From cellular perturbation to probabilistic risk assessments.

Journal: ALTEX
Published Date: May 26, 2025

Abstract

Chemical risk assessment is evolving from traditional deterministic approaches to embrace probabilistic methodologies, where risk of hazard manifestation is understood as a more or less probable event depending on exposure, individual factors, and stochastic processes. This is driven by advancements in human stem cells, complex tissue engineering, high-performance computing, and cheminformatics, and is more recently facilitated by large-scale artificial intelligence models. These innovations enable a more nuanced understanding of chemical hazards, capturing the complexity of biological responses and variability within populations. However, each technology comes with its own uncertainties impacting on the estimation of hazard probabilities. This shift addresses the limitations of point estimates and thresholds that oversimplify hazard assessment, allowing for the integration of kinetic variability and uncertainty metrics into risk models. By leveraging modern technologies and expansive toxicological data, probabilistic approaches offer a comprehensive evaluation of chemical safety. This paper summarizes a workshop held in 2023 and discusses the technological and data-driven enablers, and the challenges faced in their implementation, with particular focus on perturbation of biology as the basis of hazard estimates. The future of toxicological risk assessment lies in the successful integration of these probabilistic models, promising more accurate and holistic hazard evaluations.

Authors

  • Alexandra Maertens
    Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
  • Breanne Kincaid
    Center for Alternatives to Animal Testing (CAAT), Johns Hopkins Bloomberg School of Public Health and Whiting School of Engineering, Baltimore, MD, USA.
  • Eric Bridgeford
    Dept. of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
  • Celine Brochot
    Certara, Canterbury, Kent, UK.
  • Arthur de Carvalho E Silva
    University of Birmingham and Michabo Health Science Ltd, Birmingham, UK.
  • Jean-Lou C M Dorne
    European Food Safety Authority (EFSA), Parma, Italy.
  • Liesbet Geris
    Virtual Physiological Human Institute, Leuven, Belgium.
  • Trine Husøy
    Food Safety/ Centre for Sustainable Diets, Norwegian Institute of Public Health (NIPH), Oslo, Norway.
  • Nicole Kleinstreuer
    National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, NIEHS, Durham, North Carolina 27560, USA.
  • Luiz C M Ladeira
    Molecular and Computational Biology, University of Liège, Belgium.
  • Alistair Middleton
    Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
  • Joe Reynolds
    Safety & Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedfordshire, UK.
  • Blanca Rodriguez
    Department of Computer Science, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, UK.
  • Erwin L Roggen
    3Rs Management and Consulting ApS, Kongens Lyngby, Denmark.
  • Giulia Russo
    Department of Drug Sciences, University of Catania , Catania, Italy.
  • Kris Thayer
    Chemical & Pollutant Assessment Division (CPAD), US Environmental Protection Agency (EPA), Durham, NC, USA.
  • Thomas Hartung
    Center for Alternatives to Animal Testing (CAAT), Health and Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States.

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