Non-genotoxic carcinogenesis: implications for testing and extrapolation to man.

It is argued that non-genotoxic mechanisms may be more important than genotoxic mechanisms in the genesis of cancer and that the use of tests for genotoxicity to screen chemicals for carcinogenicity in the hope of being able to prevent human cancer is ill-based. The general applicability of the two-stage model for carcinogenesis is also questioned. It is argued that tumour promotion as a second step in a two-stage process is only one of many possible non-genotoxic mechanisms involved in carcinogenesis and not a very important one at that. Many cancers arise against a background of prolonged disturbance of hormonal status leading to hypertrophy and/or hyperplasia of the tissues in which cancers eventually arise. This sequence of events does not fit the two-stage paradigm according to which genetic-damage (initiation) is followed by the stimulation of cell proliferation (promotion). In hormonal carcinogenesis cellular proliferation precedes genetic damage. It is suggested that the genetic damage that occurs as a secondary event in hormonal carcinogenesis may be due, not to exposure to environmental (exogenous) mutagens, but to endogenous mutagens generated during normal metabolic processes in hyperplastic and hypermetabolic cells. Perhaps the rate of damage to DNA in such cells overwhelms the capacity for DNA repair. Cancer is an ageing-related disease. The incidence and severity of both non-neoplastic and neoplastic lesions are greatly enhanced by over-nutrition in laboratory rats.(ABSTRACT TRUNCATED AT 250 WORDS)