International symposium on genotoxic and carcinogenic thresholds

Abstract

New paradigms for the setting of tolerable exposure limits for carcinogenic chemicals are being discussed world wide, and there is a global discourse in this respect between toxicological science, regulatory bodies and stakeholders (Sweeney et al. 2006; Bader et al. 2007; Bolt and HuiciMontagud 2008). The traditionally accepted general dogma that health-based exposure limits cannot be derived for genotoxic carcinogens has been challenged by new research results (Hengstler et al. 2003). Against this background the Japanese National Institute of Health Science, in conjunction with the Japan Bioassay Research Center convened an international symposium in Tokyo, in order to foster the exchange of ideas between leading Japanese, American and European scientists in this Weld, and at the same time to communicate results of this discussion to Japanese authorities and stakeholders (Fig. 1). The main initiators of the symposium in particular, Shoji Fukushima and Takehiko Nohmi (Kanagawa and Tokyo), favoured a concept to diVerentiate “perfect” and “practical” thresholds for genotoxic compounds, as earlier deWned by Kirsch-Volders et al. (2000) and Hengstler et al. (2003). An analysis of Waddell et al. (2006) was cited comparing published data on GSTP-positive hepatic foci induced by N-nitroso-diethylamine. The foci were observed at doses below the threshold dose for the appearance of tumours. These results suggested that adducts and GSTP-positive foci appear at doses below those at which tumours appear. These results were interpreted to support the observations of the authors that thresholds for carcinogenicity of this genotoxin exist, and that adducts and altered foci appear at lower doses than the threshold for carcinogenicity. Potassium bromate (Kurokawa et al. 1990; Gultekin and Hicyilmaz 2007) and 1,4-dioxane (Stickney et al. 2003; Nannelli et al. 2005; Kuroiwa et al. 2007) were mentioned as examples of compounds with a “perfect threshold”. In total, the symposium covered a methodological spectrum reaching from bacterial mutagenicity assays (Nohmi 2000) up to modern transgenic mouse assays (Nohmi et al. 2000). The main focus of the symposium was on ingredients of food, e.g. heterocyclic amines, nitrosamines or mycotoxins (Huang et al. 2006; Schrickx et al. 2006; Nagashima et al. 2007). A controversial point of discussion was the evaluation of acrylamide detected recently in unexpectedly large amounts in starchy foods that had been cooked at high temperatures (Boettcher et al. 2006). This is biologically converted into the genotoxic epoxide glycidamide (Settels et al. 2008). The scientiWc evaluation of possible threshold mechanisms in this case is a matter of debate, so that mostly linear non-threshold risk extrapolation models are preferred. From the area of food toxicology parallels were drawn to the setting of occupational exposure limits and to concepts favoured by European scientiWc bodies, such as EUROTOX (Foth et al. 2005) and SCOEL (Bolt and Huici-Montagud 2008). The symposium revealed that the implementation of novel toxicological concepts within the regulatory context requires an intensive and well-founded dialogue between scientists, authorities and stakeholders, both on national and international levels. It will now be up to the scientists to further promote this dialogue. Key articles resulting from the symposium will be published in “Genes and Environment”. H. M. Bolt (&) Leibniz Research Centre for Working Environment and Human Factors, Institut fur Arbeitsphysiologie an der Universitat Dortmund, Ardeystr. 67, 44139 Dortmund, Germany e-mail: bolt@ifado.de