Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications

Abstract

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes.

A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

“…Even though PBK is a well-established tool in pharmaceutical development ( Jones et al , 2015 ), there are still issues around the confidence in predictions, especially when in vivo data is unavailable for model validation. In this work, we attempted to mitigate some of these issues by following good practices outlined in Paini et al (2017) , and applying the PBK framework developed in Moxon et al (2020) . This framework utilizes sensitivity and uncertainty analysis to guide parameter generation and attempts to increase confidence in the model output without the explicit need for in vivo studies.…”

Physiologically based mathematical models of nanomaterials for regulatory toxicology: A review

“…Regarding the acceptance and application of PBK models in public health decision making (e.g. in REACH), conclusions drawn by Tan et al [76] and Paini et al [77] hold true also for the case of PBK models applied to MNs. There are three main barriers to the more extensive reliance on PBK models for regulatory assessment purposes.…”

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making

“…As concluded from the 2017 survey [43] , training, guidance, and dialogue are three main factors that will facilitate the successful acceptance of NG-PBK modelling in regulatory decision-making.…”

“…In addition to the EURL ECVAM workshop, an international survey was conducted in 2017 to understand the applications of PBK modelling in the broader scientific and regulatory communities. An aggregate summary, including analysis of the results, has been published [43] , while results presented per individual country are available online at http://apps.klimeto.com/pbk/ . The survey provides insight into the current state of knowledge throughout the PBK modelling and user community, as well as a cursory volunteer contact list of modellers available for peer reviewing models.…”

“…The survey provides insight into the current state of knowledge throughout the PBK modelling and user community, as well as a cursory volunteer contact list of modellers available for peer reviewing models. The main findings of the survey showed that though continuous expansion of the modelling community has allowed PBK models to gain ground for use in various scientific and regulatory risk assessment applications, this remains a slow process, due to a lack of guidance, data, and expertise, which continue to limit widespread acceptance of those models in such applications [43] . Here, we also discuss recently reported activities in the field, (subsequent to the 2016 EURL ECVAM workshop) that demonstrate both ongoing developments and the continued hesitancy within public health agencies to apply PBK modelling in their decisions.…”