The extent of bioactivation of the herbal constituent estragole to its ultimate carcinogenic metabolite 1′-sulfooxyestragole depends on the relative levels of bioactivation and detoxification pathways. The present study investigated the kinetics of the metabolic reactions of both estragole and its proximate carcinogenic metabolite 1′-hydroxyestragole in humans in incubations with relevant tissue fractions. Based on the kinetic data obtained a physiologically based biokinetic (PBBK) model for estragole in human was defined to predict the relative extent of bioactivation and detoxification at different dose levels of estragole. The outcomes of the model were subsequently compared with those previously predicted by a PBBK model for estragole in male rat to evaluate the occurrence of species differences in metabolic activation. The results obtained reveal that formation of 1′-oxoestragole, which represents a minor metabolic route for 1′-hydroxyestragole in rat, is the main detoxification pathway of 1′-hydroxyestragole in humans. Due to a high level of this 1′-hydroxyestragole oxidation pathway in human liver, the predicted species differences in formation of 1′-sulfooxyestragole remain relatively low, with the predicted formation of 1′-sulfooxyestragole being twofold higher in human compared with male rat, even though the formation of its precursor 1′-hydroxyestragole was predicted to be fourfold higher in human. Overall, it is concluded that in spite of significant differences in the relative extent of different metabolic pathways between human and male rat there is a minor influence of species differences on the ultimate overall bioactivation of estragole to 1′-sulfooxyestragole.

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This is the 54th report of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). The main objective of ECVAM, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and of opportunities for the possible incorporation of alternative methods into regulatory procedures. It was decided that this would be best achieved through a programme of ECVAM workshops, each addressing a specific topic, and at which selected groups of independent international experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward.A workshop on Metabolism: a bottleneck in in vitro toxicological test development, was held at

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