10th September - 13th September : Eurotox 2023. Two posters presentation from Pierre-André BiLLAT and Raphaël BODIN

Development of a physiologically based kinetic (PBK) model to assess regional and systemic concentrations of inhaled permethrin in rats

P.-A. BILLATa, C. TEBBYa, A.-L. NGUYENb, J. PEIFFERa, E. PEYRETa, A. LECOMTEa, F. ROBIDELa, A. MESSAGERb, A. PRUVOSTb, C. BROCHOTa,c

a INERIS, Experimental toxicology and modeling unit (TEAM), Parc ALATA BP2, Verneuil en Halatte, France

b Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour La Santé (DMTS), MetaboHUB, F-91191, Gif sur Yvette, France.

c Certara UK Ltd, Simcyp Division, Sheffield, UK

Oral route is the main route of exposure to pyrethroids, a widespread pesticide, but other routes should be also considered such as topical route (anti ectoparasites sprays, treated clothes …) and inhalation route (drift from treated fields, aircraft disinfection, contaminated dusts…). Permethrin, one of the most used pyrethroid, can be found in commercial use formulations as mixtures of two isoforms: cis and trans-permethrin, showing different toxicokinetic profiles in rats and humans. However, data regarding the toxicokinetics of inhaled permethrin and its metabolism is limited. To fill this gap, we conducted a toxicokinetic study in the rat to explore the absorption, distribution, metabolism, and elimination parameters of permethrin.

Rats were exposed to nebulized permethrin isoforms for 4h at a subtoxic dose level (18.4 mg/kg) in nose-only exposure tubes. The concentration of each permethrin isomer was measured in key ADME tissues: adipose tissue, blood, brain, liver, and lung at two timepoints during exposure and three timepoints post-exposure. No clinical outcomes were observed during and up to 3 hours post exposure. A long retention time in the lung resulted in continued internal exposure to permethrin even after the end of external exposure.

A PBPK model developed previously for oral exposure to permethrin in rats was extended by adding the inhalation route via lungs. The measured concentrations in blood and several organs and tissues were used to calibrate the inhalation PBPK model in a Bayesian framework. The developed PBPK model will help to better understand the fate of permethrin in human after inhalation or multiroute exposure. In an IVIVE context, further research with other compounds is needed for mechanistic modelling of the lung compartment in order to integrate in vitro data obtained in lung epithelium cells exposed by air.

Sex specific impact of perinatal 5G exposure on the rat stereotyped behavior

R. Bodin1,2, A. Pelletier1,2, C. Seewooruttun1,2, A. Corona1,2, S. Delanaud1,2, A.-S. Bonnet1,2

1INERIS, MIV/TEAM, VERNEUIL EN HALATTE, France;

2 University Picardie Jules Verne, PERITOX – UMR-I 01,Amiens, France

The 5G electromagnetic field (EMF) network is currently being worldwide spread out. It raises concerns on the potential effects of radiofrequency on neurodevelopment. During the perinatal period, the organism is immature. Its skin and skull are thinner than in adults and less effective at preventing EMF penetration [1]. In addition, research is now focusing about the impact of the perinatal environmental exposome on maternal, fetal, and neonatal health outcomes. This concept is called the Developmental Origins of Health and Disease (DOHaD) [2,3]. 

The current study aimed to investigate the effects of daily 5G EMF exposure in the rat (n=7) from gestational day 8 to post-natal day (PND) 21. The exposure level aimed to mimic the limit of whole-body public exposure set by the International Commission on Non-Ionizing Radiation Protection (ICNIRP, 0.08 W/kg). Specific absorption rate was 0.07 W/kg for 22h/day at 3.5 GHz continuous wave (CW). Clinical observations were performed on weight, length, sex ratio, number of pups per litter and number of stillborn in sham and EMF exposed groups. The age of pinna ear detachment, incisors eruption and eyes opening were recorded. Behavioral data were also collected on righting, gripping and negative geotaxis reflexes at PND 3 or 7 and for stereotyped and horizontal movements in the open field at PND 21 and 43. 

Our results indicated that both male and female pups showed delayed incisor eruption (1 more day ; p-value=0.015 and 0.020) in the EMF exposed group compared to the sham group. Regarding stereotypic movements, females showed less activity (–60% at PND 21, p-value=0.0015; and PND 43, p-value<0.0001) and males, more (+30% at PND 43, p-value=0.0037) compared to the sham group. No significative results were observed in other parameters studied. Thus, the present study suggests that perinatal exposure to CW-EMF leads to clinical and behavioral perturbations with sex specific effects.