Critical review and analysis of literature on low dose exposure to chemical mixtures in mammalian in vivo systems.

Anthropogenic chemicals are ubiquitous throughout the environment. Consequentially, humans are exposed to hundreds of anthropogenic chemicals daily. Current chemical risk assessments are primarily based on testing individual chemicals in rodents at doses that are orders of magnitude higher than that of human exposure. The potential risk from exposure to mixtures of chemicals is calculated using mathematical models of mixture toxicity based on these analyses. These calculations, however, do not account for synergistic or antagonistic interactions between co-exposed chemicals. While proven examples of chemical synergy in mixtures at low doses are rare, there is increasing evidence that, through non-conformance to current mixture toxicity models, suggests synergy. This review examined the published studies that have investigated exposure to mixtures of chemicals at low doses in mammalian in vivo systems. Only seven identified studies were sufficient in design to directly examine the appropriateness of current mixture toxicity models, of which three showed responses significantly greater than additivity model predictions. While the remaining identified studies were unable to provide evidence of synergistic toxicity, it became apparent that many results of such studies were not always explicable by current mixture toxicity models. Additionally, two data gaps were identified. Firstly, there is a lack of studies where individual chemical components of a complex mixture (>10 components) are tested in parallel to the chemical mixture. Secondly, there is a lack of dose-response data for mixtures of chemicals at low doses. Such data is essential to address the appropriateness and validity of future chemical mixture toxicity models.