High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals with toxicology information. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the underlying biological mechanisms that lead to apical adverse health outcomes in living organisms. The chemical-agnostic Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which pathway-based data can be arranged to aid in the understanding of in vitro toxicity testing results. In addition, risk estimation also requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with concentrations that trigger a molecular initiating event (MIE) at the relevant biological target in vivo. Such target site exposures (TSEs) can be estimated using computational models to integrate exposure information with a chemical’s absorption, distribution, metabolism, and elimination (ADME) behaviors. Several case studies will be presented to demonstrate the utility of a novel tiered approach in the integration of exposure, ADME, and hazard into risk-based decision making, along with the investigation of how uncertainties in exposure and ADME might impact risk estimates. These case studies involve 1) identifying and prioritizing chemicals capable of altering biological pathways based on their potential to reach an in vivo target; 2) evaluating the influence of exposure, ADME, and hazard individually and in an integrated manner when prioritizing chemicals; and 3) identifying those chemicals that may cause in vivo effects that are unable to be captured in an in vitro environment. In addition, the Aggregate Exposure Pathway (AEP) framework is introduced as a means of providing a link between the exposure and hazard components of risk assessment, through its ability to follow a chemical from its source to the TSE-MIE interface. The approaches presented will allow for identification of data gaps on which to focus for improving confidence in risk assessment based on in vitro and in silico studies.<br/>

Tiered approach for integrating exposure and dosimetry with in vitro dose-response data in the modern risk assessment paradigm

254th National Meeting (2017)

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