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A generic PBTK model implemented in the MCRA platform : Predictive performance and uses in risk assessment of chemicals

Tebby, Cleo ; van der Voet, Hilko ; de Sousa, Georges ; Rorije, Emiel ; Kumar, Vikas ; de Boer, Waldo ; Kruisselbrink, Johannes W. ; Bois, Frédéric Y. ; Faniband, Moosa LU and Moretto, Angelo , et al. (2020) In Food and Chemical Toxicology 142.
Abstract

Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last... (More)

Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last stage, elimination or absorption parameters were calibrated based on available in vivo kinetic data. The results illustrate that parametrization plays a capital role in the output of the PBTK model, as it can change how chemicals are prioritized based on internal concentration factors. In data-poor situations, estimates can be far from observed values. In many cases of chronic exposure, the PBTK model can be summarized by an external to internal dose factor, and interspecies concentration factors can be used to perform interspecies extrapolation. We finally discuss the implementation and use of the model in the MCRA risk assessment platform.

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publication status
published
subject
keywords
Mixtures, Physiologically-based ToxicoKinetic (PBTK) model, Probabilistic model, Risk assessment
in
Food and Chemical Toxicology
volume
142
article number
111440
publisher
Elsevier
external identifiers
  • scopus:85086457026
  • pmid:32473292
ISSN
0278-6915
DOI
10.1016/j.fct.2020.111440
language
English
LU publication?
yes
id
c5b91d83-4517-4426-a09d-5be39b9855a3
date added to LUP
2020-07-02 09:39:39
date last changed
2024-06-26 18:19:39
@article{c5b91d83-4517-4426-a09d-5be39b9855a3,
  abstract     = {{<p>Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last stage, elimination or absorption parameters were calibrated based on available in vivo kinetic data. The results illustrate that parametrization plays a capital role in the output of the PBTK model, as it can change how chemicals are prioritized based on internal concentration factors. In data-poor situations, estimates can be far from observed values. In many cases of chronic exposure, the PBTK model can be summarized by an external to internal dose factor, and interspecies concentration factors can be used to perform interspecies extrapolation. We finally discuss the implementation and use of the model in the MCRA risk assessment platform.</p>}},
  author       = {{Tebby, Cleo and van der Voet, Hilko and de Sousa, Georges and Rorije, Emiel and Kumar, Vikas and de Boer, Waldo and Kruisselbrink, Johannes W. and Bois, Frédéric Y. and Faniband, Moosa and Moretto, Angelo and Brochot, Céline}},
  issn         = {{0278-6915}},
  keywords     = {{Mixtures; Physiologically-based ToxicoKinetic (PBTK) model; Probabilistic model; Risk assessment}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Food and Chemical Toxicology}},
  title        = {{A generic PBTK model implemented in the MCRA platform : Predictive performance and uses in risk assessment of chemicals}},
  url          = {{http://dx.doi.org/10.1016/j.fct.2020.111440}},
  doi          = {{10.1016/j.fct.2020.111440}},
  volume       = {{142}},
  year         = {{2020}},
}