Urinary bladder carcinogenesis by DNA reactive and non-reactive chemicals: Non-linearities and thresholds

Chemicals can increase the risk of cancer by either directly damaging DNA (DNA reactive) or increasing cell proliferation. DNA reactive carcinogens involve activation to reactive metabolites, forming DNA adducts which are mutagenic. The presence of numerous cellular repair processes suggest that these could have a threshold. The issues involved are described for 2-acetylaminofluorene urinary bladder carcinogenicity. Chemicals that act by increasing cell proliferation involve either increased cell births or decreased cell deaths, leading to an accumulation of cells. Multiple mechanisms can produce these effects, most of which have threshold processes. Arsenicals appear to act by inducing cellular cytotoxicity with regenerative proliferation, induced by generation of reactive trivalent forms which interact with critical sulfhydryl groups in cells. A more definitive threshold response is illustrated for the formation of urinary solids, either calculi (melamine) amorphous calcium phosphate-containing precipitate (sodium saccharin) or crystalluria (PPAR g agonists). Increasing evidence strongly supports the concept of thresholds in carcinogenesis, not only for chemicals acting by increasing cell proliferation but also for those acting by DNA reactivity.