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Linking mechanistic data to endpoints of regulatory concern using the adverse outcome pathway framework.
Citation:
Villeneuve, Dan. Linking mechanistic data to endpoints of regulatory concern using the adverse outcome pathway framework. SETAC Focused Topic Meeting, Durham, NC, April 16 - 18, 2018.
Impact/Purpose:
It is expected that chemical risk assessment will be increasingly informed by data generated through rapid and efficient high throughput screening (HTS) methods. However, because HTS data are typically focused on pathway-level responses measured at low levels of biological organization, they are more challenging to interpret with regard to their implications for human health or ecosystem fitness. The adverse outcome pathway (AOP) framework, which organizes information concerning measureable changes that link initial biological interactions with a chemical to adverse effects that are meaningful to risk assessment and management, can aid the translation of these data. This presentation outlines the ways in which the AOP can be used to support the application of HTS data in environmental risk assessment.
Description:
In order to increase the uptake and use of high throughput screening data in environmental risk assessment, it is important to establish scientifically credible links between measures of biological pathway perturbation and apical adverse outcomes in humans and wildlife. The adverse outcome pathway (AOP) framework is a way of organizing knowledge in a way that facilitates that translation. Applied together, high throughput screening data and AOP knowledge can facilitate a more rapid and cost effective approaches to environmental risk assessment. Gene expression, enzyme activities, receptor binding, metabolite or hormone concentrations, altered morphology, behavior, etc. are widely used endpoints in both toxicological research and high throughput screening (HTS). However, to date these types of measurements are rarely, if ever, used as primary assessment endpoints in risk assessment. The disconnect between this kind of data and the endpoints and outcomes that we generally regulate on and manage has been recognized as a major barrier to the application of HTS data in environmental risk assessment. The adverse outcome pathway (AOP) framework was designed specifically to address that barrier. An AOP is a conceptual framework that captures and organizes information concerning the linkage between some direct molecular initiating event, through which a chemical interacts with a molecule in the body of an organism to perturb its biology, and a cascade of measureable biological changes that reflect progression toward and adverse outcome considered relevant to risk assessment and regulatory decision-making. Measureable “key events” along the AOP can serve as biomarkers of exposure and/or effect. “Key event relationships” define the biological basis of the linkage, the empirical support available in the extant literature, the quantitative understanding of how much change in a biomarker signals progression toward adversity, and the biological context (in terms of life-stage, sex, taxa, etc.) in which a particular outcome is likely to be relevant. Consequently, the AOP framework is expected to play an important role in facilitating more widespread use of HTS data and steps are being taken to more tightly couple AOP information to HTS data sets. Nonetheless, broader engagement of the scientific community in AOP development is needed to provide a robust interpretive framework for HTS application.