Food Standards Agency
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Listen to this siteWednesday 24 March 2004
This project investigated, using the in vitro binucleate micronucleus assay, whether the concept of non-linear, threshold dose-response relationships can be applied to at least a proportion of the potentially mutagenic chemicals found in food.
Study Duration : October 2002 to September 2005
Contractor : University of Wales, Swansea
Food may contain a number of genotoxic substances, present at very low levels as natural constituents or as a result of unavoidable contamination. Current UK policy is that it is prudent to assume a non-threshold dose response for chemicals that are genotoxic in vivo . The Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment recently reviewed its general approach to risk assessment of in vivo mutagens and concluded that for certain substances (such as aneugens) it may be possible to identify potential threshold-related mechanisms of action. These mechanisms include DNA repair activity, compound detoxification and the existence of multiple targets for genotoxin interaction. Mechanistic and dose-response studies may support identification of a critical No Observed Adverse Effect Level (NOAEL), to which uncertainty factors could be applied in establishing a Tolerable Daily Intake (TDI).
The project is generating a database that collates information on genotoxic chemicals that may occur in food. These will be categorised by their mechanisms of genotoxic activity. Compounds with a potentially thresholded mechanism of action will then be subjected to further investigation. This will generate a priority list of compounds that will be subject to laboratory testing using in vitro models. In addition, experimental work will be carried out on a small number of chemicals that have already been identified as possibly meeting the criteria of acting via a threshold mechanism. Those selected are: bisphenol A, rotenone, fisetin and acrylamide. In addition, the project will include a study of whether exposure of mice to low levels of bisphenol A in vivo leads to an increase in abnormalities of oocyte meiosis leading to aneuploidy.
Initial work developed databases of potential genotoxins and aneugens occurring in food. Bisphenol A, bisphenol A diglycidyl ether (BADGE), acrylamide, rotenone and genistein were identified as potential aneugenic chemicals that may act via threshold mechanisms. An aneugen is a substance that, by interacting with components of the cell division apparatus, may lead to a deviation from the normal diploid number of chromosomes (called aneuploidy).
To confirm the existence of thresholds of genotoxic action for these chemicals detailed dose-response analysis was performed using the in vitro binucleate micronucleus assay with human lymphoblastoid cell lines (AHH-1 and MCL-5) and a hamster fibroblast cell line (V79). The AHH-1-related MCL-5 cell line is genetically engineered to express higher levels of the cytochromes CYP1A1, 2A6, 3A4 and 2E1 together with microsomal epoxide hydrolase.
The induction of aneuploidy by bisphenol A was further investigated in mouse oocytes exposed both in vitro and in vivo (with ex vivo oocyte maturation). These studies did not confirm a previous report of chromosome congression failure at low µg/kg bw/day dose levels. In fact, bisphenol A did not interfere with spindle formation in maturing mouse oocytes up to levels of 100 µg/kg bw/day.
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