Aggregate Exposure Pathways in Support of Risk Assessment

Abstract

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of the Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.

Keywords: Adverse Outcome Pathway; Aggregate Exposure Pathway; risk assessment.

Figure 1

Integration of dose-response data with multiple Adverse Outcome Pathways (AOPs) and one single Aggregate Exposure Pathway (AEP). The concentration of one stressor at its target site of action (i.e., target site exposure; TSE) can potentially link to several molecular initiating events (MIEs) that lead to different adverse outcomes (AOs) upon perturbation of the molecular targets, provided the TSE is sufficient to eliciting a specific MIE.

Figure 2

Integration of dose-response data with one Adverse Outcome Pathway (AOP) and multiple Aggregate Exposure Pathways (AEPs). The concentrations of multiple stressors at the same target site (i.e., target site exposures; TSEs) can lead to the activation of the same molecular initiating event (MIE) and result in one specific adverse outcome (AO). This feature is especially of interest in cumulative risk assessment because the concentration of one stressor alone may be insufficient to trigger the MIE, but addition of TSEs from multiple stressors may be sufficient.