Dose response and potential thresholds in proliferation and cell survival and death

Tumourigenicity is the result of the balance between mutations, epigenetic changes, cell
proliferation and cell death. Cell proliferation can be a primary effect of the carcinogen or
a secondary effect consequent to cell toxicity [1]. For cancer risk assessment, the role of
cell proliferation and cell death (apoptosis and necrosis) is particularly critical for nongenotoxic
agents because a threshold effect is likely (Fig. 5.1). Whether induction or
inhibition of apoptosis (or necrosis) is carcinogenic may be dependent on the type and
concentration of the carcinogen. Apoptosis is considered to be anti-carcinogenic when
eliminating mutated cells after exposure to genotoxic carcinogens or epigenetically
modified cells after exposure to non-genotoxic carcinogens. On the other hand, excessive
elimination of cells can induce compensatory cell proliferation to restore homeostasis.
This process will contribute to expansion of mutated or modified cells. Moreover, rapid
proliferation may in itself lead to genomic instability.