Distinctions between similarly and dissimilarly acting mixture components unnecessarily complicate mixture risk assessments: Implications for assessing low dose mixture exposures

Distinguishing between mixtures of substances with similar and dissimilar modes of action is believed to have implications for judgements whether mixture risks might arise when all chemicals comply with their regulatory limits. However, differentiating between similar and dissimilar action unnecessarily complicates mixture risk assessments. Whether substances in a mixture have similar or dissimilar mechanisms is often difficult to decide. Only a few cases show the validity of dissimilar action; concepts based on similar action (dose addition) generally produce good approximations of observed mixture effects. Further, the quantitative differences of mixture effect predictions that follow from assumptions of similar or dissimilar action are rather small. To avoid underestimations of mixture risks, chemicals that produce common adverse outcomes should be assessed together, and this should not be restricted to chemicals with similar mechanisms. Assertions that compliance with Health-Based Guidance Values (HBGVs) protects against mixture risks can be de-constructed to reveal several false assumptions, among them that chemicals generally act according to dissimilar action and that HBGVs are equivalent to “zero-effect levels.” The protection goals enshrined in HBGVs for single chemicals may not be realized when there is co-exposure to chemicals that produce the same effect, regardless of perceived modes of action of the mixture components.