PARC has published a new deliverable on innovative methods based on Physiologically Based Kinetic (PBK) models, highlighting major advances in the development of tools that can strengthen next-generation chemical risk assessment and support regulatory use. Bringing together 13 institutes from eight Member States, the work addresses key challenges such as lifetime internal exposure, vulnerable life stages and the FAIR implementation of PBK models, reinforcing their value for human health risk assessment.

Humans are daily exposed to numerous compounds. Human biomonitoring (HBM) surveys are performed to monitor exposures or early effects related to the presence of compounds in the body. HBM surveys consist of sample biological matrices (blood, urine, etc.) to quantify the compounds of interest. This measure includes all sources of exposure regardless of the routes of entry of compounds into the human body, the environment of exposure (e.g., home, work, etc.), and the activity or the products consumed. Combined with HBM data based on exposure scenarios and exposure data, toxicokinetic (TK) modelling can link external to internal exposure (forward dosimetry) or internal to external exposure (reverse dosimetry) over time. One class of TK models, the Physiologically Based Kinetic (PBK) models, also called PBTK or PBPK, has been identified as an essential tool in risk assessment and is continuously gaining ground in regulatory applications. These models describe in quantitative terms the Absorption, Distribution, Metabolism and Excretion (ADME) processes of compounds in the human body and subdivide the body into compartments representing organs connected by blood. PBK models are able to derive the effective and bioavailable concentration at the expected target site to better characterise the relationship between exposure and adverse effects.

The PARC project on the refinement and development of PBK models for human risk assessment aims to address the evolution of physiological and biochemical processes through life (e.g., placental transfer, blood-brain barrier, etc.), the diversity of exposure routes and their implementation in PBK models, the interpretation of biomonitoring data (e.g., concentrations of parent compounds or metabolites in blood, urine, or other biological matrices), and the kinetics of mixtures.

The deliverable reports substantial advances in PBK model development to strengthen their use in next-generation chemical risk assessment. Across multiple case studies, mercury, arsenic, lead, and PFAS, the project demonstrates how refined PBK frameworks improve the prediction of internal doses, better capture vulnerable life stages, and support regulatory decision-making.

A first major result is the collection of a comprehensive library of lifetime physiological equations, derived from 12 existing PBK models and covering 24 organs for both sexes. This resource enables realistic simulation of age-dependent organ growth and has been successfully integrated into refined PBK models for methylmercury and inorganic mercury. For arsenic, an updated PBK model incorporating recent metabolic knowledge was validated against controlled human dosing studies and then used for reverse dosimetry based on HBM4EU datasets, revealing stable exposure trends over 2010-2018 and enabling reconstruction of inorganic arsenic intakes. A pregnancy PBK model for lead was developed and calibrated with longitudinal biomonitoring data. It successfully reproduced maternal and cord blood lead ratios and quantified the contribution of maternal bone remobilization to fetal exposure, providing the first model capable of estimating prenatal brain lead levels across gestation. For PFAS, one PFOA PBK model was developed by different PARC partners, integrating mechanistic transporter data, lifetime physiological equations, and uncertainty analysis workflows. A coordinated PFAS PBK modelling group also evaluated existing models using the OECD GD331 framework and initiated the development of open, SBML-compatible models. The report also reviews oral, inhalation, and dermal exposure pathways, identifies inconsistencies in current PBK implementations, and proposes a harmonised workflow based on the PBK ontology. Finally, the deliverable reports progress toward harmonized, FAIR PBK modelling through the creation of a dedicated PBK ontology and a standardized exchange format. These tools improve the integration within the PARC modelling ecosystem, paving the way for broader regulatory uptake.

Complementary to and in synergy with current activities at the European Agencies, the project developed practical tools, models, methods, and a general strategy to enable a more appropriate use of PBK models to assess the risk over life. This PARC project proposed a coherent implementation of the models and PBK model training for evaluating the lifetime internal exposures by end-users, being PARC data owners, EFSA panels/ECHA working groups, national experts in risk assessment and other relevant stakeholders such as the chemical industry. Additionally, the proposed developments, tools, and results already used in the other PARC projects such as Real-life Mixtures and Aggregate Exposure, can be practically used by European agencies and provide a foundation for structuring future collaborations, thereby strengthening synergies between PARC and EU agencies in the development of aggregate exposure assessment.