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Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality
Citation:
Russom, C., C. LaLone, Dan Villeneuve, AND G. Ankley. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 33(10):2157-2169, (2014).
Impact/Purpose:
This paper describes an adverse outcome pathway (AOP) linking the molecular initiating event (MIE), inhibition of acetylcholinesterase (AChE), to short-term lethality (the adverse outcome (AO)), via measurable key events (KEs) at the biochemical, cellular and physiological levels. The AOP, as evaluated using modified Bradford-Hill considerations, and was developed following the OECD guidance (http://www.oecd.org/env/ehs/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm). The AOP is considered to be robust, and several lines of evidence, both empirical and theoretical. This AOP differs from others previously published in the open literature in that it (a) considers the biological conservation of the MIE and evidence supporting linkage of the MIE to AOs across a wide range of ecologically-relevant taxa at different life-stages, (b) presents a “chemical category” approach to AOP development, considering toxicity data from a diversity of organophosphate and carbamate pesticides, and (c) utilizes information in the open literature via the ECOTOX database (www.epa.gov/ecotox) in order to build the experimental weight-of-evidence supporting the pathway. In addition to its use in expanding the OECD AOP knowledgebase, this AOP is a first step in the elucidation of quantitative relationships that allow for prediction of the probability or severity of the AO (lethality) given the intensity and/or duration of the perturbation of the MIE (AChE inhibition), which would be a useful tool for risk assessors.
Description:
Adverse outcome pathways (AOPs) are designed to describe linkages of key events (KEs) within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event (MIE). Risk assessors have traditionally relied on data from apical endpoints (e.g., mortality, growth, reproduction) to derive benchmark values for use in determining the potential adverse impacts of chemicals. One goal in building reliable and well characterized AOPs is to identify relevant in vitro assays and/or in vivo biomarkers that could be used in screening potential hazard of substances, thereby reducing costs and increasing the number of chemicals that can be evaluated in a timely fashion. The Organisation for Economic Cooperation and Development (OECD) has initiated an effort to catalog AOPs with documentation as to the weight-of-evidence supporting the linkage of KEs within the pathway, and using modified Bradford-Hill considerations to assess the reliability, robustness, and overall confidence in a proposed AOP. The purpose of this review is to build an AOP for substances with a MIE of acetylcholinesterase inhibition leading to acute mortality, to help support the OECD initiative. In contrast to most other AOPs developed to-date where coverage is for a relatively limited taxonomic group and/or life-stage, this AOP is applicable to a wide range of species at multiple life-stages. Further, while development of most AOPs has relied on data for a few model chemicals, the AOP described herein captures information from a large number of studies with a diversity of organophosphate and carbamate insecticides.
