Bringing together scientific disciplines for collaborative undertakings: a vision for advancing the adverse outcome pathway framework

Abstract

Background: Decades of research to understand the impacts of various types of environmental occupational and medical stressors on human health have produced a vast amount of data across many scientific disciplines. Organizing these data in a meaningful way to support risk assessment has been a significant challenge. To address this and other challenges in modernizing chemical health risk assessment, the Organisation for Economic Cooperation and Development (OECD) formalized the adverse outcome pathway (AOP) framework, an approach to consolidate knowledge into measurable key events (KEs) at various levels of biological organisation causally linked to disease based on the weight of scientific evidence (http://oe.cd/aops). Currently, AOPs have been considered predominantly in chemical safety but are relevant to radiation. In this context, the Nuclear Energy Agency's (NEA's) High-Level Group on Low Dose Research (HLG-LDR) is working to improve research co-ordination, including radiological research with chemical research, identify synergies between the fields and to avoid duplication of efforts and resource investments. To this end, a virtual workshop was held on 7 and 8 October 2020 with experts from the OECD AOP Programme together with the radiation and chemical research/regulation communities. The workshop was a coordinated effort of Health Canada, the Electric Power Research Institute (EPRI), and the Nuclear Energy Agency (NEA). The AOP approach was discussed including key issues to fully embrace its value and catalyze implementation in areas of radiation risk assessment. Conclusions: A joint chemical and radiological expert group was proposed as a means to encourage cooperation between risk assessors and an initial vision was discussed on a path forward. A global survey was suggested as a way to identify priority health outcomes of regulatory interest for AOP development. Multidisciplinary teams are needed to address the challenge of producing the appropriate data for risk assessments. Data management and machine learning tools were highlighted as a way to progress from weight of evidence to computational causal inference.

Areas of research to support the system of radiological protection

“…These data, combined with multilevel analytic approaches such as systems biology, should improve our understanding of radiation effects. Integration of approaches, such as considering Adverse Outcome Pathways (AOP, an approach that identifies the sequence of events required to produce a toxic effect when an organism is exposed to a substance) (Preston et al 2021 ; Chauhan et al 2021 ), should help in identifying the causal sequence between exposure to ionising radiation and disease. Basic research is also essential to improve fundamental knowledge and maintain competences in the field of radiological protection.…”

Canadian Regulatory Perspective on Next Generation Risk Assessments for Pest Control Products and Industrial Chemicals

“…The Friedman et al and Health Canada work highlighted above are examples of complete progression from collaboration to development of a Canadian-specific approach. It is important to also note that partnerships between risk assessment and research experts to achieve the goal of demonstrating robustness, reliability and readiness of non-animal based approaches in regulatory applications is also a model of interest beyond the chemicals assessment community ( Chauhan et al, 2021 ).…”

New approach methodologies in human regulatory toxicology – Not if, but how and when!

“…Generally, NAMs can be broken down into in silico , in chemico , and in vitro methods where in silico approaches are computational tools aiming at modelling endpoints such as toxicokinetics ( Thompson et al 2021 ) or metabolism ( Leonard 2019 ), or at predicting effects based on chemical structural features and association with legacy data; in chemico is a general term referring to the use of abiotic chemical reactivity methods ( Gerberick et al 2008 ); in vitro data generated using human cells or organoids may be used to directly inform cellular targets and chemical-induced molecular mechanisms potentially leading to adversity, which can be conceptually organized using Adverse Outcome Pathways (AOPs) ( Ankley et al, 2010 ; Chauhan et al, 2021 ; Leist et al, 2017 ; OECD, 2021a ). Omics technologies enable insights into a broad spectrum of complex biological responses triggered by chemical perturbation ( Hartung and McBride 2011 ).…”