Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

Punt, Ans

doi:10.14573/altex.1702211

Cited by 29 publications

(35 citation statements)

References 75 publications

(129 reference statements)

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“…Therefore, comparison with the external dose can be performed only if toxicokinetic information is available (Tan et al, 2018). These may also include comparison of animal vs human in vitro metabolic information (Punt et al, 2017). Hence, the selected in vitro method (WEC) could be an alternative method applicable to hazard evaluation of novel chemicals, as an initial screening not influenced by the speciesspecific maternal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Relative potency ranking of azoles altering craniofacial morphogenesis in rats: An in vitro data modelling approach

Renzo

Metruccio

Battistoni

et al. 2019

Food and Chemical Toxicology

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 Whole embryo culture as an alternative method for pesticide hazard evaluation.  Ranking of azole pesticide activity on embryo development  In vitro evaluation of craniofacial primordia defects induced by azoles  Comparison between azole and retinoic acid dysmorphogenic activity *Accepetd manuscript Click here to view linked References 2 ABSTRACT Facial malformations represent one of the most frequent abnormality in humans. The adverse outcome pathway involved in facial defects seems to be related to retinoic acid (RA) pathway imbalance. Environmental agents inducing cranio-facial malformations in experimental models include pesticides (especially azole fungicides). By using the in vitro alternative method postimplantation rat whole embryo culture (WEC), we evaluated the intrinsic embryotoxic activity of some azole antifungals (cyproconazole, CYPRO; triadimefon, FON; flusilazole, FLUSI and prochloraz, PCZ), in comparison to RA. All the tested molecules induced in a dose-related manner specific defects of the cranio-facial structures (fused branchial arches), similar to those induced by RA. Collected data were modelled by using PROAST 65.5 software in order to characterize the relative potency factors (RPFs) versus RA. In comparison to RA, all the evaluated azoles were less potent, showing among them a similar potency. Our data suggest a possible azole-related RA signaling perturbation to be further investigated. Moreover, the present results indicate the approach used in this work as an interesting tool applicable to the hazard evaluation of novel compounds or assessment of combined exposure to azoles or other dismorphogens.

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Section: Discussionmentioning

confidence: 99%

Relative potency ranking of azoles altering craniofacial morphogenesis in rats: An in vitro data modelling approach

Renzo

Metruccio

Battistoni

et al. 2019

Food and Chemical Toxicology

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“…However, further studies are required to fully validate in silico approaches, notably with respect to the realistic conditions of environmental exposure to pesticides, i.e., low and/or chronic doses of mixtures of pesticides. In particular, in silico methods are likely to be compared with other non-animal approaches, such as in vitro methods, for human toxicokinetics in risk evaluations of pesticides [ 10 , 114 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans

Chedik

Mias‐Lucquin

Bruyère

et al. 2017

IJERPH

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Intestinal absorption and brain permeation constitute key parameters of toxicokinetics for pesticides, conditioning their toxicity, including neurotoxicity. However, they remain poorly characterized in humans. The present study was therefore designed to evaluate human intestine and brain permeation for a large set of pesticides (n = 338) belonging to various chemical classes, using an in silico graphical BOILED-Egg/SwissADME online method based on lipophilicity and polarity that was initially developed for drugs. A high percentage of the pesticides (81.4%) was predicted to exhibit high intestinal absorption, with a high accuracy (96%), whereas a lower, but substantial, percentage (38.5%) displayed brain permeation. Among the pesticide classes, organochlorines (n = 30) constitute the class with the lowest percentage of intestine-permeant members (40%), whereas that of the organophosphorus compounds (n = 99) has the lowest percentage of brain-permeant chemicals (9%). The predictions of the permeations for the pesticides were additionally shown to be significantly associated with various molecular descriptors well-known to discriminate between permeant and non-permeant drugs. Overall, our in silico data suggest that human exposure to pesticides through the oral way is likely to result in an intake of these dietary contaminants for most of them and brain permeation for some of them, thus supporting the idea that they have toxic effects on human health, including neurotoxic effects.

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“…Therefore, in vitro concentration-response data must be converted to in vivo dose-responses from which a PoD may be derived in order to have any utility in human safety testing of chemicals. The term quantitative in vitro to in vivo extrapolation (QIVIVE) is used to describe efforts addressing this problem (Bale et al, 2014 ; Hartung, 2017 ) and the use of PBPK 1 modeling-based reverse dosimetry for the translation of in vitro to in vivo responses represents a significant part of the solution (Louisse et al, 2012 , 2016 ; Bessems and Geraets, 2013 ; Coecke et al, 2013 ; Strikwold et al, 2013 , 2017a , b ; Bessems et al, 2014 ; McNally and Loizou, 2015 ; Boonpawa et al, 2017 ; Li et al, 2017 ; Punt et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

A Computational Workflow for Probabilistic Quantitative in Vitro to in Vivo Extrapolation

2018

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A computational workflow was developed to facilitate the process of quantitative in vitro to in vivo extrapolation (QIVIVE), specifically the translation of in vitro concentration-response to in vivo dose-response relationships and subsequent derivation of a benchmark dose value (BMD). The workflow integrates physiologically based pharmacokinetic (PBPK) modeling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC) and Markov Chain Monte Carlo (MCMC) simulation. For a given set of in vitro concentration and response data the algorithm returns the posterior distribution of the corresponding in vivo, population-based dose-response values, for a given route of exposure. The novel aspect of the workflow is a rigorous statistical framework for accommodating uncertainty in both the parameters of the PBPK model (both parameter uncertainty and population variability) and in the structure of the PBPK model itself recognizing that the model is an approximation to reality. Both these sources of uncertainty propagate through the workflow and are quantified within the posterior distribution of in vivo dose for a fixed representative in vitro concentration. To demonstrate this process and for comparative purposes a similar exercise to previously published work describing the kinetics of ethylene glycol monoethyl ether (EGME) and its embryotoxic metabolite methoxyacetic acid (MAA) in rats was undertaken. The computational algorithm can be used to extrapolate from in vitro data to any organism, including human. Ultimately, this process will be incorporated into a user-friendly, freely available modeling platform, currently under development, that will simplify the process of QIVIVE.

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Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

Cited by 29 publications

References 75 publications

Relative potency ranking of azoles altering craniofacial morphogenesis in rats: An in vitro data modelling approach

Relative potency ranking of azoles altering craniofacial morphogenesis in rats: An in vitro data modelling approach

In Silico Prediction for Intestinal Absorption and Brain Penetration of Chemical Pesticides in Humans

A Computational Workflow for Probabilistic Quantitative in Vitro to in Vivo Extrapolation

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