenylazojulolidine and N-methyl-5-phenylazoindoline have carcinogenic potential and that 3,5-dimethyl-4-aminoazobenzene and 4-aminoazobenzene-4'-sulphonic acid are likely to prove non-carcinogenic. Addition of azobenzene to the in vitro assay medium increases the transforming potency of DAB 25-fold. It is suggested that it acts as a competitive substrate for one of the enzymes that detoxify DAB, and that this effect is related to that produced by norharman. Sulphonic-acid derivatives of established carcinogens are usually inactive. The basis of this effect has been investigated, and it is suggested that it can operate by two separate mechanisms. It has been established that this assay cannot be relied upon to predict the in vivo potency of a carcinogen. Consideration has been given to possible changes which could be made to the liver activation system (the S-9 mix) currently used in in vitro carcinogenicity assays, and a diagram is presented of the metabolic conversions of a compound which might lead to mutation or tumour formation. This enables the term potential carcinogen to be accurately defined, and indicates a possible difference between absolute non-carcinogens and compounds which fail to produce cancer in vivo.

Cell Line↗
PubMed1978

Potentially carcinogenic analogues of the carcinogen hexamethylphosphoramide: evaluation in vitro.

Experiments conducted in vitro are described which indicate that a family of specifically substituted phosphoramides may share the carcinogenic properties displayed by the structurally novel carcinogen, hexamethylphosphoramide (HMPA). Most of the analogues tested only gave a positive response in vitro when using a substantially modified liver homogenate activation system (S-9 mix). The analogy drawn in our earlier paper between this new class of potential carcinogens and the nitrosamine carcinogens, has been strengthened. The following compounds gave a positive response in the cell transformation assay of Styles: hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide, hexamethylphosphorothioic triamide, tripiperidinophosphine oxide, phosphorothioic trimorpholide and diethoxymorpholinophosphine oxide (DEMPA).

Amides↗
PubMed1978

Thiophene analogues of the carcinogens benzidine and 4-aminobiphenyl: evaluation in vitro.

A biologically active molecule with one or more aromatic rings often retains its activity when one of these rings is replaced by an isosteric and/or isoelectronic aromatic ring. Consideration has been given to whether this effect can be expected to apply to aromatic organic carcinogens. The literature relevant to this topic has been reviewed and the thiophene analogues of the carcinogens benzidine and 4-aminobiphenyl have been synthesized and evaluated for potential carcinogenicity. The compounds prepared were 5-p-acetamidophenyl-2-thiophenamine hydrochloride (XIII), 5-phenyl-2-thiophenamine hydrochloride (XIV), N-(5-p-acetamido-phenylthiophen-2-yl)acetamide (XV) and N-(5-phenylthiophen-2-yl)-acetamide (XVI) (see Chart for structures). Each compound was evaluated in the Salmonella reverse-mutation assay of Ames and the cell-transformation assay of Styles. The activity profiles observed for these compounds in vitro were consistent with their known chemistry, and indicate potential carcinogenicity. However, their overall chemical and biological behaviour casts doubt upon whether they would be capable of eliciting tumours in vivo. Because it is important to establish the degree of reliance which can be placed upon in vitro predictions of potential carcinogenicity generated for structurally new compounds, one of the thiophene derivatives, N-(5-phenylthiophen-2-yl)acetamide ((XVI), is currently being evaluated for carcinogenicity in mice.

Aminobiphenyl Compounds↗
PubMed1977

A method for detecting carcinogenic organic chemicals using mammalian cells in culture.

A method for testing organic chemicals for their carcinogenic potential is described. Baby hamster kidney cells (BHK-21/C1 13) were exposed to different doses of test compound in liquid tissue culture medium containing rat liver post-mitochondrial supernatant and cofactors (S-9 mix) to aid metabolism, but without serum. Survival of cells following exposure to the compound was assessed by cloning in liquid growth medium. Transformation was assessed by colony growth in semi-solid agar. The dose-response curve for survival was used to determine the LC50 of the compound. A dose-response curve for transformation was constructed and a 5-fold increase in transformation frequency at the LC50 was regarded as a positive test result. The method may also be used for testing gaseous compounds. Cells grown in monolayers and overlaid with serum-free medium and S-9 mix were exposed to vinyl chloride gas mixed with air. After exposure, the treated cells were trypsinized, resuspended in growth medium, and survival and transformation assays performed. The methods described are illustrated by examples taken from an evaluation study using 120 compounds and found to be more than 90% accurate in distinguishing between carcinogens and non-carcinogens.

Animals↗
PubMed1977

Selection of an in vitro carcinogenicity test for derivatives of the carcinogen hexamethylphosphoramide.

The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced.

Anilides↗
PubMed1976

Evaluation of six short term tests for detecting organic chemical carcinogens and recommendations for their use.

Six short term tests for detecting carcinogenicity have been evaluated using 120 compounds, of which half were carcinogens and the rest non-carcinogens. The results obtained indicate that the Ames test and a "cell transformation" assay are both sufficiently sensitive to carcinogenicity, or the lack of it, in the compounds studied to enable them to be employed for detecting potential carcinogens. The consequences of using short term tests under various screening conditions have been explored. In order to have confidence in the results obtained for new or previously untested compounds it is important to use such tests in a carefully controlled manner.

Alkylating Agents↗
PubMed1976

DNA content of cultured mammalian cells exposed to smoke and smoke fractions from cigarettes containing tobacco or NSM, a tobacco substitute.

The effects of smoke and smoke fractions from tobacco and a substitute smoking material (NSM) on the DNA content of mammaliam cells in culture were measured. Tobacco smoke caused significant (P less than 0.001) changes in the DNA content of all the mammalian cells exposed compared with controls. NSM smoke did not have a significant effect on the DNA content of the exposed cells (P less than 0.95). Smoke from blends of NSM and tobacco caused changes in DNA content in proportion to the amount of tobacco in the mixtures. Condensate from cigarettes containing tobacco or blends of tobacco and NSM caused significant (P less than 0.001) changes in DNA content of mammalian cell populations in culture, whereas equal weights of condensate from NSM alone or NSM containing nicotine did not cause significant changes (P less than 0.05). NSM produces 28% of the weight of condensate per cigarette in comparison with tabacco and would, therefore, be expected to be far less biologically active than tobacco. Filtered smoke from cigarettes containing tobacco caused significant (P less than 0.001) changes in the DNA content of mammalian cells in culture. These changes were quantitatively similar to those caused by whole smoke suggesting that the gas phase of cigarette smoke is biologically more reactive than the particulate phase. The filtered smoke from the substitute smoking material NSM did not cause significant (P less than 0.95) changes in DNA content of cultured mammalian cells. Filtered smoke from blends of NSM and tobacco caused changes in DNA content in proportion to the amount of tobacco in the mixture.

Animals↗