It has been known for decades that mutagenicity plays an important role in the activity of most carcinogens. This mutagenicity can result from direct damage to DNA through a chemical being DNA reactive or from indirect effects, such as through the production of oxygen radicals that then react with DNA. This article presents a set of key events whereby DNA reactivity initiates the process of carcinogenicity that leads to the subsequent mutation induction and enhanced cell proliferation that ultimately results in tumor development. This set of key events for DNA-reactive chemicals was applied to two case studies (aflatoxin B1 and dichloromethane) with the aim of assessing the utility of the Human Relevance Framework (HRF) for this class of chemicals. The conclusions were that the HRF was a viable approach for the use of mechanistic data for DNA-reactive chemicals obtained from both laboratory animals and human cells in vivo and in vitro for predicting human carcinogenicity. In the case of aflatoxin B1, the HRF could be used to predict that carcinogenicity in humans was a likely outcome. In contrast, the HRF predicted that the human carcinogenic potential of dichloromethane was at best less likely than in rodents; this conclusion was supported by the available epidemiological data.

DNA-Reactive Carcinogens: Mode of Action and Human Cancer Hazard

Mechanisms of chemical carcinogenesis and application to human cancer risk assessment

DNA reactive and epigenetic carcinogens.

Application of mode-of-action considerations in human cancer risk assessment

A differential DNA repair test was evaluated in vitro, using derivatives of E. coli K-12 343/113 with the genotype uvrB−/recA− and uvrB+/recA+. The aim of this study was to characterize the sensitivity of the assay to different compounds in vitro and thereby provide information on the usefulness of this end-point as an indicator of genotoxicity in a host-mediated assay. Sixty-one compounds from diverse chemical groups were tested and of these 32 gave a positive result. The results obtained were compared with results from the Ames test and were in agreement for 49 out of the 61 compounds tested. Chemicals that were detected in this test but negative in the Ames test were 4-aminophenol, catechol, diethylstilbestrol, thioacetamide and thiourea. Seven of the compounds tested gave a negative result in E. coli but were positive in Salmonella. These were 4-aminobiphenyl, benzo[a]pyrene, cyclophosphamide, 1-naphthylamine, N-nitrosobutylpropylamine, quinoline and 2-toluidine. The performance of the in vitro test and reasons for the discrepant results with the Ames test are discussed. The overall concordance between the two tests was about 80%. On the basis of these results we consider these bacterial strains, and differential DNA repair as an end-point, to be sufficiently accurate as an indicator of genotoxicity in vitro and thereby also in vivo.

An evaluation of the E. coli K-12 uvrB/recA DNA repair host-mediated assay. I. In vitro sensitivity of the bacteria to 61 compounds.

This book contains the following ten chapters: A Historical Perspective of Chemical Carinogenesis; Perspectives on the Somatic Mutation Model of Carcinogenesis; Perspectives on Detection of Chemical Carcinogens as Mutagens; Metabolic Activation; Measurements of Chemical Interactions with DNA; Mammalian Cell DNA Repair Assays for Carcinogens; Mutation in Cultured Mammalian Cells; Comparison of Carcinogenesis and Mutagenesis of Mammalian Cells in Culture; A Comparison of the Animal and Human Carcinogenicity of Environmental, Occupational and Therapeutic Chemicals; and The Question of the Existence of Thresholds: Extrapolation from High to Low Dose.

W.G. Flamm

Papers

Mechanisms and toxicity of chemical carcinogens and Mutagens