PARC Projects

Biodiversity protection
Shift away from animal testing
Closing data gaps in physiologically-based kinetic modeling and quantitative in vitro to in vivo extrapolation
Human health
NGRA
Time span
-
Potential impacts
  • Close data gaps in PBK model parameterisation to advance their predictive accuracy and ultimately, regulatory acceptance in the context of animal-free next generation risk assessment
  • Innovative approaches to characterise the absorption, distribution, metabolism and excretion (ADME) of priority compounds by integrating in silico prediction and in vitro data into physiologically based kinetic (PBK) models for oral and inhalation exposures, accounting for uncertainty linked to relevant biological processes
  • Facilitate the regulatory implementation of NAM-based approaches and thus the efficient regulation of hazardous substances, benefiting public health
Partners involved
ETHZ (CH)
ANSES (FR)
AUTH (GR)
EA (GB)
IISPV (ES)
INERIS (FR)
INSERM (FR)
ISCIII (ES)
ISS (IT)
NIPH (NO)
NVI (NO)
STAMI (NO)
UFZ (DE)
UIBK (AT)
UOC (GR)
UNIVIE (AT)
WR (NL)
WU-TOX (NL)
Contacts
Sylvia Escher (Fraunhofer)
sylvia.escher [at] item.fraunhofer.de
Georg Aichinger (ETHZ)
georg.aichinger [at] hest.ethz.ch
Overview

This project is developing physiologically based kinetic (PBK) ↗ models to better predict how chemicals behave in the human body, i.e. to predict their absorption, distribution, metabolism and excretion (ADME). By performing quantitative in vitro to in vivo extrapolation (QIVIVE) and providing a link with Adverse Outcome Pathways (AOPs ↗), the project is creating a foundation for quantitative systems toxicology, which supports more accurate and ethical chemical safety assessments.

The work is addressing key scientific challenges in PBK modeling, including the development of tools to quantitatively predict how the human microbiome affects chemical metabolism, chemicals cross the blood-brain and the placental barrier, and how inhaled substances are absorbed through the lungs. Both computational and lab-based (in vitro) methodologies are developed in five case studies, using well-researched chemicals as reference compounds.

The ultimate goal is to create a reliable framework for applying QIVIVE in the regulatory settings and use this to facilitate next generation risk assessment for PARC priority chemicals in collaboration with other projects in PARC.

By facilitating the quantitative extrapolation of in vitro toxicity data to actual humans, this work is contributing to assess chemical hazards linked to critical health effects such as endocrine disruption, immune suppression, developmental neurotoxicity, and non-genotoxic cancer. In the long term, the methods developed in this project will support faster, more reliable, and animal-free approaches to chemical safety.

Achievements & Results
  • Developed and optimized a fecal fermentation – based method to quantitatively assess gut microbial biotransformation kinetics.
  • Assessed the isoform-specific metabolism of six data-rich organophosphates and performed a exemplary life stage modeling.
  • Developed a tiered in vitro testing strategy for inhalation PBK modeling.
  • Assessed the accuracy of predicting blood-brain barrier crossing from cellular models.
  • Developed and parameterized PBK models for the priority compounds Alternaria mycotoxins, Enniatins, and polyfluorinated alkylic substances.
Policy relevance

This project provides methodologies and develops data to increase the reliability and applicability of animal-free next generation risk assessment.

Related Publications

Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites
Physiologically based kinetic (PBK) modeling as a new approach methodology (NAM) for predicting systemic levels of gut microbial metabolites copied to clipboard
Authors
Stevanoska Maja, Folz Jacob, Beekmann Karsten, Aichinger Georg
Journal
Toxicology Letters
Vol. 396
94-102
Keywords
Kinetic modeling, New approach methodologies, Gut microbial metabolism, Ex vivo/in vitro models, Gut microbiome
Date of publication
copied to clipboard
1/4

The metabolism of chemicals by gut microorganisms is increasingly recognised as an important factor in chemical safety assessment.

2/4

Physiologically Based Kinetic (PBK) models can help predict how microbial metabolites circulate in the human body, improving understanding of their potential health effects.

3/4

Different ex vivo and in vitro experimental approaches can lead to conflicting conclusions from model predictions due to inconsistent measurement of microbial metabolism rates.

4/4

Developing and applying standardised methods for measuring gut microbial metabolism is crucial to make PBK models more reliable and comparable.

1/1

Including gut microbial metabolism in Physiologically Based Kinetic (PBK) models supports the development of New Approach Methodologies (NAMs) for chemical risk assessment, helping regulators replace animal testing and improve the accuracy of human health evaluations.

There is a clear need to develop new approach methodologies (NAMs) that combine in vitro and in silico testing to reduce and replace animal use in chemical risk assessment. Physiologically based kinetic (PBK) models are gaining popularity as NAMs in toxico/pharmacokinetics, but their coverage of complex metabolic pathways occurring in the gut are incomplete. Chemical modification of xenobiotics by the gut microbiome plays a critical role in the host response, for example, by prolonging exposure to harmful metabolites, but there is not a comprehensive approach to quantify this impact on human health. There are examples of PBK models that have implemented gut microbial biotransformation of xenobiotics with the gut as a dedicated metabolic compartment. However, the integration of microbial metabolism and parameterization of PBK models is not standardized and has only been applied to a few chemical transformations. A challenge in this area is the measurement of microbial metabolic kinetics, for which different fermentation approaches are used. Without a standardized method to measure gut microbial metabolism ex vivo/in vitro, the kinetic constants obtained will lead to conflicting conclusions drawn from model predictions. Nevertheless, there are specific cases where PBK models accurately predict systemic concentrations of gut microbial metabolites, offering potential solutions to the challenges outlined above. This review focuses on models that integrate gut microbial bioconversions and use ex vivo/in vitro methods to quantify metabolic constants that accurately represent in vivo conditions.

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Closing data gaps in physiologically-based kinetic modeling and quantitative in vitro to in vivo extrapolation

Time span
-
Potential impacts
  • Close data gaps in PBK model parameterisation to advance their predictive accuracy and ultimately, regulatory acceptance in the context of animal-free next generation risk assessment
  • Innovative approaches to characterise the absorption, distribution, metabolism and excretion (ADME) of priority compounds by integrating in silico prediction and in vitro data into physiologically based kinetic (PBK) models for oral and inhalation exposures, accounting for uncertainty linked to relevant biological processes
  • Facilitate the regulatory implementation of NAM-based approaches and thus the efficient regulation of hazardous substances, benefiting public health
ETHZ (CH)
ANSES (FR)
AUTH (GR)
EA (GB)
IISPV (ES)
INERIS (FR)
INSERM (FR)
ISCIII (ES)
ISS (IT)
NIPH (NO)
NVI (NO)
STAMI (NO)
UFZ (DE)
UIBK (AT)
UOC (GR)
UNIVIE (AT)
WR (NL)
WU-TOX (NL)
Overview

This project is developing physiologically based kinetic (PBK) ↗ models to better predict how chemicals behave in the human body, i.e. to predict their absorption, distribution, metabolism and excretion (ADME). By performing quantitative in vitro to in vivo extrapolation (QIVIVE) and providing a link with Adverse Outcome Pathways (AOPs ↗), the project is creating a foundation for quantitative systems toxicology, which supports more accurate and ethical chemical safety assessments.

The work is addressing key scientific challenges in PBK modeling, including the development of tools to quantitatively predict how the human microbiome affects chemical metabolism, chemicals cross the blood-brain and the placental barrier, and how inhaled substances are absorbed through the lungs. Both computational and lab-based (in vitro) methodologies are developed in five case studies, using well-researched chemicals as reference compounds.

The ultimate goal is to create a reliable framework for applying QIVIVE in the regulatory settings and use this to facilitate next generation risk assessment for PARC priority chemicals in collaboration with other projects in PARC.

By facilitating the quantitative extrapolation of in vitro toxicity data to actual humans, this work is contributing to assess chemical hazards linked to critical health effects such as endocrine disruption, immune suppression, developmental neurotoxicity, and non-genotoxic cancer. In the long term, the methods developed in this project will support faster, more reliable, and animal-free approaches to chemical safety.

Achievements & Results
  • Developed and optimized a fecal fermentation – based method to quantitatively assess gut microbial biotransformation kinetics.
  • Assessed the isoform-specific metabolism of six data-rich organophosphates and performed a exemplary life stage modeling.
  • Developed a tiered in vitro testing strategy for inhalation PBK modeling.
  • Assessed the accuracy of predicting blood-brain barrier crossing from cellular models.
  • Developed and parameterized PBK models for the priority compounds Alternaria mycotoxins, Enniatins, and polyfluorinated alkylic substances.
Policy relevance

This project provides methodologies and develops data to increase the reliability and applicability of animal-free next generation risk assessment.

Contacts
Sylvia Escher (Fraunhofer)
sylvia.escher [at] item.fraunhofer.de
Georg Aichinger (ETHZ)
georg.aichinger [at] hest.ethz.ch
Topics
Biodiversity protection
Shift away from animal testing
Keywords
Human health
NGRA

Related Projects

Harmonised workflow for human relevance assessment of Adverse Outcome Pathways (AOPs) and New Approach Methodologies (NAMs)
Advancing endocrine disruptor assessment
Alternative predictive toxicology integrative approaches for chemical safety