Theoretical considerations for thresholds in chemical carcinogenesis.

There is increasing evidence for non-linear relationships for gene mutations, chromosomal aberrations and even tumor incidences in response to low doses of genotoxic carcinogens. To attain the biological relevance of such non-linear responses, there is a need to identify the underlying defense mechanisms that allow tolerance to low doses of genotoxicants. This communication discusses presumptive cancer prevention mechanisms that may contribute to thresholds, i.e. points of departure, for each endpoint, from initial DNA lesion to tumor formation. We discuss a sequential order of genome protection during carcinogenesis where genotoxicant scavenging, cellular efflux, DNA repair, elimination of damaged cells by apoptosis, autophagy, silencing by DNA damage-triggered replicative senescence, and finally, elimination of transformed (premalignant) cells by the immune system are thought to be responsible for a threshold in tumor formation. We highlight DNA repair, for which experimental evidence has been recently provided to dictate a role in PoDs. In conclusion, from a theoretical perspective it is reasonable to posit that tolerance to low dose levels exists for each requisite step of tumor formation and these tolerance mechanisms are critical in determining thresholds in chemical carcinogenesis.