The genetic toxicology of acridines

Acridine and its derivatives are planar polycyclic aromatic molecules which bind tightly but reversibly to DNA by intercalation, but do not usually covalently interact with it. Acridines have a broad spectrum of biological activities, and a number of derivatives are widely used as antibacterial, antiprotozoal and anticancer drugs. Simple acridines show activity as frameshift mutagens, especially in bacteriophage and bacterial assays, by virtue of their intercalative DNA-binding ability. Acridines bearing additional fused aromatic rings (benzacridines) show little activity as frameshift mutagens, but interact covalently with DNA following metabolic activation (forming predominantly base-pair substitution mutations). Compounds where the acridine acts as a carrier to target alkylating agents to DNA (e.g. the ICR compounds) cause predominantly frameshift as well as base-pair substitution mutations in both bacterial and mammalian cells. Nitroacridines may act as simple acridines or (following nitro group reduction) as alkylating agents, depending upon the position of the nitro group. Acridine-based topoisomerase II inhibitors, although frameshift mutagens in bacteria and bacteriophage systems, are primarily chromosomal mutagens in mammalian cells. These mutagenic activities are important, since the compounds have considerable potential as clinical antitumour drugs. Although evidence suggests that simple acridines are not animal or human carcinogens, a number of the derived compounds are highly active in this capacity.     

DNA amplification in genetic toxicology

Chemical compounds can cause amplification of specific DNA sequences. DNA amplification may result in an enhanced production of gene products which help cells to cope with the chemicals. This may lead to a resistance of the cells toward the agent. Additionally, initiation of transformation or progression of transformed cells to tumorigenicity may also involve DNA amplification. Therefore, it is of interest to study the potential of chemicals to induce DNA amplification. This report focuses on the investigation of a variety of chemicals in 2 systems with which the amplification of viral DNA is measured within cells in culture. One model system comprises the measurement of SV40 DNA content in an SV40-transformed Chinese hamster cell line following chemical treatment. Antitumor agents as well as genotoxic and non-genotoxic compounds were studied in this system as a first step to determine the DNA amplification-inducing potential of a variety of differently acting chemical compounds. Also, a novel assay based on adeno-associated virus infection of cells is described. This system may offer the possibility of studying DNA amplification in a variety of different target cells. For the future, the need is stressed to develop and analyze versatile systems to study amplification of specific target genes in untransformed cells and in tumor cells.     

The genetic toxicology of ortho-toluidine.

ortho-Toluidine, a monosubstituted aniline and an intermediate in the dyeing industry, with a number of uses in other fields such as rubber processing and pharmaceutical production, has been in production for over 100 years. It is metabolised in vivo into a number of compounds, some of which are active genotoxins. It has been demonstrated to be a carcinogen in mice and rats and is a suspected human carcinogen. o-Toluidine has a wide range of genetic effects. It is a weak bacterial, fungal and mammalian mutagen, although the conditions required are stringent. The metabolising system used is of particular importance. o-Toluidine is also a clastogen, generally on prolonged exposure. It induces aneuploidy in both fungi and mammalian cultured cells. It also produces DNA damage (single-strand breaks and unscheduled DNA synthesis, UDS) and causes cell transformation. o-Toluidine can be considered a general genotoxin demonstrable under special conditions, particularly with regard to metabolism.     

The genetic toxicology of Gene-Tox non-carcinogens

The Gene-Tox Program has identified 61 chemicals that have been tested in chronic rodent carcinogenesis bioassays and found to be inactive. The genetic toxicology data of these 61 non-carcinogens is reviewed and summarized. A large proportion of these chemicals have been tested to a limited extent in genetic toxicity bioassays: 32 in 2 tests or less. Of the remaining 29 chemicals, 28% have been tested in 9 or more tests which encompass a range of genetic endpoints: gene mutation, chromosomal effects, other genetic endpoints, and cell transformation. The genetic toxicity of 12 chemicals with sufficient data is discussed in detail: benzoin, caffeine caprolactam, ethanol, halothane, hycanthone methanesulfonate, malathion, maleic hydrazide, methotrexate, 1-naphthylamine, 4-nitro-o-phenylenediamine, and p-phenylenediamine. A new technique for the evaluation of multiple test data, the "genetic activity profile", has been applied to 6 of these chemicals, allowing the qualitative and quantitative information to be compared collectively. In the evaluation of the genotoxicity effects of these non-carcinogens, a number of discrepancies between the results from genetic toxicity bioassays and chronic rodent bioassays have been uncovered. These discrepancies are discussed in light of current knowledge on the strengths and weaknesses of both genetic toxicity bioassays and chronic rodent bioassays.     

The genetic toxicology of putative nongenotoxic carcinogens

This report examines a group of putative nongenotoxic carcinogens that have been cited in the published literature. Using short-term test data from the U.S. Environmental Protection Agency/International Agency for Research on Cancer genetic activity profile (EPA/IARC GAP) database we have classified these agents on the basis of their mutagenicity emphasizing three genetic endpoints: gene mutation, chromosomal aberration and aneuploidy. On the basis of results of short-term tests for these effects, we have defined criteria for evidence of mutagenicity (and nonmutagenicity) and have applied these criteria in classifying the group of putative nongenotoxic carcinogens. The results from this evaluation based on the EPA/IARC GAP database are presented along with a summary of the short-term test data for each chemical and the relevant carcinogenicity results from the NTP, Gene-Tox and IARC databases. The data clearly demonstrate that many of the putative nongenotoxic carcinogens that have been adequately tested in short-term bioassays induce gene or chromosomal mutations or aneuploidy.     

The genetic toxicology of benzoin and caprolactam

A summary is presented of the published literature on the genetic toxicology of the two rodent non-carcinogens benzoin and caprolactam.