Toxicity-distribution relationships among 3-alkylfurans in mouse liver and kidney

Wiley, Robert A.; Traiger, George J.; Baraban, Steve; Gammal, Lynda M.

doi:10.1016/0041-008x(84)90263-1

Cited by 31 publications

(23 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both types of agents may participate in early events in the carcinogenic process as well as influence the development of preneoplastic lesions. Chemicals that cause proliferation via regeneration following cell killing would likely have a threshold dose, below which no cytotoxicity, induced proliferation or increased risk of cancer would result [Butterworth, 19891. The data presented here and that of others indicate that furan is acutely cytotoxic to hepatocytes [Burka et al, 1991;McMurtry and Mitchell, 1977;Corsi et al, 1983;Wiley et al, 1984;Terrill et al, 1989;Maronpot et al, 19911. Administration of the bioassay doses of furan for 6 weeks did not result in an increase in the liver weight to body weight ratio (data not shown).…”

Section: Discussionmentioning

confidence: 98%

“…The profile of macromolecular binding indicated that furan metabolites were reactive with protein but not with DNA [Burka et al, 19911. The hepatic and renal toxicities of furan were decreased by prior administration of diethyldithiocarbamate, suggesting that toxicity is mediated by the formation of reactive metabolites [Masuda et al, 19841. In laboratory animals, furan is toxic to the liver, kidneys, and lung [McMurtry and Mitchell, 1977;Kirk-Othmer, 1978;Engle and Gochberg, 1979;Corsi et al, 1983;Wiley et a]., 1984;Terrill et al, 19891. A preliminary summary from a National Toxicology Program (NTP) sponsored bioassay indicates furan induced hepatocellular carcinomas in both sexes of B6C3F1 mice and male Fischer 344 (F-344) rats and cholangiocarcinomas in both sexes of rats (Table I) [Maronpot et a]., 1991; R. Maronpot, personal communication].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan

Wilson

Goldsworthy

Popp

et al. 1992

Environ and Mol Mutagen

View full text Add to dashboard Cite

Preliminary results from the National Toxicology Program (NTP) bioassays of furan given by gavage indicate the induction of hepatocellular carcinomas in male F-344 rats and in both sexes of B6C3F1 mice, and cholangiocarcinomas in both sexes of rats. To assess the genotoxicity of furan, chemically induced unscheduled DNA synthesis was evaluated in the in vivo hepatocyte DNA repair assay. Furan did not induce unscheduled DNA synthesis in hepatocytes isolated after single gavage treatment of male F-344 rats (5, 30, and 100 mg/kg) or male B6C3F1 mice (10, 50, 100, and 200 mg/kg). Furan induced cytotoxicity and enhanced cell proliferation were evaluated in livers of rats and mice as events that also might give rise to mutations and/or drive tumor formation. The labeling index (LI, percentage of hepatocyte nuclei in S-phase) was measured histoautoradiographically following a single gavage administration of furan (30 mg/kg, male rats; 50 mg/kg, male mice) followed by an injection of 3H-thymidine 2 hr prior to sacrifice. Hepatocellular necrosis and a sharp increase in LI (23.9 for mice and 17.8 for rats vs. less than 0.5 for controls) was observed 48 hr after treatment with furan, indicative of restorative cell proliferation secondary to cytotoxicity. Hepatocyte proliferation was evaluated also at the highest NTP bioassay dose (15 mg/kg/day for mice and 8 mg/kg/day for rats, 5 days/week) by labeling with 3H-thymidine administered via a 6 day osmotic pump implanted subcutaneously. Necrosis and inflammation were observed along the subcapsular visceral surface of the left or caudate liver lobes, likely due to diffusion of furan directly through the stomach to the liver. After 6 weeks of furan administration, male and female rats, but not mice, exhibited bile duct hyperplasia as well as metaplasia in the areas of fibrosis along the subcapsular visceral surface of the left or caudate liver lobes. The fold increase in hepatocyte LI in treated animals relative to the combined controls measured at weeks 1, 3, and 6 ranged from 39 to 5 for male mice, 18 to 51 for male rats, and 12 to 19 for female rats. Taken together, these data suggest that mechanisms other than direct DNA-reactivity might explain the profile of oncogene mutations observed in the mouse liver tumors, including selective promotion of different subpopulations of preneoplastic cells and/or mutational events secondary to sustained cell proliferation or inflammation. The extensive amount of furan-induced cell proliferation subsequent to cytotoxicity likely had a significant impact on tumor development, and such data should be considered in risk evaluations for this compound.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan

Wilson

Goldsworthy

Popp

et al. 1992

Environ and Mol Mutagen

View full text Add to dashboard Cite

show abstract

“…In the lungs, fluid accumulation and inflammatory reactions were found after inhalation. Wiley et al (1984) injected furan i.p. in male ICR mice.…”

Section: Toxicity In Experimental Animalsmentioning

confidence: 99%

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

Knutsen¹,

Alexander²,

Barregård³

et al. 2017

EFS2

View full text Add to dashboard Cite

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.

show abstract

“…Furan and 2-methylfuran were found to be potent hepatotoxins (Wiley et al 1984;Ravindranath et al 1986). Little toxicological information is available for 2-methylfuran where the preferred route of administration was by inhalation (Egle and Gochberg 1979) or intraperitoneal injection.…”

Section: Introductionmentioning

confidence: 99%

A 28-day Gavage Toxicity Study in Male Fischer 344 Rats with 2-methylfuran

et al. 2013

View full text Add to dashboard Cite

In most thermally treated products, a series of alkylated furan derivatives have been found, in particular 2-substituted alkylfurans such as 2-methylfuran. These methyl analogs are metabolically activated in a similar fashion as the parent furan, yielding highly reactive unsaturated dialdehydes. There is currently limited toxicological data available for 2-methyl furan exposure by any route that makes conducting a risk assessment difficult. In this pilot study, we report the general toxicology findings affecting tissue morphology, histopathology, clinical biochemistry, and hematology in a 28-day gavage study. The liver was the primary target organ that developed dose-dependent toxicity. Relative liver weights were increased by 42% at 25.0 mg/kg/body weight (bw)/day. Histological changes in the liver were observed at 0.4, 1.5, 3.0, 6.0, 12.0, and 25.0 mg/kg bw/ day. These changes were not accompanied by clinical changes in the serum enzyme markers such as alanine transaminase, alkaline phosphatase, and aspartate transaminase. Clinical biochemistry markers for kidney were altered, but these were not accompanied by histological changes. The prostate was significantly decreased in size at the 25.0 mg/kg bw/day dose of 2-methyfuran. Some hematological parameters were also altered.

show abstract

Toxicity-distribution relationships among 3-alkylfurans in mouse liver and kidney

Cited by 31 publications

References 14 publications

Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan

Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan

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

A 28-day Gavage Toxicity Study in Male Fischer 344 Rats with 2-methylfuran

Contact Info

Product

Resources

About