Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans

Grill, Alexander E; Schmitt, Thaddeus; Gates, Leah; Ding, Lei; Bandyopadhyay, Dipankar; Yuan, Jian Min; Murphy, Sharon E.; Peterson, Lisa A.

doi:10.1021/acs.chemrestox.5b00189

Cited by 28 publications

(40 citation statements)

References 43 publications

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“…Of the amino‐adducts in urine from rats exposed to furan, next to NAC‐BDA‐lys, lower levels of NAC‐BDA‐spermidine, but no ornithine adducts could be found (Peterson et al., ). For the cysteine‐containing adducts also the corresponding sulfoxides have been reported in bile of rats and in urine of rats, mice and humans (Kellert et al., ; Lu et al., ; Hamberger et al., ; Peterson et al., ; Grill et al., ). Lu and Peterson () provided evidence that the cys‐BDA‐lys adduct is an important intermediate in the formation of the N‐acetylated, de‐aminated or sulfoxidated urinary metabolites of furan in vivo .…”

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 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: 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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“…Sulfoxides have been previously observed as human urinary metabolites of a number of compounds including acrylamide [25], furan [26], and the anti-cancer agent bendamustine [27]. These observations encouraged us to analyze for sulfoxides 8 , 11 , 15 , and 18 in this study.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the presence in human urine of mercapturic acids derived from phenanthrene, a representative polycyclic aromatic hydrocarbon

Cheng

Zarth

Upadhyaya

et al. 2017

Chemico-Biological Interactions

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Polycyclic aromatic hydrocarbons (PAH) are environmental carcinogens implicated as causes of cancer in certain industrial settings and in cigarette smokers. PAH require metabolic activation to exert their carcinogenic effects. One widely accepted pathway of metabolic activation proceeds through formation of “bay region” diol epoxides which are highly reactive with DNA and can cause mutations. Phenanthrene (Phe) is the simplest PAH with a bay region and an excellent model for the study of PAH metabolism. In previous studies in which [D10]Phe was administered to smokers, we observed higher levels of [D10]Phe-tetraols derived from [D10]Phe-diol epoxides in subjects who were null for the glutathione-S-transferase M1 (GSTM1) gene. We hypothesized that Phe-epoxides, the primary metabolites of Phe, were detoxified by glutathione conjugate formation, which would result ultimately in the excretion of the corresponding mercapturic acids in urine. We synthesized the four stereoisomeric mercapturic acids that would result from attack of glutathione on Phe-epoxides followed by normal processing of the conjugates. We also synthesized the corresponding dehydrated metabolites and sulfoxides. These 12 standards were used in liquid chromatography-nanoelectrospray ionization-high resolution tandem mass spectrometry analysis of urine samples from smokers and creosote workers, the latter exposed to unusually high levels of PAH. Only the sulfoxide derivatives were consistently detected in the urine of creosote workers; none of the compounds was detected in the urine of smokers. These results demonstrate a new pathway of PAH-mercapturic acid formation, but do not provide an explanation for the role of GSTM1 null status on Phe-tetraol formation.

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“…This may point at the need for grouping of biomarkers and related exposures especially when the biomarker indicates at a specific biological potential or adverse effect. Also the smoking status of human subjects has been found to affect biomarkers of for example acrolein, acrylamide, furan and glycidyl ester exposure (Landin et al 1997 ; Grill et al 2015 ). In addition, inter-individual differences in both endogenous formation and in metabolic pathways leading to biomarker formation upon external exposure need to be taken into account when considering extrapolation of biomarker levels to external dose levels.…”

Section: Discussionmentioning

confidence: 99%

“…No examples of application of these biomarkers to correlate dietary furan exposure in animals or humans are available yet. However, one study addressed the presence of urinary furan exposure biomarkers in three cohorts of smokers versus non-smokers comprising between 5 and 15 subjects per group (Grill et al 2015 ). Metabolites derived from direct interaction of BDA with lysine and from crosslinks of cysteine-BDA-lysine (Fig.…”

Section: State Of the Artmentioning

confidence: 99%

“…Its levels were more than 10 times higher in urine from smokers than in urine from non-smokers, and levels decreased immediately upon cessation of smoking. The NAcCys-BDA-Lys sulfoxide ( 5 ) was postulated to be a degradation product of adducted proteins, and as such a promising marker for furan metabolism to BDA and also a potential biomarker of furan toxicity (furan induced protein damage) (Grill et al 2015 ). Besides degradation of protein adducts, enzymatic processing of the GSH-BDA-Lys conjugate ( 4 ) (Fig.…”

Section: State Of the Artmentioning

confidence: 99%

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Exposure assessment of process-related contaminants in food by biomarker monitoring

et al. 2018

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Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario’s and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment.

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Abundant Rodent Furan-Derived Urinary Metabolites Are Associated with Tobacco Smoke Exposure in Humans

Cited by 28 publications

References 43 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

Investigation of the presence in human urine of mercapturic acids derived from phenanthrene, a representative polycyclic aromatic hydrocarbon

Exposure assessment of process-related contaminants in food by biomarker monitoring

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