Cytogenetic alterations induced by flupyradifurone, a new butenolide insecticide, in human lymphocytes

Abstract

Flupyradifurone (FPD), a member of the new class of butenolide insecticides, acts on nicotinic acetylcholine receptors. Studies on genotoxic and carcinogenic effects of FPD are very limited. This is the first study to investigate the cytotoxic and genotoxic effects of FPD and its metabolites on human lymphocyte cultures with or without a metabolic activation system (S9 mix) using chromosomal aberration (CA) and micronucleus (MN) tests. The cultures were treated with 85, 170, and 340 µg/ml of FPD in the presence (3 h treatment) and absence (48 h treatment) of S9 mix. Dimethyl sulfoxide (DMSO) was used as a solvent control. Statistically significant decreases were detected at the medium and highest concentrations for 48 h treatments while decreases in mitotic index (MI) in the presence of the S9 mix were found statistically significant at all FPD concentrations tested when compared with the solvent control. FPD also decreased the nuclear division index (NDI) at the highest concentration (340 µg/ml) in the absence of S9 mix. When compared with the solvent control, increases in CA frequencies were significant at the medium and highest concentrations. Significantly increased MN frequency was only found at the highest FPD concentration in cultures without S9 mix compared with the solvent control while increases in the MN frequencies in the presence of S9 mix were statistically significant at all FPD concentrations. The results of the present study indicate that FPD and its metabolites can show cytotoxic and genotoxic effects in human lymphocytes. More genotoxicity studies are necessary to make a possible risk assessment in humans.

Statement on the active substance flupyradifurone

“…For the toxicological endpoint category genotoxicity, the PPR Panel concluded, following detailed assessment of the available evidence and uncertainties, that moving to the EKE was not necessary. The available evidence from the study by Sekeroglu et al ( 2018 ) is not able to modify the conclusion reached by EFSA ( 2015a ). The details of the uncertainty analysis showed that in this in vitro study there was a statistically significant increase in chromosomal aberrations without metabolic activation at the two highest concentrations tested and that the number of micronuclei was statistically significant increased at all the concentrations tested with metabolic activation and at the highest concentration tested without metabolic activation.…”

“…After a screening, only one of the two references (RefID 10 – Sekeroglu et al, 2018 ) was considered further in the assessment. The reference contained information on in vitro lines of evidence for the genotoxicity assessment endpoint category.…”

“…Although the study from Sekeroglu et al, ( 2018 ; RefID 10) was considered of good quality (class 1 in the RoB assessment), the outcome from in vivo studies included in the EFSA conclusion (EFSA, 2015a ) was considered as sufficient evidence for addressing the genotoxicity potential of flupyradifurone in line with the Scientific Committee Opinions on genotoxicity (EFSA Scientific Committee, 2011b , 2017 ). Therefore, the additional study submitted does not trigger a new concern and does not provide any solution for addressing the uncertainties listed above.…”

Genetic polymorphisms as determinants of pesticide toxicity: Recent advances

“…macrophages, lymphocytes, etc. ), leading to the onset of a pro-inflammatory microenvironment responsible for the accumulation of genetic damages and, in turn, for the accumulation of altered cells that were not correctly removed by the immune system [22,23]. Indeed, it is well known that macrophages alterations, and in particular the abnormal secretion of several secreted proteins, play a key role in tumorigenesis and autoimmune diseases [[24], [25], [26], [27], [28]].…”