Adverse Outcome Pathway ‘footprinting’

Adverse Outcome Pathway ‘footprinting’: an integrated read-across approach to the assessment of mixtures


Jason Lambert




Human health and ecological viability are challenged daily by mixtures of chemical and non-chemical stressors.  However, the cumulative impact of mixture exposures are often exceedingly difficult to characterize due to the lack of available hazard and dose-response information for many stressors.  With the advent of 21st century toxicity testing and approaches such as adverse outcome pathways (AOP), opportunities to evaluate hazards associated with exposure to ‘data-poor’ mixture stressors has advanced significantly.  Potential health impact(s) of mixtures stressors may be informed using an integrated read-across approach that includes AOP ‘footprinting’ when adverse outcome data derived from traditional bioassays is lacking.  AOP footprinting is the stepwise profiling and comparison of AOPs at the level of key events moving backward from the most downstream key event to the molecular initiating event.  The goal is to identify the key event(s) within each AOP suspected of contributing to a given adverse outcome at which similarity between mixture stressors can confidently be determined.  These key events are identified as the ‘footprint’ for a given AOP.  Mixture stressors are then assigned to the appropriate ‘footprint’ category, and the key event dose-response relationship(s) for each stressor within a category are then used to evaluate mixture additivity.  When adverse outcome data is lacking, the integration of AOP footprinting with structural, physicochemical, and/or toxicokinetic information will significantly advance read-across application in mixtures risk assessment by providing a more biologically-based hazard categorization or grouping strategy, and, providing a critical alternative for dose-response assessment of environmental stressors.        

The views expressed in this abstract are those of the author and do not necessarily reflect the views and policies of the U.S. EPA.