Abstract
Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration-time profile at the target site. Physiologically-based kinetic (PBK) models can predict organ-level concentration-time profiles, however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.
Highlights
Humans, like other animals, are exposed daily to a multitude of chemicals of anthropogenic origin, including pharmaceuticals, food additives, pesticides, consumer goods and cosmetic ingredients
Kinetic data is a specific requirement for plant protection and biocidal product safety assessment and, whilst not formally required, incorporation of such data is widely recommended in other regulations, such as for classification, labelling and packaging (CLP) and the Registration, Evaluation Authorisation and restriction of Chemicals (REACH).[2]
This systematic review was prospectively registered on PROSPERO, the National Institute for Health Research’s international prospective registration system with the review question stipulated as: “For which substances are physiologically-based kinetic (PBK) models available and which species, genders, life-stages and routes of administration have been investigated for these substances? This will include determining the chemical space coverage of the models and the availability of the associated model equations within the literature.”[25]. The review complies with the PRISMA reporting standards - the PRISMA checklist is available as Supplementary Material (iii)
Summary
Like other animals, are exposed daily to a multitude of chemicals of anthropogenic origin, including pharmaceuticals, food additives, pesticides, consumer goods and cosmetic ingredients. The safety assessment of chemicals is a legal requirement and essential to ensure safe use for workers and consumers, as well as protection of domestic/farm animals and environmental species. Predicting toxicity requires knowledge of both the intrinsic activity of the chemical (or its derivatives) and the extent to which the organism is exposed. Kinetic data is a specific requirement for plant protection and biocidal product safety assessment and, whilst not formally required, incorporation of such data is widely recommended in other regulations, such as for classification, labelling and packaging (CLP) and the Registration, Evaluation Authorisation and restriction of Chemicals (REACH).[2] Guidance documents from the European Chemicals Agency[3] and the Scientific Committee on Consumer Safety[4] recommend making use of all available data (including kinetic data) to support decisionmaking. Physiologically-based kinetic (PBK) models (synonymous with physiologically-based pharmacokinetic, toxicokinetic or biokinetic (PBPK, PBTK or PBBK) models) are employed in numerous industries to provide such predictions
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