Role of tumor promotion in affecting the multi-hit nature of carcinogenesis

The assessment of risk from low-level exposure to radiation and chemicals is hindered by the basic lack of scientific understanding of the complex nature of the multiple levels of protective or synergistic interactions. Radiation and chemicals have the potential of inducing mutations, cell death and altered gene expression. The biological consequences of each of these effects is again complex, since many factors can enhance or mask the effect of a single mutation, cytotoxic or gene modulatory change. Carcinogenesis, representing but one chronic disease state, is a multi-step process, involving the clonal expansion of a single altered cell (that is, the initiation event). Radiation and chemicals appear to contribute to the initiation process by their ability to induce viable mutations. Insufficient theoretical and empirical knowledge precludes a determination of whether mutagenesis and, hence, initiation exhibit a threshold phenomenon. Because of a variety of redundancy mechanisms on the genetic and cellular levels, the physiological impact of a single dysfunctional cell is felt only after it is amplified to a large number (the promotion phase of carcinogenesis). Radiation and chemical-induced cytotoxicity, as well as noncytotoxic chemical induction of mitogenesis, can induce surviving single dysfunctional stem cells to multiply. If during this multiplication of dysfunctional cells, the initiated cells are further exposed chronically to low levels of mutagens, there is an enhanced probability of additional genetic changes. The accumulation of foci of dysfunctional cells can occur in any stem cell population of any tissue. As with mutagens, the existence of threshold levels for promoting conditions and chemicals is still not yet scientifically validated. However, specific examples of the actions of a few promoters does seem to be consistent with that idea. The concepts of initiation and promotion imply the existence of anti-initiation and antipromotion conditions. Together with genetic factors, the complex and unpredictable interactions of radiation and chemicals as initiators, anti-initiators, promoters and antipromoters, defy prospects of an easy means to predict the consequences of exposure to chronic low levels of radiation and chemicals.