Quantifying health effects from the combined action of low-level radiation and other environmental agents: can new approaches solve the enigma?

Efforts to assess and quantify deleterious effects from toxicants are directed mainly towards single agents, whereas real world environmental and occupational exposures to natural and anthropogenic agents quite often entail the concomitant presence of several toxicants. These combined exposures may lead to health risks that differ from those expected from simple addition of the individual risks. For example, combined exposures to physical and chemical agents such as radon and smoking or asbestos and smoking produce over-additive effects at exposure levels typical for earlier workplaces. In tumour therapy, the modulation of radiation effects by cytotoxic drugs is widely used to enhance the therapeutic gain. Whether interactions occurring at high exposure levels are important at the low exposure levels set for the public and for modern workplaces is difficult to answer. A scientifically sound extrapolation from these high to low-dose levels should be based on dose-effect relationships of the relevant agents alone and in combination. In general this information is not available. The existing data base 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 between 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. To generalise and predict the outcome of combined exposures, agents will have to be grouped depending on their physical or chemical mode of action on the molecular and cellular level. Such a grouping must be guided by specific mechanistic studies designed to examine the underlying hypothesis regarding how various classes of agents interact.