Fundamental aspects: mechanisms of carcinogenesis and dose-effect relationship.

Oncogenesis is a multistep process, which is the outcome of the accumulatio n in a single cell of genetic and epigenetic events. The events alter proto -oncogenes, which are converted into oncogenes with gain of function and tu mor suppressor genes with loss of function. Cellular mechanisms (e.g. apopt osis) protect tissues against the malignant transformation of cells and lim it, for each tissue, the combinations of efficient genetic alterations. The number of generic events required for conversion to malignancy is still de bated, but, at least in the case of many solid turners (e.g. colon carcinom as), this number may be as high as seven to eight, which implies that a gen etic instability occurs during cancer progression. In most cancers the prob ability of occurrence of oncogenic genetic events is increased by exposure to behavioural and environmental factors. In the case of chemical carcinoge ns, the dose-effect relationship is strongly affected by their effects on c ellular proliferation, which should be taken account into when the experime ntal data of animal experiments are extrapolated to human exposures. When n on-genotoxic carcinogens are considered, a threshold in the dose-effect rel ationship is generaly observed. For genotoxic carcinogens, it is hard to pr ove experimentally that a threshold exists and linear no-threshold relation ships are generally used tu evaluate permissible levels of human exposures. (C) 2000 Academie des sciences/Editions scientifiques et medicales Elsevie r SAS.