S5: Applying Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks
Applying Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to link toxicity testing data to exposure-relevant and biologically-relevant responses
Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which in vitro toxicity testing and other data can be arranged to aid in the interpretation of these results in terms of biologically-relevant responses, as an AOP connects an upstream molecular initiating event (MIE) to a downstream adverse outcome. In addition to hazard assessment, risk estimation also requires reconciling in vitro concentrations sufficient to produce bioactivity with in vivo concentrations that can trigger a MIE at the relevant biological target. Such target site exposures (TSEs) can be estimated by integrating pharmacokinetic considerations with environmental and exposure factors. Environmental and exposure data have been historically scattered in various resources, such as monitoring data for air pollutants or exposure models for specific chemicals. The Aggregate Exposure Pathway (AEP) framework is introduced to organize existing knowledge concerning biologically, chemically, and physically plausible, as well as empirically supported, links between the introduction of a stressor into the environment (i.e., source) and its concentration at the TSEs. Thus, at the TSE-MIE interface, the AEP and AOP frameworks can be integrated to form a construct that aids in understanding the processes that occur from source to exposure, as well as how that exposure event may lead to an adverse outcome. Such integration also allows for identifying data gaps on which to focus for improving confidence in risk assessment based on in vitro and in silico methods.