The role of cytotoxicity in the process of carcinogenesis.

Enhanced cancer prevalence findings restricted to high, cytotoxic dose levels in long-term animal cancer studies are generally assumed to be a consequence of-indirect or secondary-mutational effects, e.g. DNA damage mediated by generation of reactive oxygen species (ROS) or replication errors occurring during regenerative cell proliferation. An alternative explanation is provided by recent findings suggesting that cell lysis caused by cytotoxic doses of non-genotoxic agents may give rise to tumor promotion by selective growth stimulation of pre-existing (already mutated) dormant tumor precursor cells. This growth stimulation is assumed to be mediated by damage-associated molecular pattern (DAMP) signaling ("sterile inflammation"). Here, we discuss the differing views on cancer findings observed only at high cytotoxic doses in particular with respect to the implications for the risk assessment of the agents.