Authors L. Edler, K. Poirier, M. Dourson, J. Kleiner, B. Mileson, H. Nordmann, A. Renwick, W. Slob, K. Walton, G. Wurtzen
Abstract
The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible.
It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output. Research needs:
Structure-activity relationship (SAR) and Threshold of toxicological concern (TTC) expansion of data bases of chemical structure and thresholds for different types of toxicities updated validity of the Cramer decision tree Threshold development and validation of appropriate uncertainty factors (Ufs) for different species and different categories of metabolic fate and mechanisms of action validity of the default UF by analysis of historical data concerning human versus animal or/and human subpopulations Chemical specific adjustment factor (CSAF) modelling availability of toxico dynamic data for the subdivision of the 10-fold default inter- and intraspecies Ufs Non-threshold knowledge of the shape of the dose-response curve at low doses better understanding of the biological basis for the extrapolation e.g. by using biomarkers, tumour precursors, genetically modified animals, and by including toxico kinetic (TK) for target dose estimation optimal designs with regard to number of animals and number of dose groups Benchmark Dose (BMD) understanding of adversity of the effect size for getting consensus on the benchmark response level combined analysis of different populations for more precisely estimating BMD ratios optimal designs w.r.t number animals combining studies Probabilistic Risk Assessment (RA) analysis of historical data concerning human versus animal or/and human subpopulations for updating default uncertainty distributions specific experiments filling data gaps in the literature application of probabilistic RA in parallel with the traditional UF approach Categorical Regression guidelines for application and validation of models used criteria for the assignment of severity categories criteria for combining studies (e.g. weighting small and large studies) Physiologically based toxicokinetic (PBTK) models extension of the TK model to a complete TKTD model lack of basic information on human variability in physiological parameters knowledge to translate in vitro information to in vivo information validation of physiological parameters in humans using pharmaceutical research results.
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