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Highlights: [•] Animal-free risk assessment must increasingly use human toxicokinetics predictions. [•] Only human physiologically-based toxicokinetic (PBTK) modelling can serve this need. [•] Freely-available open source PBTK modelling platforms are lacking largely. [•] In vitro and in silico (QSAR) tools to meaure and predict needed parameters are rather scarce. [•] Presented are a state of the art overview and five high priority recommendations. [Copyright &y& Elsevier]

Abstract: The increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in various jurisdictions necessitates the development of internationally recognized good modelling practice (GMP). These practices would facilitate sharing of models and model evaluations and consistent applications in risk assessments. 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 model developers to understand expectations for various purposes e.g., research versus application in risk assessment. Next steps in the development of guidance for GMP and research to improve the scientific basis of the models are described based on a review of the current status of the application of physiologically based pharmacokinetic (PBPK) models in risk assessments in Europe, Canada, and the United States at the International Workshop on the Development of GMP for PBPK Models in Greece on April 27–29, 2007. [Copyright &y& Elsevier]

Abstract: An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose–response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure–activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose–response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose–response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose–response data derived from sensitized patients, be included in risk assessment. [Copyright &y& Elsevier]

Xenobiotic metabolizing Cytochrome P450 (P450) enzymes were investigated in leukapheresed samples from 50 human individuals. It was the aim of the study (a) to get insight into the extent of extrahepatic P450 variability, (b) to investigate whether and to which extent P450 expression and variability as it is seen in the liver corresponds to P450 expression at extrahepatic sites, and (c) to contribute to the replacement of traditionally used default factors (usually 10 for interindividual variability) by data-derived factors in the risk assessment process. P450 enzymes were determined by Western Blotting. Immunoquantification was performed for P450 1A, 1B1, 2C, 2D6, 2E1, and 3A which were—with the exception of the polymorphically expressed CYP2D6—detectable in all samples investigated. Amounts of P450 enzymes in leukapheresed samples were (except CYP1B1) lower compared to those reported for the liver. The P450 variabilities were expressed by the ratios between the 95th and the 5th percentiles. They displayed 7-(CYP1A), 4-(CYP1B1), 6-(CYP2C), 30-(CYP2D6), 3-(CYP2E1), and 4-(CYP3A) fold variability in specific protein content. The results show (a) qualitative and quantitative differences in the expression of P450 proteins in leukapheresed samples from 50 individuals compared to liver, (b) a different extent of variability depending on the P450 enzyme, and (c) in cases where polymorphically distributed P450 enzymes are involved, the traditionally used factor of 10 might be too low to account for interindividual variability in both toxicokinetics and toxicodynamics. [Copyright &y& Elsevier]