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A tiered approach for integrating exposure and dosimetry with in vitro dose-response data in the modern risk assessment paradigm
Leonard, J., D. Chang, H. El-Masri, S. Edwards, C. Stevens, K. Mansouri, P. Egeghy, AND C. Tan. A tiered approach for integrating exposure and dosimetry with in vitro dose-response data in the modern risk assessment paradigm. 254th ACS National Meeting & Exposition, Washington, DC, August 20 - 24, 2017.
Agency decision-making processes concerned with ecological and human health risk have traditionally relied on low throughput in vivo studies involving one chemical at a time. The power of the adverse outcome pathway (AOP) concept arises from its ability to analyze large numbers of chemicals in a high throughput manner via utilization of pathway-based data to support risk assessment. The AOP itself is not chemical specific to serve as a knowledge bridge that links high throughput toxicity (HTT) testing results with adverse outcome of regulatory interest. Application of the AOP framework and HTT predictions in chemical-specific risk assessment requires comparison between the in vitro concentration expected to sufficiently perturb the AOP and the in vivo concentration at the target site, thus requiring consideration of chemical properties that influence both external doses and internal pharmacokinetic characteristics.
High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. 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 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) processes. In this presentation, the utility of a tiered approach for integrating exposure, ADME, and hazard into risk-based decision making will be demonstrated using several case studies, 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 but 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 also allow for identifying data gaps on which to focus for improving confidence in risk assessment based on in vitro and in silico studies. “The views expressed in this abstract are those of the authors and do not represent Agency policy or endorsement. Mention of trade names of commercial products should not be interpreted as an endorsement by the U.S. Environmental Protection Agency.”
Record Details:Record Type: DOCUMENT (PRESENTATION/SLIDE)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL EXPOSURE RESEARCH LABORATORY
COMPUTATIONAL EXPOSURE DIVISION
HUMAN EXPOSURE & DOSE MODELING BRANCH