Low dose assessment of the carcinogenicity of furan in male F344/N Nctr rats in a 2-year gavage study

Tungeln, Linda S. Von; Walker, Nigel J.; Olson, Greg R.; Mendoza, Maria C.B.; Felton, Robert P.; Thorn, Brett T.; Marques, M. Matilde; Pogribny, Igor P.; Doerge, Daniel R.; Beland, Frederick A.

doi:10.1016/j.fct.2016.11.015

Cited by 48 publications

(40 citation statements)

References 59 publications

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“…Other significant changes observed were biliary tract hyperplasia, cytoplasmic vacuolisation of oval cells and regenerative hypertrophy (Table ). Interim analyses at 36 and 60 weeks showed similar responses with the significance at lower doses increasing with the time (NCTR, ; Von Tungeln et al., ).…”

Section: Assessmentmentioning

confidence: 87%

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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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Section: Assessmentmentioning

confidence: 87%

“…Samples (23 from 2 mg/kg bw and 6 from 8 mg/kg bw) from the NTP study (1993) were re‐examined following the guidelines described by Thoolen et al. () and it is now clear that cholangiocarcinomas were only observed at the highest dose (NCTR, ; Von Tungeln et al., ) while cholangiofibrosis was observed at the lower doses.…”

Section: Assessmentmentioning

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 BMD is used to derive a “Point of Departure” (PoD), a dose used to calculate the MoE with estimated human dietary exposure. Several groups, including food safety authorities, have included BMD modeling in their reports (Carthew, DiNovi, & Setzer, ; EFSA, ; JECFA, ; Von Tungeln et al., ). JECFA () selected the study of Moser et al.…”

Section: Aspects Important For Risk Assessmentmentioning

confidence: 99%

“…Using the combination of this and the data set from the previous NTP study (NTP, ), EFSA determined a BMDL 10 of 1.31 mg/kg bw/day for the same endpoint, following the EFSA guidelines for BMD modeling (EFSA, ). BMD modeling was recently also applied to the non‐neoplastic endpoint of cholangiofibrosis in rats (EFSA, ; Von Tungeln et al., ). Again, slightly different BMDL 10 levels were obtained by EFSA, following the EFSA guidelines (BMDL 10 of 0.064 mg/kg bw/day), compared to the modeling following the EPA suite for BMD modeling (BMDL 10 of 0.11 to 0.12 mg/kg bw/day), based on the same rodent data set (Von Tungeln et al., ).…”

Section: Aspects Important For Risk Assessmentmentioning

confidence: 99%

“…The BMD is used to derive a "Point of Departure" (PoD), a dose used to calculate the MoE with estimated human dietary exposure. Several groups, including food safety authorities, have included BMD modeling in their reports (Carthew, DiNovi, & Setzer, 2010;EFSA, 2017;JECFA, 2011;Von Tungeln et al, 2017). JECFA (2011) selected the study of Moser et al (2009) for deriving the BMDL 10 as the PoD (that is, the lower confidence limit of the dose resulting in 10% increase in tumor incidence above background), for combined liver adenoma and carcinoma in female mice (neoplastic endpoint), because of the lowest level of uncertainty in the data.…”

Section: Bmd Modeling Of Furanmentioning

confidence: 99%

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Furan and Methylfurans in Foods: An Update on Occurrence, Mitigation, and Risk Assessment

Kettlitz¹,

Scholz

Theurillat

et al. 2019

Comp Rev Food Sci Food Safe

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The acceptance of many foods is related to traditional cooking practices, which create taste and texture and are important to digestibility, preservation, and the reduction of foodborne illnesses. A wide range of compounds are formed during the cooking of foods, a number of these have been shown to lead to adverse effects in classical toxicological models and are known as food processing contaminants (FPC). It is essential that the presence and effects of such compounds alone and in combination within the diet are understood such that proportionate risk management measures can be developed, while taking a holistic view across the whole value chain. Furan and alkylfurans (principally 2‐ and 3‐methylfuran) are highly volatile FPC, which are formed in a wide range of foods at low amounts. The focus of research to‐date has been on those foods, which have been identified to be most consequential in terms of being sources of exposure, namely jarred and canned foods for infants and young children (meals and drinks) and coffee (roast and ground, soluble). This report presents (i) new industry data on the occurrence of furan and methylfurans in selected food categories following previous coffee studies, (ii) the most salient parameters that impact furan formation, and (iii) aspects of importance for the risk assessment.

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In Vitro and In Vivo Model Systems of Cholangiocarcinoma

Brandi

Tavolari

2021

Diagnosis and Management of Cholangiocarcinoma

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Low dose assessment of the carcinogenicity of furan in male F344/N Nctr rats in a 2-year gavage study

Cited by 48 publications

References 59 publications

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

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

Furan and Methylfurans in Foods: An Update on Occurrence, Mitigation, and Risk Assessment

In Vitro and In Vivo Model Systems of Cholangiocarcinoma

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