TOXICOLOGY OF CHEMICAL-MIXTURES - CHALLENGES FOR TODAY AND THE FUTURE

A major challenge for the toxicologist involved in safety evaluation o f chemical mixtures is to test the hypothesis that as a rule exposure to mixtures of chemicals at (low) non-toxic doses of the individual ch emicals is of no health concern. A series of repeated dose studies in rats with defined mixtures of chemicals with the same or different tar get organs revealed that exposure to a combination of chemicals compar ed with exposure to the individual compounds did not constitute an evi dently increased hazard, provided each chemical was administered at a level similar to, or slightly lower than, its own 'No-Observed-Adverse -Effect-Level'. The results of subacute oral toxicity studies in rats with defined mixtures of nephrotoxicants with similar mode of action u nderlined the applicability of the additivity assumption for a mixture of chemicals with simple similar action. Safety evaluation of complex chemical mixtures is a challenge that can be tackled as follows: firs t, identify the (e.g, ten) most risky chemicals in the mixture, and, s econd, assess the hazard and the potential health risk of the mixture of the most risky chemicals, using procedures developed for defined mi xtures. To identify interactions between individual compounds, a most promising testing strategy appeared to be a statistical approach using a fractional two-level factorial design. A challenge for today and th e future is to gradually substitute mixture-oriented (real life-orient ed) standard setting for (unrealistic) single chemical-oriented standa rd setting.