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Theoretical Framework to Extend Adverse Outcome Pathways to Include Pharmacokinetic Considerations
Citation:
Phillips, M., R. Brooks, AND C. Tan. Theoretical Framework to Extend Adverse Outcome Pathways to Include Pharmacokinetic Considerations. Adverse Outcome Pathways: From Research to Regulation Workshop, Bethesda, MD, September 03 - 05, 2014.
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:
Adverse Outcome Pathways (AOPs) have generated intense interest for their utility in linking known population outcomes to a molecular initiating event (MIE) that can be quantified using in vitro methods. While there are tens of thousands of chemicals in commercial use, biology has a tendency to act through a limited number of common biochemical pathways. Starting from these common pathways reduces the complexity that must be considered. Despite the conceptual clarity proffered by this framework, practical application of AOPs in chemical-specific risk assessment requires consideration of exposure as well as absorption, distribution, metabolism, and excretion (ADME) properties for chemicals. A chemical that shows a toxic effect based on in vitro assays may never reach the target site to trigger the MIE. In the current study, acetylcholinesterase (AChE) inhibition was used as an example AOP to demonstrate the importance of considering ADME. In the U.S. EPA’s ToxCastTM program, an enzyme reporter assay was used to measure AChE inhibition in 1059 chemicals; thirty chemicals (3%) were found to be active. We examined the five most active chemicals with respect to exposure and ADME properties. Of the five chemicals with the greatest activity in the AChE assay, one (1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-B]quinazoline hydrochloride, CAS 149062-75-9) was considered to have a low probability of triggering the MIE due to lack of exposure and a second (anthralin) was considered to have a low probability of triggering the MIE due to lack of systemic absorption. The remaining chemicals were organophosphate pesticides, naled and chlorpyrifos oxon, and a carbamate pesticide, carbofuran. Metabolism played an important but variable role in bioactivation and/or detoxification for these three chemicals. Our study establishes a workflow for incorporating exposure and ADME knowledge in the evaluation of chemicals using the AOP framework.