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

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.

Development of an adverse drug event network to predict drug toxicity.

Despite of their therapeutic effects, drug's exposure may have negative effects on human health such as adverse drug reaction (ADR) and side effects (SE). Adverse drug events (ADEs), that correspond to an event occurring during the drug treatment (i.e. ADR and SE), is not necessarily caused by the drug itself, as this is the case with medical errors and social factors. Due to the complexity of the biological systems, not all ADEs are known for marketed drugs. Therefore, new and effective methods are needed to determine potential risks, including the development of computational strategies. We present an ADE association network based on 90,827 drug-ADE associations between 930 unique drug and 6221 unique ADE, on which we implemented a scoring system based on a pull-down approach for prediction of drug-ADE combination. Based on our network, ADEs proposed for three drugs, safinamide, sonidegib, rufinamide are further discussed. The model was able to identify, already known drug-ADE associations that are supported by the literature and FDA reports, and also to predict uncharacterized associations such as dopamine dysregulation syndrome, or nicotinic acid deficiency for the drugs safinamide and sonidegib respectively, illustrating the power of such integrative toxicological approach.