Assessment of mechanisms driving non-linear dose-response relationships in genotoxicity testing.

In genetic toxicology, risk assessment has traditionally adopted linear dose-responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non-linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose mechanisms, this review aims to clarify which mechanistic data are required to support the use of non-linear dose-response models in risk assessment. Such key experiments are presented and discussed for alkylating agents, oxidants, particulate matter, nucleoside analogues, topoisomerase inhibitors and aneugens and exemplify the use of gene knockout models or transgenic models as well as chemical modulators of key effectors of relevant pathways and their impact on dose-response relationships. In vitro studies are particularly valuable to elucidate mechanisms of low-dose protection or lack thereof, while in vivo experiments are most appropriate for deriving a safe dose. In order to evaluate the existence of non-linear dose-response relationships for genotoxicants, we suggest that careful attention should be given to the mode of genotoxic action, relevant biomarkers of exposure, as well as to the existence and impact of potential cytoprotective mechanisms like detoxifying metabolism and DNA repair.

[Scientific policy advice on food safety provided by the Senate Commission on Food Safety]. / Politikberatung zur Lebensmittelsicherheit durch die Senatskommission zur gesundheitlichen Bewertung von Lebensmitteln (SKLM).

The Senate Commission on Food Safety (SKLM, Senatskommission zur gesundheitlichen Bewertung von Lebensmitteln) of the German Research Foundation (DFG, Deutschen Forschungsgemeinschaft) is a transdisciplinary expert committee, providing advice on food safety to the government, parliament, and authorities. Consultation is based on a scientific assessment with the aim to give expert advice to authorities, so that they can make appropriate decisions. The SKLM is independent in its scientific deliberations and under no directive in the selection of issues to work on. Topics considered may result from requests of the Federal Ministry of Food, Agriculture, and Consumer Protection (BMELV, Bundesministeriums für Ernährung, Landwirtschaft und Verbraucherschutz). Other issues may be raised by the SKLM, if they are regarded to be of particular importance for consumer health protection. Issues encompass the scientific assessment of safety and nutritional benefit of food ingredients and additives, of novel and functional food, as well as of novel food technologies. The SKLM identifies gaps in knowledge, research needs, and need for action.

Studies on the inhibition of tumor cell growth and microtubule assembly by 3-hydroxy-4-[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2-dione, an intensively coloured Maillard reaction product.

Very recently, 3-hydroxy-4-[(E)-(2-furyl)methylidene]methyl-3-cyclopentene-1,2-dione (1) has been successfully identified as an intensively coloured Maillard product formed from glucose and L-proline upon thermal food processing. Using a biomimetic synthetic strategy, reference material of compound 1 was prepared and purified, and then used to study its effect on the growth of human tumor cells. Compound 1 was found to potently inhibit the growth of human tumor cells in vitro. Using a reporter gene assay we could show that in growth inhibitory concentrations compound 1 effectively inhibits the phosphorylation of the transcription factor Elk-1. In addition, 1 was found to affect the microtubule skeleton. The human mammary carcinoma cell line MCF-7 exhibits a decrease of the microtubule organisation when treated for 24 h with 1 (> or =20 microM). At concentrations of 30 microM and above a loss of microtubule integrity is observed after 1 h incubation. In vitro studies demonstrated that the polymerisation and, to a minor extent, also the depolymerisation of tubulin, isolated and purified from bovine brain, is inhibited in a dose-dependent manner at concentrations of 30 microM and above. This is the first time that a non-enzymatically formed browning compound of known structure was reported to effectively inhibit tumor cell growth and microtubule assembly.