Modern methodologies and tools for human hazard assessment of chemicals

Abstract

This scientific report provides a review of modern methodologies and tools to depict toxicokinetic and toxicodynamic processes and their application for the human hazard assessment of chemicals. The application of these methods is illustrated with examples drawn from the literature and international efforts in the field. First, the concepts of mode of action/adverse outcome pathway are discussed together with their associated terminology and recent international developments dealing with human hazard assessment of chemicals. Then modern methodologies and tools are presented including in vitro systems, physiologically-based models, in silico tools and OMICs technologies at the level of DNA/RNA (transcriptomics), proteins (proteomics) and the whole metabolome (metabolomics). Future perspectives for the potential applications of these modern methodologies and tools in the context of prioritisation of chemicals, integrated test strategies and the future of risk assessment are discussed. The report concludes with recommendations for future work and research formulated from consultations of EFSA staff, expert Panels and other international organisations.

Scientific Opinion of the Scientific Panel on Plant Protection Products and their Residues (PPR Panel) on testing and interpretation of comparative in vitro metabolism studies

“…As part of the DG‐Sante, EURL ECVAM has a specific mandate specified in EU legislation and includes a number of duties to advance the 3Rs principles of animal testing. In this context and based on the internationally established principles of the 3Rs, EFSA is committed to promote use of data derived from alternative approaches or NAMs, where possible (EFSA, 2014 ). The commitment also applies to EMA, having established a specific WG on the Application of the 3Rs in Regulatory Testing of Medicinal Products (EMA, 2017a , b ) and to ECHA ( 2017 ).…”

New approach methodologies (NAMs) for human-relevant biokinetics predictions

“…As the field of toxicology is moving away from "black box" animal experimentation towards approaches to better understand the internal concentrations of compounds in relation to their mecha-nisms of toxicity in humans (NRC, 2007;Thomas et al, 2017), the potential of NAMs for biokinetics is increasingly recognized by regulatory bodies (ECHA, 2014;EFSA, 2014;EMA, 2018;FDA, 2020). Formal incorporation of these approaches in regulatory toxicology (for, e.g., plant protection products, pharmaceuticals, chemicals or food additives) is, however, still limited (Gellatly and Sewell, 2019;Punt, 2018;Tan et al, 2018;Zhuang and Lu, 2016).…”

“…Table 1 provides a summary of ADME considerations within regulatory risk evaluations that can be addressed with NAMs for biokinetics. This overview was obtained by exploring EU guidelines for chemical risk evaluations within different domains (e.g., pharmaceuticals, chemical substances, food additives, cosmetics) (ECHA, 2013(ECHA, , 2014(ECHA, , 2016(ECHA, , 2017aEFSA, 2010EFSA, , 2014EMA, 2018;EU, 2010;SCCS, 2018).…”

Assessment and Reproducibility of Quantitative Structure–Activity Relationship Models by the Nonexpert

“…The traditional use of animal models to identify potential effects of chemicals has been criticized in terms of scientific relevance, time, and costdriving the quest for suitable alternatives − Quantitative structure–activity relationship (QSAR) modeling is a widely used approach for predicting properties of chemicals, predicated on a mathematical relationship being derived between a chemical’s structure and its physicochemical or biological (toxicological) properties. Acceptance of QSAR methods is increasing with the European Chemicals Agency (ECHA) reporting that, for information on endpoints concerning vertebrate animals, 34% contain one or more QSAR predictions (6290 substances analyzed).…”