Thresholds in Genotoxicity and Carcinogenicity: Urinary Bladder Carcinogenesis

Genes and Environment

Samuel M. Cohen¹ 

[1] Department of Pathology & Microbiology and Eppley Institute for Cancer Research University of Nebraska Medical Center

关键词: sodium saccharin;    calculi;    arsenic;    acetylaminofluorene;    genotoxicity;   

DOI  :  10.3123/jemsge.30.132

学科分类：分子生物学，细胞生物学和基因

来源: Japanese Environmental Mutagen Society / Nihon Kankyo Hen igen Gakkai

【 摘 要 】

References(26)Cited-By(5)Cancer is due to multiple alterations to DNA. Chemicals can increase the cancer risk by directly damaging DNA (DNA reactivity) or by increasing cell proliferation (DNA replications), increasing the number of opportunities for spontaneous DNA damage. Genotoxicity is a more comprehensive term than DNA reactivity. Many of the mechanisms of genotoxicity, such as clastogenicity, inhibition of DNA repair, or damage to the mitotic apparatus, produce DNA damage indirectly. These non-DNA reactive mechanisms involve interactions with proteins and mechanistically are threshold phenomena. 2-Acetylaminofluorene (AAF) is DNA reactive. Its dose response for urinary bladder DNA adduct formation is linear, whereas the tumor response is non-linear. Non-linearity is at the dose at which increased cell proliferation occurs, related to the threshold phenomenon of cytotoxicity. Non-linearity for DNA reactive carcinogens can also be produced by changes in metabolic processes of activation and/or deactivation due to saturable kinetics. Arsenic produces bladder cancer with a non-linear dose response in animal models and humans. Genotoxicity of arsenic occurs secondarily to indirect mechanisms, not DNA reactivity, it has a non-linear dose response, and the genotoxic mechanism appears to have a threshold, occurring only at doses in excess of toxic concentrations. Numerous non-genotoxic agents have been identified as bladder carcinogens in rodent models, most acting by inducing cytotoxicity with regenerative proliferation. Cytotoxicity can be produced by formation of urinary solids or by urinary reactive chemicals. Urinary solids are a defined threshold phenomenon based on the physical-chemical property of solubility. Likewise, chemical induction of cytotoxicity is a known threshold phenomenon. Non-genotoxic chemicals have a threshold dose response with respect to carcinogenesis, as do most genotoxic agents. DNA reactive chemicals have a non-linear dose response.

【 授权许可】

Unknown