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A three-tiered approach for linking pharmacokinetic considerations to the adverse outcome pathway framework for chemical-specific risk assessment
Citation:
Tan, C., J. Leonard, D. Chang, H. El-Masri, S. Edwards, AND R. Goldsmith. A three-tiered approach for linking pharmacokinetic considerations to the adverse outcome pathway framework for chemical-specific risk assessment. SETAC, Salt Lake City, UT, Salt Lake City, UT, November 01 - 04, 2015.
Impact/Purpose:
The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports Goal 1 (Clean Air) and Goal 4 (Healthy People) of EPA strategic plan. More specifically, our division conducts research to characterize the movement of pollutants from the source to contact with humans. Our multidisciplinary research program produces Methods, Measurements, and Models to identify relationships between and characterize processes that link source emissions, environmental concentrations, human exposures, and target-tissue dose. The impact of these tools is improved regulatory programs and policies for EPA.
Description:
The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreting high throughput (HT) toxicity screening results. Application of the AOP framework and HT predictions in ecological and human health risk assessment, however, requires the consideration of chemical-specific properties that influence external exposure doses and target tissue doses. To address this requirement, a three-tiered approach was developed to provide a workflow for connecting biology-based AOPs to biochemical-based pharmacokinetic properties (absorption, distribution, metabolism, excretion; ADME), and then to chemical/human activity-based exposure pathways. This approach included: (1) The power of the adverse outcome pathway (AOP) framework arisesfrom its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that lead to an adverse outcome relevant for regulatory purposes. The AOP itself is not chemical specific, thus providing the biological context necessary for interpreting high throughput (HT) toxicity screening results. Application of the AOP framework and HT predictions in ecological and human health risk assessment, however, requires the consideration of chemical-specific properties that influence external exposure doses and target tissue doses. To address this requirement, a three-tiered approach was developed to provide a workflow for connecting biology-based AOPs to biochemical-based pharmacokinetic properties (absorption, distribution, metabolism, excretion; ADME), and then to chemical/human activity-based exposure pathways. This approach included: (1)Qualitative refinement of HT results through identification of false positives (in vitro active chemicals that cannot access the molecular target in vivo) and false negatives (in vitro inactive chemicals that are progenitors of active metabolites in vivo); (2) Quantitative scoring to rank active chemicals based on estimates of ADME rates used as surrogates of target tissue doses; and (3) Quantitative modeling to prioritize active chemicals by incorporating information on hazard potencies, environmentalexposures, and chemical-specific ADME characteristics. Three case studies involving acetylcholinesterase inhibitors and thyroid peroxidase inhibitors are presented to demonstrate the implementation of these techniques. Findings in these case studies also highlight how decision makers can use alternative tools based on exposure and ADME informationavailable to them to apply the AOP framework in chemical-specific risk assessment.
