Abstract
BACKGROUND: A key question in the risk assessment of exposures to multiple chemicals is whether mixture effects may occur when chemicals are combined at low doses which individually do not induce observable effects. However, a systematic evaluation of experimental studies addressing this issue is missing. OBJECTIVES: With this contribution, we wish to bridge this gap by providing a systematic assessment of published studies against well-defined quality criteria. RESULTS: On reviewing the low-dose mixture literature, we found good evidence demonstrating significant mixture effects with combinations of chemicals well below their individual no observable adverse effect levels (NOAELs), both with mixtures composed of similarly and dissimilarly acting agents. CONCLUSIONS: The widely held view that mixtures of dissimilarly acting chemicals are "safe" at levels below NOAELs is not supported by empirical evidence. We show that this view is also based on the erroneous assumption that NOAELs can be equated with zero-effect levels. Thus, on the basis of published evidence, it is difficult to rule out the possibility of mixture effects from low-dose multiple exposures.