Scripts and programs

Whole-body PBPK model over the human lifespan

We developed a PBPK model based on a detailed compartmentalization of the human body and parameterized with new relationships describing the time evolution of physiological and anatomical parameters. To take into account the impact of human variability on the predicted toxicokinetics, we defined probability distributions for key parameters related to the xenobiotics absorption, distribution, metabolism and excretion.

Recently, pregnancy and lactation sub-model was calibrated in a population framework to provide quantitative estimates for the PFOA and PFOS placental transfers in humans (Brochot et al. 2109). The MCSim script of the PBPK is freely available below.

• • Beaudouin, R., Micallef, S., Brochot, C., 2010. A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan. Regulatory Toxicology and Pharmacology 57, 103-116.

• Brochot, C., Casas, M., Manzano-Salgado, C., Zeman, F.A., Schettgen, T., Vrijheid, M., Bois, F.Y., 2019. Prediction of maternal and foetal exposures to perfluoroalkyl compounds in a Spanish birth cohort using toxicokinetic modelling. Toxicology and Applied Pharmacology 379, 114640.

COSMOS PBPK models

Various versions of the COSMOS PBPK model developed at INERIS are available at gitlab.com/fredomatic/COSMOS-PBPK. The model has been described in various publications, in particular:

• • Bois F., Diaz Ochoa J.G. Gajewska M., Kovarich S., Mauch K., Paini A., Péry A., Sala Benito J.V., Teng S., Worth A., 2017, Multiscale modelling approaches for assessing cosmetic ingredients safety, Toxicology, 392:130-139, doi:10.1016/j.tox.2016.05.026.

  • Berggren E., White A., Ouedraogo G., Paini A., Richarz A.-N., Bois F., Exner T., Leite S., van Grunsven L.A., Worth A., Mahony C., in press, Ab initio chemical safety assessment: a workflow based on exposure considerations and non-animal methods, Computational Toxicology, doi: 10.1016/j.comtox.2017.10.001.

The model has been readapted as a generic model in the MCRA toolbox and is available in this version on Zenodo at DOI 10.5281/zenodo.3553689  :

• Tebby, C., van der Voet, H., de Sousa, G., Rorije, E., Kumar, V., de Boer, W., Kruisselbrink, J. W., Bois, F. Y., Faniband, M., Moretto, A., Brochot, C. 2020. A generic PBTK model implemented in the MCRA platform: Predictive performance and uses in risk assessment of chemicals. Food and Chemical Toxicology, 142, 111440.

In vitro pharmacokinetic distribution models

Two models have been developed by us within EU-ToxRisk and the R scripts of both models are freely available at the end of this page. 

1. VIVD model

VIVD model is an in vitro distribution model, based on the Fick-Nernst Planck equation accounting for differential compound ionisation in culture medium and intracellular water.

The model considers permeability of ionised and unionised species and accounts for membrane potential in the partitioning of ionised moieties. By accounting for lipid and protein binding in culture medium, binding to cell culture plastic, air-partitioning, and lipid binding in the cell, the model can predict chemical concentrations (free and total) in medium and cells.

• Fisher, C., Siméon, S., Jamei, M., Gardner, I., Bois, Y.F., 2018. VIVD: Virtual in vitro distribution model for the mechanistic prediction of intracellular concentrations of chemicals in in vitro toxicity assays. Toxicology in Vitro.

2. Generic zebrafish embryo PBPK model

To better explain, predict, or extrapolate to humans the developmental toxicity effects of chemicals to zebrafish embryo, we developed a physiologically-based pharmacokinetic (PBPK) model able to predict organ concentrations of neutral or ionizable chemicals, up to 120 hours post fertilization.

• • S Siméon, K Brotzmann, C Fisher, I Gardner, S Silvester, R Maclennan, P Walker, T Braunbeck and FY Bois. Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid. 93:219-229, Reproductive Toxicology.

qAOP modelling

In  EUToxRisk project, we calibrated a qAOP model for mitochondrial toxicity based on in vitro data obtained in three cell lines. A working example for rotenone in neuronal and liver cells, using R and rstan is provided at DOI https://doi.org/10.5281/zenodo.5549495.

• Tebby, C., W. Gao, J. Delp, G. Carta, W. van der Stel, M. Leist, P. Jennings, B. van de Water and F. Y. Bois (2022). "A quantitative AOP of mitochondrial toxicity based on data from three cell lines." Toxicology in Vitro 81: 105345.

Scripts and codes in environmental risk assessment

1. Generic physiologically-based toxicokinetic (PBTK) modelling for fish

Many research efforts have aimed to improve the quantification of dose-response relationships through the integration of toxicokinetics. For this purpose, PBTK models have been developed to estimate internal doses from external doses in a time-dependent manner for rainbow trout (Onchorhynchus mykiss), zebrafish (Danio rerio), fathead minnow (Pimephales promelas), and three-spined stickleback (Gasterosteus aculeatus).

PBTK model and its applications to the four fish species are available on EFSA knowledge junction under the DOI https://doi.org/10.5281/zenodo.1414325.

• Grech, A., Tebby, C., Brochot, C., Bois, F.Y., Bado-Nilles, A., Dorne, J.L., Quignot, N., Beaudouin, R., 2019. Generic physiologically-based toxicokinetic modelling for fish: Integration of environmental factors and species variability. Science of the total environment 651, 516-531.

2. DEB-IBM population dynamic model

DEB and DEBtox models have already been developed for different organisms in METO such as crustacea (Massarin et al., 2011), worm (Goussen et al., 2015) and fish (Le Loutre et al., 2016 and David et al., 2018). The R and MCSim scripts of the DEB model described in David et al., (2018) is freely available below.

• • David, V., Goussen, B., Tebby, C., Joachim, S., Porcher, J.M., Beaudouin, R., 2018. Modelling historical mesocosm data: application of a fish bioenergetics model in semi-natural conditions. Ecology of Freshwater Fish 27, 1101-1113.

DEB-IBM models have already been developed in the METO team for chironomus (Beaudouin et al, 2012), the zebrafish (Beaudouin et al, 2015) and for the threespined stickleback (David et al, 2019a et b). The Netlogo script of the model described in David et al, (2019) is freely available below.

• • David, V., Joachim, S., Tebby, C., Porcher, J.M., Beaudouin, R., 2019. Modelling population dynamics in mesocosms using an individual-based model coupled to a bioenergetics model. Ecological Modelling 398, 55-66.

3. ToxicoDynamic PBTK (PBTK-TD) models for mixtures in fish

The PBTK model for fish was extended with a toxicodymic component for studying TK and/or TD interactions between melamine and cyanuric acid in rainbow trout, and between chlorpyrifos and atrazine:

• Tebby C., Brochot C., Dorne J.-L., Beaudouin R., 2019. Investigating the interaction between melamine and cyanuric acid using a Physiologically-Based Toxicokinetic model in rainbow trout. Toxicology and Applied Pharmacology 370, 184-195.

The model code for Tebby et al. (2019) is available on Zenodo DOI 10.5281/zenodo.2609136

• Mit C, Tebby C, Gueganno T, Bado-Nilles A, Beaudouin R. Modeling acetylcholine esterase inhibition resulting from exposure to a mixture of atrazine and chlorpyrifos using a physiologically-based kinetic model in fish. Sci Total Environ Volume 773, 15 June 2021, 144734. doi: 10.1016/j.scitotenv.2020.144734.

GNU MCSim

GNU MCSim is a simulation and statistical inference tool for algebraic or differential equation systems, optimized for performing Monte Carlo analysis. The software comprises a model generator and a simulation engine:

• • The model generator facilitates structural model definition and maintenance, while keeping execution time short. The model is coded using a simple grammar, and the generator translates it into C code. Starting with version 5.3.0, models coded in SBML can also be used.

  • The simulation engine is a set of routines that are linked to the model in order to produce executable code. The result is that one can run simulations of the structural model under a variety of conditions.

Internally, the software uses the GNU Scientific Library for some of its numerical calculations.

• • GNU MCSim software: a general modeling and simulation software (free, GPL). Extensively used in our projects.

  • GNU MCSim on wikipedia: see it also on wikipedia.

  • Convanal: a C language utility (to compile) for checking MCMC chains' convergence.