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Role of genetic and non-genetic mechanisms in furan risk

Final Report Summary - FURAN-RA (Role of genetic and non-genetic mechanisms in furan risk)

In a recent investigation, the United States (US) Food and Drug Administration (FDA) identified the chemical furan in a variety of food items that undergo heat treatment. Furan is a potent hepatotoxicant and liver carcinogen in rodents. Although data on human intake of furan is limited, it appears that there is a relatively narrow margin between human exposure and doses which cause liver tumours in rodents, suggesting that the presence of furan in food may present a potential risk to human health.

However, the presently available data on furan toxicity is insufficient to perform a risk assessment and more research regarding the mechanism of furan carcinogenicity is needed. The project addressed modes of action for tumour induction in liver by the food contaminant furan, which is formed by processing of food resulting in widespread human exposure. There is uncertainty regarding the relevance of tumours induced in rodents to human risk assessment because the mechanisms are unclear. The research is addressing the role of DNA and protein binding of furan, oxidative DNA damage, non-genotoxic alteration of proliferation and apoptosis, cytogenetics and cytotoxicity in furan-mediated liver toxicity and carcinogenicity.

A combination of in vivo and in vitro systems, analytical chemistry, cell biology and 'omics' technologies was applied. In rodents, in vivo, extent and dosedependence of covalent binding to DNA, cytogenetic changes and geno- and cytotoxicity in target cells in the liver were addressed after oral administration of furan. In addition, the induction of oxidative DNA-modifications and mechanisms of mutations have been investigated in genetically modified rodent models. These in vivo studies characterise the mode of action of furan and also address irreversible metaplasia, changes in cell signalling and inflammation. The interaction of these effects with possible genetic changes in liver cells including aspects of forced cell proliferation have been included.

The in vivo work has been complemented by studying mode of mutation of furan and its metabolite cis-2-butene-1,4-dial in cell culture models resembling the target cells. The content of furan in food was determined and human exposures were assessed using probabilistic modelling. Mechanisms of formation of furan in food may open ways to reduce exposures.

The results provide data on the mode-of-action of furan induced liver carcinogenesis as a basis for a conclusive assessment of health risks in humans due to dietary exposure. The combination of these findings provide a risk / benefit analysis and a scientific basis to justify limits for human furan exposures.

Due to genotoxicity and DNA-binding of furan established in the project, the current risk assessment for furan requires application of a linear dose response relationship. Exposures to furan in adults are estimated to be less than 0.5 µg/kg bw/day, data from this project also support a similar intake of furan in children. Due to the high incidence of tumours induced by furan in rats even at the lowest applied dose, a linear extrapolation of the animal data to calculate possible human tumour risks is uncertain. When using a margin-of-exposure assessment, MoEs to a dose inducing a significant tumour incidence are calculated as only 1000 to 2000. The low MoEs warrant further reductions in furan-exposures.