Metabolism: A Bottleneck in In Vitro Toxicological Test Development

Abstract

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

Setting Properties and Cytotoxicity Evaluation of a Premixed Bioceramic Root Canal Sealer

“…Another important issue to consider is the fact that culture conditions are not homeostatic, and there is no elimination of toxic substances as there would be in vivo. The lack of biotransformation capabilities is probably the best-known limitation in cell culture systems (28) although the lack of defense mechanisms probably has a stronger impact on the precision of toxicity estimations (29). By contrast, the human body possesses a lymphatic system and periapical defenses such as polymorphonuclear leukocytes, plasma cells, and macrophages to help eliminate toxic substances (30).…”

Towardin vitrobiomarkers for developmental toxicity and their extrapolation to thein vivosituation

“…In in vitro test systems, the expression levels of biotransformation enzymes might be too low to bioactivate the parent compounds [69]. The addition of a bioactivation system might increase the in vitro developmental toxicity potency of a proteratogen.…”

“…However, no increase in the in vitro potency was obtained for the proteratogen valpromide, using the same experimental procedure, because the levels of the active metabolite (valproic acid) in the culture medium were too low to increase the toxicity [70]. Furthermore, using preconditioned medium will not increase a proteratogen's potency in a test system, when the toxic bioactivation products are unstable [69].…”

High-content screening imaging and real-time cellular impedance monitoring for the assessment of chemical’s bio-activation with regards hepatotoxicity

“…The eight compounds were selected based on their toxicity profile and bio-activation properties, i.e. direct or indirect toxicity (linked to the biotransformation process), from lists in "the report and recommendations of ECVAM workshop 54" of products recommended for validation studies of alternative methods (Coecke et al, 2006). These can be found in the fourteenth updated edition of the bibliographic database of liver injuries and related drugs (Biour et al, 2004) or from the REACH concern products list.…”