Complex exposures: potentials for assessing integrated exposures

To determine empirically the most probable mode of interaction of chemicals given in combination, major occupational health, environmental health, and toxicology journals published in the past 10 years were sorted by eye for studies on noncarcinogenic and nonteratogenic effects of industrial and environmental chemicals in combination. Of the 159 relevant studies, 49 reported "more than additive" effects; however, most of these had methodological weakness in extrapolating the observation to effects in humans; e.g., the dose used was much larger than expected exposure levels in real life. After excluding the studies that were based on unrealistic conditions, the "more than additive" effect was observed in < 5% of the studies reviewed. In the absence of information to suggest otherwise, therefore, the risk of underestimating toxicity by assuming the additiveness is probably < 5%.