Physicologically Based Toxicokinetic Models of Tebuconazole and Application in Human Risk Assessment

Abstract

A series of physiologically based toxicokinetic (PBTK) models for tebuconazole were developed in four species, rat, rabbit, rhesus monkey, and human. The developed models were analyzed with respect to the application of the models in higher tier human risk assessment, and the prospect of using such models in risk assessment of cumulative and aggregate exposure is discussed. Relatively simple and biologically sound models were developed using available experimental data as parameters for describing the physiology of the species, as well as the absorption, distribution, metabolism, and elimination (ADME) of tebuconazole. The developed models were validated on in vivo half-life data for rabbit with good results, and on plasma and tissue concentration-time course data of tebuconazole after i.v. administration in rabbit. In most cases, the predicted concentration levels were seen to be within a factor of 2 compared to the experimental data, which is the threshold set for the use of PBTK simulation results in risk assessment. An exception to this was seen for one of the target organs, namely, the liver, for which tebuconazole concentration was significantly underestimated, a trend also seen in model simulations for the liver after other nonoral exposure scenarios. Possible reasons for this are discussed in the article. Realistic dietary and dermal exposure scenarios were derived based on available exposure estimates, and the human version of the PBTK model was used to simulate the internal levels of tebuconazole and metabolites in the human body for these scenarios. By a variant of the models where the R(-)- and S(+)-enantiomers were treated as two components in a binary mixture, it was illustrated that the inhibition between the two tebuconazole enantiomers did not affect the simulation results for these realistic exposure scenarios. The developed models have potential as an important tool in risk assessment.

Quantitative in Vitro to in Vivo Extrapolation (QIVIVE) for Predicting Reduced Anogenital Distance Produced by Anti-Androgenic Pesticides in a Rodent Model for Male Reproductive Disorders

“…Data in EFSA DARs are typically reported as residues of the parent compound (and its metabolites), which were measured in adult non-pregnant animals (blood plasma, organs, urine, bile, residual carcass) at several time points following a single oral dose (usually within the first 3 d) and were used to estimate kinetic parameters such as the daily excretion rate, the distribution of the compound as percentage total administered dose per time point of measurement etc. We fitted the PBK model to the reported ADME data in a two-step approach (with preference to data from low doses): at first, we estimated the first-order rates for fecal, urine and metabolic elimination directly from the ADME data without consideration of the PBK model structure (Jónsdóttir et al 2016); conducted in SAS/ STAT ® software (version 9.4; SAS Inc.). These estimates guided as input values for the final PBK model calibration, with the full PBK model referring to GD2, that is, placental and fetal compartments are nonactivated at that time.…”

Toxicokinetics of a urinary metabolite of tebuconazole following controlled oral and dermal administration in human volunteers

“…The PBTK modeling was performed using Berkeley Madonna software package v8.3.18. The time courses of excretion obtained from the volunteers were compared to a simulation of TEB-OH excretion in urine over time by use of an existing PBTK model that was specifically developed for TEB (Jónsdóttir et al 2016). This model was extended by…”

“…The two enantiomers of TEB were not modeled separately as a racemic mixture of TEB was administered to the volunteers. Compound-specific parameters, physiological parameters for humans (i.e., cardiac output, tissue volumes, organ blood flows), and parameters for metabolism were adopted under the same assumptions as in the original model (Jónsdóttir et al 2016). For the compound-specific parameters of the metabolite, we assumed that the partition coefficients were decreased with the ratio of the log P o/w of the metabolite over that of the parent compound.…”

Tebuconazole Fungicide Induces Lipid Accumulation and Oxidative Stress in HepG2 Cells

“…Ingested TEB residues are absorbed in the gastrointestinal tract and are mainly metabolized to TEB-1-hydroxy and TEB-carboxylic acid via CYP-mediated oxidation in the liver for excretion into urine and feces [6]. However, CYP catalytic cycles for xenobiotic biotransformation (e.g., TEB) generate various reactive oxygen species (ROS), including hydrogen Foods 2021, 10, 2242 2 of 13 peroxide and superoxide anion [7].…”