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Integration of chemical-specific exposure and pharmacokinetic information with the chemical-agnostic AOP framework to support high throughput risk assessment
Citation:
Tan, C., H. El-Masri, S. Edwards, J. Leonard, S. Suarez, AND K. Fay. Integration of chemical-specific exposure and pharmacokinetic information with the chemical-agnostic AOP framework to support high throughput risk assessment. Chemical Safety for Sustainability Subcommittee Meeting, Durham, NC, November 16 - 17, 2016.
Impact/Purpose:
Agency decision-making processes concerned with ecological and human health risk have traditionally relied on 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. To address this need, the AOP-DD Task 1.4b is developing a tiered approach to provide a workflow, and ultimately support the development of a ADME (absorption, distribution, metabolism, and excretion) module in the AOP KB, for connecting biological process-based AOPs to biochemical process-based pharmacokinetic behaviors. The tiered approach includes (1) qualitative refinement of HTT results through identification of false positives and false negatives; (2) quantitative scoring of exposure and ADME-related properties to rank active chemicals identified from HTT assays; and (3) quantitative modeling (e.g., physiologically based pharmacokinetic modeling) to prioritize active chemicals by integrating HTT hazard estimates, high throughput exposure predictions, and estimated ADME rates. The AOP-DD Task 1.4b is also developing a similar framework as the AOP, the Aggregate Exposure Pathway (AEP), to organize exposure data from a chemical’s introduction to the target site exposure, which can be linked to molecular initiating events in AOPs.
Description:
Application of the Adverse Outcome Pathway (AOP) framework and high throughput toxicity testing in chemical-specific risk assessment requires reconciliation of chemical concentrations sufficient to trigger a molecular initiating event measured in vitro and at the relevant target site in vivo, thus requiring consideration of chemical properties that influence both external exposures and internal pharmacokinetic characteristics. To address this need, a tiered approach ― involving qualitative refinement, quantitative ranking, and quantitative modeling ― was developed to connect biological process-based AOPs to biochemical process-based pharmacokinetic behaviors (absorption, distribution, metabolism, and excretion). In addition, the Aggregate Exposure Pathway (AEP) framework was conceptualized to organize exposure data and provide the missing chemical-specific exposure and ADME link to the AOP framework.