Functional and proliferative effects of repeated low‐dose oral administration of furan in rat liver

Mally, Angela; Graff, Carmen; Schmal, Olga; Moro, Sabrina; Hamberger, Carolin; Schauer, Ute M.D.; Brück, Jens; Özden, Sibel; Sieber, Max; Steger, Ulrich; Schrenk, Dieter; Hard, Gordon C.; Chipman, J.K.; Dekant, W.

doi:10.1002/mnfr.201000064

Cited by 22 publications

(18 citation statements)

References 26 publications

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“…Assessment of hepatocyte proliferation in subcapsular areas of the left and caudate lobes of male F344 rats treated with 0, 0.1, 0.5, and 2 mg/kg bw furan for 4 weeks revealed a dose‐related increase in the BrdU‐labeling index. Although statistical significance was only reached at 2 mg/kg bw , changes in the rate of cell proliferation were accompanied by a statistically significant increase in the expression of genes involved in the processes of apoptosis and cell cycle even at the lowest dose of 0.1 mg/kg bw . These findings are in line with a recent 90‐day toxicity study in F344 rats orally treated with furan doses of 0.0, 0.03, 0.12, 0.5, 2.0, and 8.0 mg/kg, from which a NOAEL of 0.03 mg/kg bw/day was derived .…”

Section: Mechanisms Of Furan Carcinogenicitysupporting

confidence: 88%

Furan in heat‐treated foods: Formation, exposure, toxicity, and aspects of risk assessment

Moro

Chipman

Wegener

et al. 2012

Molecular Nutrition Food Res

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100

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Furan is formed in a variety of heat-treated foods through thermal degradation of natural food constituents. Relatively high levels of furan contamination are found in ground roasted coffee, instant coffee, and processed baby foods. European exposure estimates suggest that mean dietary exposure to furan may be as high as 1.23 and 1.01 μg/kg bw/day for adults and 3- to 12-month-old infants, respectively. Furan is a potent hepatotoxin and hepatocarcinogen in rodents, causing hepatocellular adenomas and carcinomas in rats and mice, and high incidences of cholangiocarcinomas in rats at doses ≥ 2 mg/kg bw. There is therefore a relatively low margin of exposure between estimated human exposure and doses that cause a high tumor incidence in rodents. Since a genotoxic mode of action cannot be excluded for furan-induced tumor formation, the present exposures may indicate a risk to human health and need for mitigation. This review summarizes the current knowledge on mechanisms of furan formation in food, human dietary exposure to furan, and furan toxicity, and highlights the need to establish the risk resulting from the genotoxic and carcinogenic properties of furan at doses lower than 2 mg/kg bw.

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Section: Mechanisms Of Furan Carcinogenicitysupporting

confidence: 88%

Furan in heat‐treated foods: Formation, exposure, toxicity, and aspects of risk assessment

Moro

Chipman

Wegener

et al. 2012

Molecular Nutrition Food Res

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100

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“…The ductular structures either differentiated into hepatocytes or transformed into ductular cholangiofibrotic structures. Mally et al (2010) treated male Fischer 344 rats orally (gavage) at doses of 0.1, 0.5 and 2 mg/kg bw for 28 days (5 days per week), with an interim sacrifice after 5 days of treatment. An off-dose recovery group (0 and 2 mg/kg bw dose groups only) was kept for additional 2 weeks (recovery period) after the end of the 4-week treatment period.…”

Section: A Furanmentioning

confidence: 99%

Risks for public health related to the presence of furan and methylfurans in food

Knutsen¹,

Alexander²,

Barregård³

et al. 2017

EFS2

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The European Commission asked EFSA for a scientific evaluation on the risk to human health of the presence of furan and methylfurans (2-methylfuran, 3-methylfuran and 2,5-dimethylfuran) in food. They are formed in foods during thermal processing and can co-occur. Furans are produced from several precursors such as ascorbic acid, amino acids, carbohydrates, unsaturated fatty acids and carotenoids, and are found in a variety of foods including coffee and canned and jarred foods. Regarding furan occurrence, 17,056 analytical results were used in the evaluation. No occurrence data were received on methylfurans. The highest exposures to furan were estimated for infants, mainly from ready-to-eat meals. Grains and grain-based products contribute most for toddlers, other children and adolescents. In adults, elderly and very elderly, coffee is the main contributor to dietary exposure. Furan is absorbed from the gastrointestinal tract and is found in highest amounts in the liver. It has a short half-life and is metabolised by cytochrome P450 2E1 (CYP2E1) to the reactive metabolite, cis-but-2-ene-1,4-dialdehyde (BDA). BDA can bind covalently to amino acids, proteins and DNA. Furan is hepatotoxic in rats and mice with cholangiofibrosis in rats and hepatocellular adenomas/carcinomas in mice being the most prominent effects. There is limited evidence of chromosomal damage in vivo and a lack of understanding of the underlying mechanism. Clear evidence for indirect mechanisms involved in carcinogenesis include oxidative stress, gene expression alterations, epigenetic changes, inflammation and increased cell proliferation. The CONTAM Panel used a margin of exposure (MOE) approach for the risk characterisation using as a reference point a benchmark dose lower confidence limit for a benchmark response of 10% of 0.064 mg/kg body weight (bw) per day for the incidence of cholangiofibrosis in the rat. The calculated MOEs indicate a health concern. This conclusion was supported by the calculated MOEs for the neoplastic effects.

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“…for up to 4 weeks (Mally et al, 2010). However, whether or not membrane transporters represent furan target proteins remains to be established.…”

Section: Hamberger Et Almentioning

confidence: 99%

Hepatobiliary Toxicity of Furan: Identification of Furan Metabolites in Bile of Male F344/N Rats

Hamberger

Kellert²,

Schauer³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Furan, which occurs in a wide variety of heat-treated foods, is a potent hepatotoxicant and liver carcinogen in rodents. In a 2-year bioassay, furan caused hepatocellular adenomas and carcinomas in mice and rats but also high incidences of bile duct tumors in rats. Furan is bioactivated by cytochrome P450 enzymes to cis-2-butene-1,4-dial, an ␣,␤-unsaturated dialdehyde, which readily reacts with tissue nucleophiles. The objective of this study was to structurally characterize furan metabolites excreted with bile to better understand the potential role of reactive furan intermediates in the biliary toxicity of furan. Bile duct-cannulated F344/N rats (n ‫؍‬ 3) were administered a single oral dose of 5 mg/kg b.wt. The main metabolite was a cyclic monoglutathione conjugate of cis-2-butene-1,4-dial, which was previously detected in urine of furan-treated rats. Furthermore, a N-acetylcysteine-N-acetyllysine conjugate, previously observed in rat urine, and a cysteinylglycine-glutathione conjugate were identified as major metabolites. These data suggest that degraded protein adducts are in vivo metabolites of furan, consistent with the hypothesis that cytotoxicity mediated through binding of cis-2-butene-1,4-dial to critical target proteins is likely to play a key role in furan toxicity and carcinogenicity.

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Functional and proliferative effects of repeated low‐dose oral administration of furan in rat liver

Cited by 22 publications

References 26 publications

Furan in heat‐treated foods: Formation, exposure, toxicity, and aspects of risk assessment

Furan in heat‐treated foods: Formation, exposure, toxicity, and aspects of risk assessment

Risks for public health related to the presence of furan and methylfurans in food

Hepatobiliary Toxicity of Furan: Identification of Furan Metabolites in Bile of Male F344/N Rats

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