Metabolites in the regulatory risk assessment of pesticides in the EU

Olavi Pelkonen; Khaled Abass; Juan Manuel Parra Morte; Martina Panzarea; Emanuela Testai; Serge Rudaz; Jochem Louisse; Ursula Gundert-Remy; Gerrit Wolterink; Dorne Jean-Lou Cm; Sandra Coecke; Camilla Bernasconi

doi:10.3389/ftox.2023.1304885

Metabolites in the regulatory risk assessment of pesticides in the EU

Front Toxicol. 2023 Dec 19:5:1304885. doi: 10.3389/ftox.2023.1304885. eCollection 2023.

Authors

Olavi Pelkonen¹, Khaled Abass^{2

3

4}, Juan Manuel Parra Morte⁵, Martina Panzarea⁵, Emanuela Testai⁶, Serge Rudaz⁷, Jochem Louisse^{5

8}, Ursula Gundert-Remy⁹, Gerrit Wolterink¹⁰, Dorne Jean-Lou Cm⁵, Sandra Coecke¹¹, Camilla Bernasconi¹¹

Affiliations

¹ Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
² Department of Environmental Health Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
³ Sharjah Institute for Medical Research (SIMR), University of Sharjah, Sharjah, United Arab Emirates.
⁴ Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁵ EFSA, European Food Safety Authority, Parma, Italy.
⁶ Mechanisms, Biomarkers and Models Unit, Environment and Health Department, Istituto Superiore di Sanità, Rome, Italy.
⁷ School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland.
⁸ Wageningen Food Safety Research (WFSR), Wageningen, Netherlands.
⁹ Institute of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.
¹⁰ Centre for Prevention, Lifestyle and Health, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
¹¹ European Commission, Joint Research Centre (JRC), Ispra, Italy.

Abstract

A large majority of chemicals is converted into metabolites through xenobiotic-metabolising enzymes. Metabolites may present a spectrum of characteristics varying from similar to vastly different compared with the parent compound in terms of both toxicokinetics and toxicodynamics. In the pesticide arena, the role of metabolism and metabolites is increasingly recognised as a significant factor particularly for the design and interpretation of mammalian toxicological studies and in the toxicity assessment of pesticide/metabolite-associated issues for hazard characterization and risk assessment purposes, including the role of metabolites as parts in various residues in ecotoxicological adversities. This is of particular relevance to pesticide metabolites that are unique to humans in comparison with metabolites found in in vitro or in vivo animal studies, but also to disproportionate metabolites (quantitative differences) between humans and mammalian species. Presence of unique or disproportionate metabolites may underlie potential toxicological concerns. This review aims to present the current state-of-the-art of comparative metabolism and metabolites in pesticide research for hazard and risk assessment, including One Health perspectives, and future research needs based on the experiences gained at the European Food Safety Authority.

Keywords: analytical methods; disproportionate human metabolite; in vitro/in silico testing; pesticide metabolite; risk assessment; unique human metabolite; xenobiotic metabolism.

Publication types

Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Original sketches were discussed during the work of the EFSA working group, in which Alfonso Lostia was an EFSA Staff member, and realized after the publication of the Scientific Opinion (EFSA PPR Panel et al., 2021b). No additional funding sources were available as WG members developed this review in their own time for the memory of Alfonso.