Fundamental aspects: mechanisms of carcinogenesis and dose-effect relationship

Oncogenesis is a multistep process, which is the outcome of the accumulation in a single cell of genetic and epigenetic events. The events alter proto-oncogenes, which are converted into oncogenes with gain of function and tumor suppressor genes with loss of function. Cellular mechanisms (e.g. apoptosis) protect tissues against the malignant transformation of cells and limit, for each tissue, the combinations of efficient genetic alterations. The number of genetic events required for conversion to malignancy is still debated, but, at least in the case of many solid tumors (e.g. colon carcinomas), this number may be as high as seven to eight, which implies that a genetic instability occurs during cancer progression. In most cancers the probability of occurrence of oncogenic genetic events is increased by exposure to behavioural and environmental factors. In the case of chemical carcinogens, the dose-effect relationship is strongly affected by their effects on cellular proliferation, which should be taken account into when the experimental data of animal experiments are extrapolated to human exposures. When non-genotoxic carcinogens are considered, a threshold in the dose-effect relationship is generally observed. For genotoxic carcinogens, it is hard to prove experimentally that a threshold exists and linear no-threshold relationships are generally used to evaluate permissible levels of human exposures.