Adverse Outcome Pathways and Their Role in Helping to Formulate Mechanistically Relevant Chemical Categories

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Adverse Outcome Pathways and Their Role in Helping to Formulate Mechanistically Relevant Chemical Categories

Terry Schultz & Bob Diderich, Organization for Economic Cooperation and Development

Published: March 4, 2011

The views expressed in this article are the sole responsibility of the authors and do not necessarily reflect the views of OECD.

Adverse outcome pathways (AOPs) and their role in helping to formulate mechanistically relevant chemical categories was the topic of discussion at the Organization for Economic Cooperation and Development (OECD) Workshop on “Using Mechanistic Information in Forming Chemical Categories” in December of 2010. An AOP delineates the documented, plausible, and testable processes by which a chemical induces molecular perturbations and the associated biological responses which describe how the molecular perturbations cause effects at the subcellular, cellular, tissue, organ, whole animal, and population levels of observation. The AOP can then be used to form categories by integrating knowledge of how chemicals interact with biological systems (i.e., the molecular initiating events) and in vitro and in vivo knowledge of the biological responses.

AOPs represent a synthesis of known chemical interactions, metabolism, systems biology, and ecology. All of these are large and diverse areas of science which are difficult to integrate due to the high degree of specialization in the respective fields. The intrinsic potency, or relative order, of hundreds of possible molecular perturbations is not always solely dependent on either chemistry or biology. The relative potency of molecular perturbations and the AOPs they initiate cannot be predicted until a specific chemical is defined. This is because the principle interface for integration is at the level of the molecular initiating event which is chemical structure-dependent. AOPs describe the biological linkages between adverse effects induced by chemicals as they progress from molecular perturbations to observable effects in vivo. The upstream terminus of the AOP is the molecular initiating event that represents the chemical-induced perturbation of some biological system. The downstream terminus of the AOP is the adverse biological effect endpoints which are also suitable for regulatory hazard assessment. Because adverse effects measured at any level of biological organization may result from multiple upstream causes and may cause, in turn, multiple downstream effects, the relationships between molecular perturbations and in vivo effects resemble biological networks common to systems biology. While in the short term AOPs will be qualitative, the goal is to make AOPs quantitative in terms of predicting target organ effects over time and improving the grouping of chemicals into categories.

The Workshop participants were presented a series of case studies and asked to answer five questions.

Question 1:

What are the major issues that need to be addressed to make the AOP concept usable in grouping chemicals or developing categories?

Question 2:

How can an AOP approach be used to inform an integrated approach to testing and assessment (e.g. a tiered approach including alternative methods as well as in vivo testing)?

Question 3:

How can AOPs be used to guide QSAR methods to predict key events?

Question 4:

How can the AOP approach be used to better capture interspecies variability, and improve species extrapolation models? To what extent might AOPs help to identify pathways that are conserved, across taxa (from eco to human), and assist in identifying points where pathways diverge based on taxa?

Question 5:

Considering the strengths and weaknesses of the case studies, what best principles can be defined for use in developing an AOP for use in chemical grouping?

The Workshop participants agreed that AOPs are a means of building chemical categories, especially for complex endpoints such as the Lowest Observable Adverse Effect Concentration (LOAEC) for repeat dose toxicity where the specific in vivo endpoint varies (e.g., effects on liver, blood, or kidney).

The participants agreed that in order to use AOPs in developing chemical categories there are three information libraries which must be collated, programmed, and integrated. One library is a directory of effects used in hazard assessment. The second library is list of molecular initiating events which will become the basis for forming the initial chemical category. The third is a library of AOPs which will serve as the transparent mechanistic basis for forming the chemical category. The participants further agreed that there is the need to establish the work flow for integrating AOPs into chemical category formation.

The full workshop report will be published soon.