The field of chemical risk assessment is evolving rapidly with the introduction of innovative approaches like Physiologically-Based Kinetic (PBK) models. These models, which simulate what the body does to a chemical rather than focusing on what the chemical does to the body, play a crucial role in modernising how we evaluate chemical risks to human health.

What are PBK models?

PBK models describe, in quantitative terms, the Absorption, Distribution, Metabolism, and Excretion (ADME) processes of substances in the human body. They subdivide the body into compartments representing organs connected by blood to better characterise the relationship between the exposure and the adverse effects.

Essentially, PBK models use mathematical equations to quantify these processes, taking into account various factors such as age, body weight, enzyme activity, and exposure routes. By developing these models, researchers can simulate how a substance behaves in the body, providing more accurate predictions about its effects.

PBK models are essential tools for extrapolating results using the Quantitative In Vitro to In Vivo Extrapolation (QIVIVE) approach. This allows researchers to predict human health impacts from experimental data, particularly when in vivo animal data is unavailable. This is especially relevant for Next-Generation Risk Assessment (NGRA), where human-relevant data are needed for chemical safety evaluations.

PBK models in PARC

PARC initiative has been instrumental in advancing PBK models, with several deliverables laying the groundwork for their broader use in risk assessment:

• An initial PARC report on PBK models: This deliverable (AD6.4, Work Package 6) provides a comprehensive inventory of existing PBK models and highlights gaps in knowledge, particularly in terms of models for sensitive populations and exposure routes like dermal absorption. It sets the stage for refining PBK models for better regulatory integration.
• A follow-up report on methodological innovation: Expanding on AD6.4, this document (D6.2, Work Package 6) focuses on methodological innovations in PBK modelling. By introducing uncertainty analysis, probabilistic modelling, and lifetime exposure scenarios, D6.2 helps ensure that PBK models can provide more reliable predictions across various exposure routes, supporting regulatory frameworks and improving data transparency.
• A PARC report on the application of PBK models to hazard assessment: As the final piece of the puzzle, this deliverable (D5.2, Work Package 5) directly applies PBK models to hazard assessment. While WP6 focuses on the development and integration of PBK models, D5.2 bridges the gap by showing how these models can be used to assess chemical risks and provide evidence-based insights into human health hazards. This is key for NGRA, as it supports more precise, human-relevant risk assessments that can guide policy and regulation.

The Contribution of Deliverable D5.2 to NGRA

The PARC deliverable D5.2 First Report on PBK Models plays a pivotal role in applying PBK models to hazard assessment. It focuses on the development of generic physiologically based kinetic models, which use New Approach Methodologies (NAMs) like in silico and in vitro models, to characterize the compounds specific parameter on absorption, distribution, metabolism or excretion (ADME). By using PBK models to assess human exposure pathways, D5.2 bridges the gap between in vitro data and real-world risk evaluation, advancing risk assessment towards more predictive, ethical and mechanism-based tools.

The new modeling approaches are worked out in case studies, which address specific data and knowledge gaps:

• AThe human microbiome and xenobiotic metabolism: Exploring how gut microbial activity alters chemical fate before systemic exposure.
• ADME properties of PFAS: Addressing the persistence and unique kinetics of PFAS compounds, a recognized regulatory priority.
• Integration of isoform-specific metabolism into PBK models: Improving predictions by accounting for variability between human metabolic enzyme isoforms.
• Tiered testing approach for inhalable compounds: Developing new methods to assess chemicals entering the body via the respiratory system.
• The role of the blood-brain barrier in PBK models: Understanding how neurological protection mechanisms influence internal exposure of the brain.

Why this work matters

The document is essential for Next Generation Risk Assessment by showing how PBK models can be applied to real-world chemical risk assessments. By developing case studies that focus on toxicokinetics (how chemicals are processed by the body) and human exposure metrics, it ensures that PBK models are not just theoretical tools but practical instruments for chemical risk management.

Next generation risk assessment relies on new approach methodologies (NAMs) to identify and evaluate chemical hazards. PBK models are crucial to this process, as they help convert lab-based data into human relevant predictions, which serves as a point of departure for setting safe exposure limits.

D5.2 contributes to explain how PBK models and Quantitative In Vitro to In Vivo Extrapolation (q-IVIVE) can be used in decision-making for chemical safety regulations. It highlights both the challenges and advantages of using these models compared to traditional approaches. By improving how chemicals are assessed, D5.2 strengthens the acceptance of NAM-based models, supports the move toward non-animal testing, and advances more accurate, human-focused risk assessments.

Georg Aichinger, ETH Zürich, Group Leader, explains:

In closing data gaps for multimodal and animal-free parameterization of PBK models, we contribute an essential puzzle piece to extrapolate NAM toxicity data to actual human exposures, enabling quantitative next generation risk assessment for animal-free regulatory risk assessment.