• Tissue residue approach;
  • Mode of toxic action;
  • Internal concentration;
  • Concentration addition;
  • Independent action


At the SETAC Pellston Workshop “The Tissue Residues Approach for Toxicity Assessment,” held in June 2007, we discussed mixture toxicology in terms of the tissue residue approach (TRA). This article reviews the literature related to the TRA for mixtures of chemicals and recommends a practical, tiered approach that can be implemented in regulatory or risk assessment applications. As with the toxicity of individual chemicals, addressing mixture toxicity by means of the TRA has a number of significant advantages. Early work provided a theoretical basis and experimental data to support the use of TRA for mixtures; later work provided a field-based validation of the integration. However, subsequent development has been hindered by the lack of mixture toxicity data expressed in tissue or preferably target-site concentrations. We recommend a framework for addressing the toxicology of mixtures that integrates the TRA and mixture toxicology in a 3-tier approach. Tier I uses concentration addition (CA) to estimate the toxicity of mixtures regardless of the mechanism of action of the components. However, the common approach that uses a bioaccumulation factor (BAF) to predict TR from the exposure–water concentration for organics must be modified slightly for metals because, unlike organics, the BAF for a metal changes as 1) the aqueous exposure concentration changes, and 2) the concentration of other metals changes. In addition, total tissue residues of a metal are not a good predictor of toxicity, because some organisms store high concentrations of metals internally in detoxified forms. In tier I, if the combination of measured concentrations in the mixture exceeds that predicted to produce adverse effects or above-reference levels, it is necessary to proceed to tier II. Tier II is a mixed model that employs CA and independent action to estimate mixture toxicity. Tiers I and II estimate the toxicity of mixtures to individual species. In tier III, the TRA is integrated with the multisubstance potentially affected fraction (ms-PAF) method to derive TR levels that are protective of a selected percentage of species in aquatic communities (e.g., hazardous concentration for 5% of the species [HC5]). Integr Environ Assess Manag 2011;7:99–115. © 2010 SETAC