RT Journal Article
T1 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.
A1 EFSA Panel on Plant Protection Products and their Residues (EFSA PPR Panel), 
A1 Hernandez-Jerez, Antonio F
A1 Adriaanse, Paulien
A1 Aldrich, Annette
A1 Berny, Philippe
A1 Coja, Tamara
A1 Duquesne, Sabine
A1 Focks, Andreas
A1 Marinovich, Marina
A1 Millet, Maurice
A1 Pelkonen, Olavi
A1 Pieper, Silvia
A1 Tiktak, Aaldrik
A1 Topping, Christopher J
A1 Widenfalk, Anneli
A1 Wilks, Martin
A1 Wolterink, Gerrit
A1 Gundert-Remy, Ursula
A1 Louisse, Jochem
A1 Rudaz, Serge
A1 Testai, Emanuela
A1 Lostia, Alfonso
A1 Dorne, Jean-Lou
A1 Parra Morte, Juan Manuel
K1 PBK
K1 QSAR
K1 clearance
K1 in silico
K1 interspecies metabolism
K1 reactive metabolites
K1 suspension/plated hepatocytes
K1 xenobiotic
AB EFSA asked the Panel on Plant Protection Products and their residues to deliver a Scientific Opinion on testing and interpretation of comparative in vitro metabolism studies for both new active substances and existing ones. The main aim of comparative in vitro metabolism studies of pesticide active substances is to evaluate whether all significant metabolites formed in the human in vitro test system, as a surrogate of the in vivo situation, are also present at comparable level in animal species tested in toxicological studies and, therefore, if their potential toxicity has been appropriately covered by animal studies. The studies may also help to decide which animal model, with regard to a particular compound, is the most relevant for humans. In the experimental strategy, primary hepatocytes in suspension or culture are recommended since hepatocytes are considered the most representative in vitro system for prediction of in vivo metabolites. The experimental design of 3 × 3 × 3 (concentrations, time points, technical replicates, on pooled hepatocytes) will maximise the chance to identify unique (UHM) and disproportionate (DHM) human metabolites. When DHM and UHM are being assessed, test item-related radioactivity recovery and metabolite profile are the most important parameters. Subsequently, structural characterisation of the assigned metabolites is performed with appropriate analytical techniques. In toxicological assessment of metabolites, the uncertainty factor approach is the first alternative to testing option, followed by new approach methodologies (QSAR, read-across, in vitro methods), and only if these fail, in vivo animal toxicity studies may be performed. Knowledge of in vitro metabolites in human and animal hepatocytes would enable toxicological evaluation of all metabolites of concern, and, furthermore, add useful pieces of information for detection and evaluation of metabolites in different matrices (crops, livestock, environment), improve biomonitoring efforts via better toxicokinetic understanding, and ultimately, develop regulatory schemes employing physiologically based or physiology-mimicking in silico and/or in vitro test systems to anticipate the exposure of humans to potentially hazardous substances in plant protection products.
YR 2021
FD 2021-12-23
LK https://hdl.handle.net/10668/26744
UL https://hdl.handle.net/10668/26744
LA en
DS RISalud
RD Apr 5, 2025