Possible Mechanisms of Practical Thresholds for Genotoxicity

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  • Nohmi Takehiko
    Division of Genetics and Mutagenesis, National Institute of Health Sciences

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An axiom in regulatory sciences is that there are no thresholds for genotoxicity of chemicals. It leads to another default assumption that genotoxic carcinogens impose cancer risk on humans without thresholds, i.e., a linear non-threshold model. Therefore, no acceptable daily intake (ADI) is set for food additives, pesticides and veterinary drugs when they have genotoxic and carcinogenic activities. However, humans possess a number of defense mechanisms such as metabolic inactivation, DNA repair, error-free translesion DNA synthesis and so on. These mechanisms may constitute practical thresholds for genotoxicity. Error-free translesion DNA synthesis is a process where DNA polymerases bypass lesions in DNA by insertion of correct bases opposite the lesion and continue replication of whole chromosomes. These mechanisms might have been evolved because organisms from bacteria to humans are exposed to endogenous as well as exogenous genotoxic compounds. In fact, levels of spontaneous mutagenesis are strongly influenced by ability of DNA repair and translesion DNA synthesis of the host cells. Here, I show evidence that DNA repair and translesion DNA synthesis play roles in practical genotoxic thresholds in Salmonella typhimurium used for bacterial mutation assays, and discuss future directions of the research on genotoxic thresholds in vivo.<br>

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