Mutation Research\/reviews in Genetic Toxicology 

About: Mutation Research\/reviews in Genetic Toxicology is an academic journal. The journal publishes majorly in the area(s): Genotoxicity & DNA damage. Over the lifetime, 366 publications have been published receiving 27239 citations.

Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP.

Abstract: An analysis is presented in which are evaluated correlations among chemical structure, mutagenicity to Salmonella, and carcinogenicity to rats and mice among 301 chemicals tested by the U.S. NTP. Overall, there was a high correlation between structural alerts to DNA reactivity and mutagenicity, but the correlation of either property with carcinogenicity was low. If rodent carcinogenicity is regarded as a singular property of chemicals, then neither structural alerts nor mutagenicity to Salmonella are effective in its prediction. Given this, the database was fragmented and new correlations sought between the derived sub-groups. First, the 301 chemicals were segregated into six broad chemical groupings. Second, the rodent cancer data were partially segregated by target tissue. Using the previously assigned structural alerts to DNA reactivity (electrophilicity), the chemicals were split into 154 alerting chemicals and 147 non-alerting chemicals. The alerting chemicals were split into three chemical groups; aromatic amino/nitro-types, alkylating agents and miscellaneous structurally-alerting groups. The non-alerting chemicals were subjectively split into three broad categories; non-alerting, non-alerting containing a non-reactive halogen group, and non-alerting chemicals with minor concerns about a possible structural alert. The tumor data for all 301 chemicals are re-presented according to these six chemical groupings. The most significant findings to emerge from comparisons among these six groups of chemicals were as follows: 1. (a) Most of the rodent carcinogens, including most of the 2-species and/or multiple site carcinogens, were among the structurally alerting chemicals. 2. (b) Most of the structurally alerting chemicals were mutagenic; 84% of the carcinogens and 66% of the non-carcinogens. 100% of the 33 aromatic amino/nitro-type 2-species carcinogens were mutagenic. Thus, for structurally alerting chemicals, the Salmonella assay showed high sensitivity and low specificity (0.84 and 0.33, respectively). 3. (c) Among the 147 non-alerting chemicals From these facts we conclude that the concepts of genotoxic and non-genotoxic rodent carcinogenicity are worthy of continued attention. Also, that it is meaningless to discuss the sensitivity/specificity of the Salmonella assay without defining the broad chemical classes under discussion. This last conclusion is important to any model for screening environmental chemicals for potential carcinogens. Some rodent tissues, such as the lung and Zymbal's gland, are uniquely associated with genotoxic carcinogenesis, while others are equally susceptible to non-genotoxic carcinogenesis. Four such tissues are currently studied as possible sites of non-genotoxic carcinogenicity, and these were separately considered; male rat kidney-specific carcinogenic effects, rodent leukaemogens, rodent thyroid gland carcinogens and mouse liver carcinogens (the latter being the largest group, 97 of the 301 chemicals having increased tumor incidences in this tissue). Chemicals inducing tumors in these tissues were of disparate chemical classes and were predominantly non-mutagenic. These facts, together with the specificity of teh carcinogenic effects, is indicative of carcinogenicity resulting from a specific interaction between the chemical and the tissue, rather than it being an intrinsic and unique property of the chemical. Even when tumours in these four tissues were eliminated from the database, the Salmonella assay was only positive for 67% of the remaining 113 carcinogens (derived from a total of 162 carcinogens in the database). This indicates that a range of additional sites are subject to tissue-specific carcinogenesis by putative non-genotoxins. A distribution chart is presented which represents the 301 chemicals according to the 6 chemical groupings and the level of carcinogenic effect. From this it becomes apparent that the NTP database is dominated by two major groups of chemicals. First, a group of structurally-alerting and mutagenic carcinogens that are predominantly active in both species and/or at multiple sites, and second a group of non-alerting, non-mutagenic non-carcinogens. In between these two groups is a diffusely spread group of species/sex/tissue specific carcinogens, only some of which are mutagenic and/or structurally alerting. It is among the last group of carcinogens that reseach is required to understand their mechanism of action and their significance to man. The in vivo mammalian cell genotoxicity database of the TNP failed to distinguish these last carcinogens from the non-carcinogens, and this endorses that research into the mode of action of these carcinogens should not be concerned with their genotoxicity. Our overall conclusion is that rodent carcinogenicity can no longer be regarded as a single entity. Structural alerts and mutagenicity to Salmonella are useful but non-definitive indicators of the overt carcinogens in the database, and the activity of the remaining (putative non-genotoxic) carcinogens is no predictable using current techniques. To pool rodent carcinogens and to attempt to find a single method for their prediction is no longer tenable. Rather, it is suggested that genotoxic carcinogens should be predicted by reference to chemical structure and the intelligent use of in vitro and in vivo genotoxicity assays, and that non-genotoxic carcinogens require basic studies to understand the subtle effects that occur in rodents upon protracted dosing with chemicals. It will also be necessary to consider which of these effects may be ancillary and which are critical to increases in tumor incidences. Some such indicators are emerging (e.g. peroxisome proliferation in the rodent liver), but much uncertainty remains in this area. The suspected nature of non-genotoxic carcinogenesis indicates that studies into its mechanisms and prediction will be most effectively progressed in vivo, rather than in vitro.

Mutagenicity and genotoxicity of nitroarenes: All nitro-containing chemicals were not created equal

Abstract: The nitrated polycyclic aromatic hydrocarbons constitute a group of chemicals of environmental concern which display a broad spectrum of mutagenic, genotoxic and carcinogenic properties. Some members of the group are the most potent direct-acting bacterial mutagens while others exhibit low levels of potencies which require metabolic activation mixtures. Bacterial mutagenicity is dependent upon reduction of the nitro function. In mammalian cell systems the genetic and genotoxic effects of these nitrated chemicals include the induction of unscheduled DNA synthesis, sister-chromatid exchanges, chromosomal aberrations, gene mutations and cell transformation. The qualitative as well as quantitative expression of these effects is dependent upon the species and tissue of origin as well as culture history of the cell which in turn determine their enzymic capabilities and the conversion of these nitroarenes to ultimate mutagens and genotoxicants. In eukaryotic cells the following bioactivation pathways have been recognized: (a) reduction of the nitro moiety, (b) ring oxidation (the nature of which is influenced by the nitro function) followed by reduction of the nitro group, and (c) ring oxidation without concomitant reduction of the nitro moiety.

Sister-chromatid exchanges: a report of the GENE-TOX program.

Abstract: This paper reviews the ability of a number of chemicals to induce sister-chromatid exchanges (SCEs). The SCE data for animal cells in vivo and in vitro, and human cells in vitro are presented in 6 tables according to their relative effectiveness. A seventh table summarizes what is known about the effects of specific chemicals on SCEs for humans exposed in vivo. The data support the concept that SCEs provide a useful indication of exposure, although the mechanism and biological significance of SCE formation still remain to be elucidated.

Mutagenicity of azo dyes: structure-activity relationships.

Abstract: Azo dyes are extensively used in textile, printing, leather, paper making, drug and food industries. Following oral exposure, azo dyes are metabolized to aromatic amines by intestinal microflora or liver azoreductases. Aromatic amines are further metabolized to genotoxic compounds by mammalian microsomal enzymes. Many of these aromatic amines are mutagenic in the Ames Salmonella/microsomal assay system. The chemical structure of many mutagenic azo dyes was reviewed, and we found that the biologically active dyes are mainly limited to those compounds containing p-phenylenediamine and benzidine moieties. It was found that for the phenylenediamine moiety, methylation or substitution of a nitro group for an amino group does not decrease mutagenicity. However, sulfonation, carboxylation, deamination, or substitution of an ethyl alcohol or an acetyl group for the hydrogen in the amino groups leads to a decrease in the mutagenic activity. For the benzidine moiety, methylation, methoxylation, halogenation or substitution of an acetyl group for hydrogen in the amino group does not affect mutagenicity, but complexation with copper ions diminishes mutagenicity. The mutagenicity of benzidine or its derivatives is also decreased when in the form of a hydrochloride salt with only one exception. Mutagenicity of azo dyes can, therefore, be predicted by these structure-activity relationships.