Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making

A. Paini*, J.A. Leonard, E. Joossens, J.G.M. Bessems, A. Desalegn, J.L. Dorne, J.P. Gosling, M.B. Heringa, M. Klaric, T. Kliment, N.I. Kramer, G. Loizou, J. Louisse, A. Lumen, J.C. Madden, E.A. Patterson, S. Proença, A. Punt, R.W. Setzer, N. Suciu & 4 others J. Troutman, M. Yoon, A. Worth, Y.M. Tan

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)

Abstract

The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) – European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on “Physiologically-Based Kinetic modelling in risk assessment – reaching a whole new level in regulatory decision-making” held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

Original languageEnglish
Pages (from-to)61-72
JournalComputational Toxicology
Volume9
DOIs
Publication statusPublished - Feb 2019

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Decision Making
Decision making
Kinetics
Animals
Computer Simulation
Risk assessment
Toxicology
Animal Testing Alternatives
Testing
European Union
Parameterization
Extrapolation
Italy
Uncertainty
Toxicity
Hazards
In Vitro Techniques
Education
Research

Keywords

  • In silico
  • In vitro
  • PBPK
  • PBTK
  • Physiologically based kinetic models
  • Toxicokinetics

Cite this

Paini, A., Leonard, J. A., Joossens, E., Bessems, J. G. M., Desalegn, A., Dorne, J. L., ... Tan, Y. M. (2019). Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making. Computational Toxicology, 9, 61-72. https://doi.org/10.1016/j.comtox.2018.11.002
Paini, A. ; Leonard, J.A. ; Joossens, E. ; Bessems, J.G.M. ; Desalegn, A. ; Dorne, J.L. ; Gosling, J.P. ; Heringa, M.B. ; Klaric, M. ; Kliment, T. ; Kramer, N.I. ; Loizou, G. ; Louisse, J. ; Lumen, A. ; Madden, J.C. ; Patterson, E.A. ; Proença, S. ; Punt, A. ; Setzer, R.W. ; Suciu, N. ; Troutman, J. ; Yoon, M. ; Worth, A. ; Tan, Y.M. / Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making. In: Computational Toxicology. 2019 ; Vol. 9. pp. 61-72.
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abstract = "The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) – European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on “Physiologically-Based Kinetic modelling in risk assessment – reaching a whole new level in regulatory decision-making” held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.",
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Paini, A, Leonard, JA, Joossens, E, Bessems, JGM, Desalegn, A, Dorne, JL, Gosling, JP, Heringa, MB, Klaric, M, Kliment, T, Kramer, NI, Loizou, G, Louisse, J, Lumen, A, Madden, JC, Patterson, EA, Proença, S, Punt, A, Setzer, RW, Suciu, N, Troutman, J, Yoon, M, Worth, A & Tan, YM 2019, 'Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making', Computational Toxicology, vol. 9, pp. 61-72. https://doi.org/10.1016/j.comtox.2018.11.002

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making. / Paini, A.; Leonard, J.A.; Joossens, E.; Bessems, J.G.M.; Desalegn, A.; Dorne, J.L.; Gosling, J.P.; Heringa, M.B.; Klaric, M.; Kliment, T.; Kramer, N.I.; Loizou, G.; Louisse, J.; Lumen, A.; Madden, J.C.; Patterson, E.A.; Proença, S.; Punt, A.; Setzer, R.W.; Suciu, N.; Troutman, J.; Yoon, M.; Worth, A.; Tan, Y.M.

In: Computational Toxicology, Vol. 9, 02.2019, p. 61-72.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making

AU - Paini, A.

AU - Leonard, J.A.

AU - Joossens, E.

AU - Bessems, J.G.M.

AU - Desalegn, A.

AU - Dorne, J.L.

AU - Gosling, J.P.

AU - Heringa, M.B.

AU - Klaric, M.

AU - Kliment, T.

AU - Kramer, N.I.

AU - Loizou, G.

AU - Louisse, J.

AU - Lumen, A.

AU - Madden, J.C.

AU - Patterson, E.A.

AU - Proença, S.

AU - Punt, A.

AU - Setzer, R.W.

AU - Suciu, N.

AU - Troutman, J.

AU - Yoon, M.

AU - Worth, A.

AU - Tan, Y.M.

PY - 2019/2

Y1 - 2019/2

N2 - The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) – European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on “Physiologically-Based Kinetic modelling in risk assessment – reaching a whole new level in regulatory decision-making” held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

AB - The fields of toxicology and chemical risk assessment seek to reduce, and eventually replace, the use of animals for the prediction of toxicity in humans. In this context, physiologically based kinetic (PBK) modelling based on in vitro and in silico kinetic data has the potential to a play significant role in reducing animal testing, by providing a methodology capable of incorporating in vitro human data to facilitate the development of in vitro to in vivo extrapolation of hazard information. In the present article, we discuss the challenges in: 1) applying PBK modelling to support regulatory decision making under the toxicology and risk-assessment paradigm shift towards animal replacement; 2) constructing PBK models without in vivo animal kinetic data, while relying solely on in vitro or in silico methods for model parameterization; and 3) assessing the validity and credibility of PBK models built largely using non-animal data. The strengths, uncertainties, and limitations of PBK models developed using in vitro or in silico data are discussed in an effort to establish a higher degree of confidence in the application of such models in a regulatory context. The article summarises the outcome of an expert workshop hosted by the European Commission Joint Research Centre (EC-JRC) – European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), on “Physiologically-Based Kinetic modelling in risk assessment – reaching a whole new level in regulatory decision-making” held in Ispra, Italy, in November 2016, along with results from an international survey conducted in 2017 and recently reported activities occurring within the PBK modelling field. The discussions presented herein highlight the potential applications of next generation (NG)-PBK modelling, based on new data streams.

KW - In silico

KW - In vitro

KW - PBPK

KW - PBTK

KW - Physiologically based kinetic models

KW - Toxicokinetics

U2 - 10.1016/j.comtox.2018.11.002

DO - 10.1016/j.comtox.2018.11.002

M3 - Article

VL - 9

SP - 61

EP - 72

JO - Computational Toxicology

JF - Computational Toxicology

SN - 2468-1113

ER -