Mode of action as a determining factor in additivity models for chemical mixture risk assessment

It is inevitable that in a lifetime humans will be exposed to a diverse array of chemical mixtures through occupational, recreational, and/or domestic activities. These mixtures may be simple, consisting of two or more definable compounds, or may be more complex containing several hundred related congeners and/or unrelated compounds. Due to a paucity of mixtures toxicity data, the estimation of risk of adverse health effects associated with mixtures typically comes from empirical observations of single chemical exposures. Under existing policy, characterizing the relative contribution of each compound depends on identification of the target organ or tissue dose, mode of action, and duration of effect. Currently, there is no consensus on what constitutes a toxic mode or mechanism of action, nor is there a universally accepted framework to determine similarity or independence of mode of action for mixtures risk assessment. This lack of a comprehensive classification paradigm for mode or mechanism of toxic action continues to be a major rate-limiting step in the advancement of mixtures risk assessment. A potential unifying approach to characterizing mode of action involves critical evaluation of data at all levels of biological organization for identification of 'key events'. Development of a biologically plausible weight of evidence description of the key obligatory steps in mechanistic pathways may facilitate selection of the most appropriate component-based mixtures risk assessment approach. Hypothetical case studies are presented to demonstrate the quantitative impact of the choice of dose addition or response addition to estimate risk.