Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations

Abstract

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA.

Keywords: Adverse outcome pathways; Biomarkers of effect; Hazard assessment; Mechanistic toxicology; New approach methodologies; Regulatory risk assessment.

Fig. 1

The place of the AOP framework in bridging the different components of next generation risk assessment, improving causal inference in exposure-health relationships in epidemiological studies, and identifying and validating biomarkers of effects. Abbreviations: HBM, human biomonitoring; PBPK, physiologically based pharmacokinetic modelling; NAMs, new approach methodologies; AOP, adverse outcome pathway; MIE, molecular initiating event; KE, key event; AO, adverse outcome; EC50, half maximal effective concentration; NOAEL, no observed adverse effect level; BMDL, benchmark dose level.

Fig. 2

Strengths and limitations of AOPs as a tool to translate scientific data into regulatory relevant knowledge to support risk assessment . Five regulatory applications (light grey box) benefit from the curated and chemical-agnostic AOP-knowledge (light yellow box and yellow arrowhead), but the full adoption of AOPs is currently hindered by several limitations (light blue box and blue arrowhead). Some ongoing or proposed initiatives should help overcome the limitations in future (ways forward). Benefits, applications, limitations and ways forward are all commented in greater details in the manuscript. Abbreviations: AOP, adverse outcome pathway; IATAs, integrated approaches to testing and assessment; BoE, biomarkers of effect; KE, key events; KERs, key event relationships; NGRA, next generation risk assessment. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)