Tab. 5:

Major workshops on physiology-based pharmacokinetic/toxicokinetic modeling (PBPK) for risk assessment

Workshop/reference	Brief summary
ECVAM: The use of biokinetics and in vitro methods in toxicological risk evaluation, 1995, Utrecht, The Netherlands (Blaauboer et al., 1996)	Recommendations to encourage and guide future work in the PBK model field. 1. Explore possibilities to integrate in vitro data into the models; 2. Models are built on a case-by-case basis; 3. Establish documentation to illustrate what is needed experimentally; 4. Availability of data required for constructing models; 5. Establish databases; 6. Refine the partition coefficient; 7. Penetration rate should be incorporated into PBK models (barriers information); 8. Biotransformation CYP P450 reactions and information should be included into the model; 9. Emphasis on species comparison (rodent versus human); 10. Target organs and metabolism; 11. In vitro systems should be a reliable representation of in vivo; 12. PBK models should include dynamics; 13. Validation of PBK models should be done with independent data set; 14. Evaluation of the different software; 15. Sensitivity analysis employed to identify potential source of errors
ECVAM: Physiologically based kinetic (PBK) modelling: Meeting the 3Rs agendas, 2005, Ispra, Italy (Bouvier d’Yvoire et al., 2007)	To better define the potential role of PBK modelling as a set of techniques capable of contributing to the 3Rs in the risk assessment process of chemicals; needs for technical improvements and applications; needs to increase understanding and acceptance by regulatory authorities of the capabilities and limitations of these models. The recommendations were categorized into i) quality of PBK modelling; ii) availability of reference data and models; and iii) development of testing strategy
EPA/NIEHS/CIIT/ INERIS: Uncertainty and variability in PBPK models, 2006, RTP, NC, USA (Barton et al., 2007)	Better statistical models and methods; better databases for physiological properties and their variation; explore a wide range of chemical space; training, documentation, and software.
The Mediterranean Agronomic Institute of Chania: The International Workshop on the Development of GMP for PBPK models, 2007, Crete, Greece (Loizou et al., 2008)	Clear descriptions of good practices for (1) model development, i.e., research and analysis activities, (2) model characterization, i.e., methods to describe how consistent the model is with biology and the strengths and limitations of available models and data such as sensitivity analyses, (3) model documentation, and (4) model evaluation, i.e., independent review that will assist risk assessors in their decisions of whether and how to use the models, and also for model developers to understand expectations of various model purposes, e.g., research versus application in risk assessment
EPAA & EURL ECVAM: Potential for further integration of toxicokinetic modelling into the prediction of in vivo dose-response curves without animal experiments, 2011, Joint Research Centre, Italy (Bessems et al., 2014)	The aim of the workshop was to critically appraise PBK modelling software platforms as well as a more detailed state-of-the-art overview of non-animal based PBK parameterization tools. Such as: 1) Identification of gaps in non-animal test methodology for the assessment of ADME. 2) Addressing user-friendly PBK software tools and free-to-use web applications. 3) Understanding the requirements for wider and increased take up and use of PBK modelling by regulators, risk assessors and toxicologists in general. 4) Tackling the aspect of obtaining in vivo human toxicokinetic reference data via micro-dosing following the increased interest by the research community, regulators, and politicians
US FDA: Application of Physiologically-based pharmacokinetic (PBPK) modelling to support dose selection, 2014, Silver Spring, MD, USA (Wagner et al., 2015)	Workshop to (i) assess the current state of knowledge in the application of PBK in regulatory decision-making, and (ii) share and discuss best practices in the use of PBK modelling to inform dose selection in specific patient populations
EURL ECVAM: Physiologically-based kinetic modelling in risk assessment – Reaching a whole new level in regulatory decision-making, 2016, Joint Research Centre, Italy (Paini et al., 2017)	Strategies to enable prediction of systemic toxicity by applying new approach methodologies (NAM) using PBK modelling to integrate in vitro and in silico methods for ADME in humans for predicting whole-body TK behavior, for environmental chemicals, drugs, nano-materials, and mixtures. (i) identify current challenges in the application of PBK modelling to support regulatory decision-making; (ii) discuss challenges in constructing models with no in vivo kinetic data and opportunities for estimating parameter values using in vitro and in silico methods; (iii) present the challenges in assessing model credibility relying on non-animal data and address strengths, uncertainties and limitations in such an approach; (iv) establish a good kinetic modelling practice workflow to serve as the foundation for guidance on the generation and use of in vitro and in silico data to construct PBK models designed to support regulatory decision making. Recommendations on parameterization and evaluation of PBK models: (i) develop a decision tree for model construction; (ii) set up a task force for independent model peer review; (iii) establish a scoring system for model evaluation; (iv) attract additional funding to develop accessible modelling software; (v) improve and facilitate communication between scientists (model developers, data provider) and risk assessors/regulators; and (vi) organize specific training for end users. Critical need for developing a guidance document on building, characterizing, reporting, and documenting PBK models using non-animal data; incorporating PBK models in integrated strategy approaches and integrating them with in vitro toxicity testing and adverse outcome pathways.