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The Practical Applicability of Toxicokinetic Models in the Risk Assessment of Chemicals pp 155–194Cite as

The Prediction of Systemic Toxicity by Integrating the Results of Biokinetic Models and Biologically Based In Vitro Test Methods

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Summary

We have evaluated the possibilities to predict the systemic toxic doses of chemicals on the basis of an integration of data derived from in vitro biologically based test systems and physio-logically-based biokinetic modelling for a number of neurotoxic compounds. This study was part of the ERGATT/CFN Integrated Toxicity Testing Scheme (ECITTS). In this programme, biokinetic models were constructed, where possible solely on the basis of in vitro-derived parameters for biotransformation as well as on partition coefficients determined or calculated from physicochemical structures. A test battery for relevant neurotoxic endpoints was developed in one of the co-operating laboratories. Effective concentrations in the most relevant test formed the basis of a calculation of the compound’s effective dose, making use of the biokinetic model. This formed the basis of the prediction of a compound’s systemic toxicity for acute or (sub) chronic exposure, expressed as a Lower Observed Effect Level (LOEL). Both the kinetic and the dynamic models were compared with known in vivo data. In general, the predictions were in good agreement with these data. The discrepancy between estimated and experimental LOELs ranged from approximately a factor two, for compounds with a low toxicity (i.e. a high LOEL), to a factor 10, for compounds with a high toxicity (i.e. a low LOEL). Building on the experience gained in this programme a Task Force on Integrated Toxicity Testing has been established by the European Centre for the Validation of Alternative Methods (ECVAM). The Task Force proposed a generalised scheme for a stepwise (decision tree) procedure for the use of data derived from different approaches (structure, in vitro systems and computational models) in risk assessments. This scheme would allow for assessing risks of chemicals on the basis of non-animal studies or at least with a strongly reduced number of animals.

This paper is based on the work for the ECITTS programme (1995-1998) and the ECVAM Task Force in Integrated Testing. The author wishes to acknowledge the contribution of the following people, who were involved in one or both activities.

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Authors and Affiliations

  1. Research Institute of Toxicology, Utrecht University, Utrecht, The Netherlands

    Bas J. Blaauboer & Joost DeJongh

  2. Dept of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden

    Anna Forsby

  3. Department of Pharmacy, University of Manchester, UK

    J. Brian Houston

  4. INSERM U456, Unité Detoxication et Réparation Tissulaire, Rennes, France

    André Guillouzo

  5. Marlin Consultancy, Carlton, Bedford, UK

    Martin D. Barratt

  6. National Board for Laboratory Animals (CFN), Stockholm, Sweden

    Marie Beckman

  7. FRAME, Nottingham, UK

    Robert D. Combes

  8. Leiden Advanced Pharmacokinetics & Pharmacodynamics (LAP&P) Consultants, The Netherlands

    Joost DeJongh

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Blaauboer, B.J. et al. (2002). The Prediction of Systemic Toxicity by Integrating the Results of Biokinetic Models and Biologically Based In Vitro Test Methods. In: Krüse, J., Verhaar, H.J.M., de Raat, W.K. (eds) The Practical Applicability of Toxicokinetic Models in the Risk Assessment of Chemicals. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-3437-0_9

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