Combined effect of radiation and other agents: is there a synergism trap?

Most assessments of possible deleterious outcomes from environmental and occupational exposures concentrate on single agents and neglect the potential for combined effects--that is, synergisms or antagonisms. Biomechanistic considerations based on multistep processes, such as carcinogenesis, indicate the potential for highly detrimental interactions if two or more consecutive rate-limiting steps are specifically effected by different agents. However, low specificity toward molecular structure or DNA sequence--and, therefore, exchangeability--of many genotoxic agents indicate little functional specificity and, hence, little vulnerability toward synergism in most occupational and environmental exposure situations. It is also evident that a low potential exists for the combined effects of common low-exposure situations wherein nongenotoxic agents with highly nonlinear dose-effect relationships and apparent thresholds are involved. A quantitative assessment of the contribution of synergistic interactions to the total detriment from natural and man-made toxicants based on experimental data is far away. There are important examples of combined exposures shown to lead to health effect risks that differ from those expected from simple addition-for example, the influence of smoking on radon- or asbestos-induced lung cancer and on ethanol-induced esophageal cancer. The existing data on combined effects is rudimentary, mainly descriptive, and rarely covers exposure ranges large enough to make direct inferences to present-day low-dose exposure situations. In view of the multitude of possible interactions among the large number of potentially harmful agents in the human environment, descriptive approaches will have to be supplemented by the use of mechanistic models for critical health endpoints, such as cancer. Finally, considering the shape of dose-effect relationships for ionizing radiation, an important question arises from the unresolved question of whether real or apparent thresholds may be used for any genotoxic agent, separately or one time, for an exposed genome.