Advancing alternatives analysis: The role of predictive toxicology in selecting safer chemical products and processes : Predictive Toxicology in Alternatives Analysis

Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk-effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework.

An adverse outcome pathway (AOP) is a conceptual framework that organizes existing knowledge concerning biologically plausible, and empirically supported, links between molecular-level perturbation of a biological system and an adverse outcome at a level of biological organization of regulatory relevance. Systematic organization of information into AOP frameworks has potential to improve regulatory decision-making through greater integration and more meaningful use of mechanistic data. However, for the scientific community to collectively develop a useful AOP knowledgebase that encompasses toxicological contexts of concern to human health and ecological risk assessment, it is critical that AOPs be developed in accordance with a consistent set of core principles. Based on the experiences and scientific discourse among a group of AOP practitioners, we propose a set of five fundamental principles that guide AOP development: (1) AOPs are not chemical specific; (2) AOPs are modular and composed of reusable components-notably key events (KEs) and key event relationships (KERs); (3) an individual AOP, composed of a single sequence of KEs and KERs, is a pragmatic unit of AOP development and evaluation; (4) networks composed of multiple AOPs that share common KEs and KERs are likely to be the functional unit of prediction for most real-world scenarios; and (5) AOPs are living documents that will evolve over time as new knowledge is generated. The goal of the present article was to introduce some strategies for AOP development and detail the rationale behind these 5 key principles. Consideration of these principles addresses many of the current uncertainties regarding the AOP framework and its application and is intended to foster greater consistency in AOP development.

Background: Systematic-review methodologies provide objectivity and transparency to the process of collecting and synthesizing scientific evidence in reaching conclusions on specific research questions. There is increasing interest in applying these procedures to address environmental health questions. Objectives: The goal was to develop a systematic-review framework to address environmental health questions by extending approaches developed for clinical medicine to handle the breadth of data relevant to environmental health sciences (e.g., human, animal, and mechanistic studies). Methods: The Office of Health Assessment and Translation (OHAT) adapted guidance from authorities on systematic-review and sought advice during development of the OHAT Approach through consultation with technical experts in systematic review and human health assessments, as well as scientific advisory groups and the public. The method was refined by considering expert and public comments and through application to case studies. Results and Discussion: Here we present a seven-step framework for systematic review and evidence integration for reaching hazard identification conclusions: 1) problem formulation and protocol development, 2) search for and select studies for inclusion, 3) extract data from studies, 4) assess the quality or risk of bias of individual studies, 5) rate the confidence in the body of evidence, 6) translate the confidence ratings into levels of evidence, and 7) integrate the information from different evidence streams (human, animal, and “other relevant data” including mechanistic or in vitro studies) to develop hazard identification conclusions. Conclusion: The principles of systematic review can be successfully applied to environmental health questions to provide greater objectivity and transparency to the process of developing conclusions. Citation: Rooney AA, Boyles AL, Wolfe MS, Bucher JR, Thayer KA. 2014. Systematic review and evidence integration for literature-based environmental health science assessments. Environ Health Perspect 122:711–718; http://dx.doi.org/10.1289/ehp.1307972