Urinary excretion of the acrylonitrile metabolite 2-cyanoethylmercapturic acid is correlated with a variety of biomarkers of tobacco smoke exposure and consumption

There are established guidelines for bioanalytical assay validation and qualification of biomarkers. In this review, they were applied to a panel of urinary biomarkers of tobacco smoke exposure as part of a “fit for purpose” approach to the assessment of smoke constituents exposure in groups of tobacco product smokers. Clinical studies have allowed the identification of a group of tobacco exposure biomarkers demonstrating a good doseresponse relationship whilst others such as dihydroxybutyl mercapturic acid and 2-carboxy-1-methylethylmercapturic acid – did not reproducibly discriminate smokers and non-smokers. Furthermore, there are currently no agreed common reference standards to measure absolute concentrations and few inter-laboratory trials have been performed to establish consensus values for interim standards. Thus, we also discuss in this review additional requirements for the generation of robust data on urinary biomarkers, including toxicant metabolism and disposition, method validation and qualification for use in tobacco products comparison studies.

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“…, 2001; Minet et al . , 2011a). 3-HPMA has been used in product switching studies and smoking cessation studies (Carmella et al .…”

Section: Resultsmentioning

confidence: 99%

“…For acrylonitrile, data on the biomarker N-acetyl-S-(2-carboxyethyl)- l -cysteine (CEMA) assay validation and some comparisons of smokers and non-smokers are available (Minet et al . , 2011a; Schettgen et al . , 2009), but sample storage stability, use in long-term studies of smokers and inter-laboratory comparisons were not found.…”

Section: Resultsmentioning

confidence: 99%

Urinary biomarkers of smokers’ exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach

2013

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“…Once absorbed in the body, acrylonitrile is metabolised through:

Epoxidation to glycidonitrile, which in turn can form DNA and protein/haemoglobin adducts such as 2-cyanoethylvaline (CEVal; Figure 1) which can be released by a modified Edman degradation procedure.

Reaction with glutathione (GSH) possibly catalysed by GSTs (Figure 1). As final products of the reaction with GSH, a number of mercapturic acids are formed which are excreted into the urine, the most important of which is 2-cyanoethylmercapturic acid (CEMA; Figure 1; Minet et al, 2011).

Figure 1.Simplified metabolic pathways leading to the formation of CEMA, CEVal, 4-aminobiphenyl N -glucuronide and 4-ABP-Hb. …”

Section: Introductionmentioning

confidence: 99%

A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers

et al. 2014

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The urinary metabolites 2-cyanoethylmercapturic acid and 4-aminobiphenyl have been correlated with tobacco smoke exposure. Similarly, 2-cyanoethylvaline and 4-aminobiphenyl haemoglobin adducts have been used as biomarkers of effective dose for the exposure to acrylonitrile and 4-aminobiphenyl, respectively. Each pair of biomarkers is derived from the same parent chemical; however, the correlation between the urinary and the haemoglobin biomarkers has not been investigated. Using clinical study samples, we report a weak correlation between urinary and haemoglobin biomarkers due to different accumulation and elimination rates. Time course analysis showed that a reduction in exposure was paralleled by a delayed reduction in haemoglobin adducts.

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“…Die CVR für LU-und PU-Test-Proben lagen bei 9,1-31,9% (Mittelwert: 18,8%) bzw. 13,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27],0% (Mittelwert: 18,5%) und wiesen auf eine begrenzte Reproduzierbarkeit in der Analyse von 3-HPMA bei beiden Probentypen hin. Die Neuberechnung der PU-Ergebnisse unter Anwendung einer eingebettenen Kalibrierung, die aus den berichteten Peak-Bereichen für die LU-Testproben abgeleitet war, führte zu einer gewissen Verbesserung der CV R -Werte (Bereich: 9,6-28,8%, Mittelwert: 16,7% The measurement of suitable biomarkers of exposure and effect is central to the evaluation of these products in humans.…”

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“…Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is the most frequently used methodology for 3-HPMA determination in urine (11)(12)(13)(14)(15)(16)(17). In a series of studies, urinary 3-HPMA levels were analyzed in smokers and non-smokers, showing, on average, about 5-fold higher levels in smokers (12,13,16,(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

Editors’ Note

Heller¹,

Scherer²

2016

Beiträge Zur Tabakforschung International/Contributions to Tobacco Research

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Summary An inter-laboratory comparison study on the acrolein biomarker of exposure 3-hydroxypropyl-mercapturic acid (3-HPMA) with 12 laboratories from 7 globally distributed countries was performed. The laboratories received coded triplicates of 4 spiked and lyophilized urine samples (LU, 12 samples) as well as 5 authentic urine pool samples (PU, 15 samples) covering the 3-HPMA concentration range from background (non-smoking) to heavy smoking levels for analysis by using their own (in-house) analytical method. All laboratories applied liquid chromatography with tandem mass spectrometry (LC-MS/MS), with most of them (10 of 12) using solid phase extraction (SPE) as sample work-up procedure. The intra-laboratory variation (indicating repeatability) was determined by calculating the standard deviation (sr) and the coefficient of variation (CVr) of the triplicates, whereas the inter-laboratory variation (indicating reproducibility) was determined by calculating the standard deviation between laboratories (sR) and the corresponding coefficient of variation (CVR). After removal of outlier samples or laboratories, the mean CVr values for LU and PU test samples ranged from 2.1–3.6% (mean: 2.8%) and 2.4–3.7% (mean: 3.3%), respectively, indicating good repeatability for the determination of 3-HPMA in both sample types. CVR for LU and PU test samples ranged from 9.1–31.9% (mean: 18.8%) and 13.9–27.0% (mean: 18.5%), respectively, indicating limited reproducibility in 3-HPMA analysis for both sample types. Re-calculation of the PU results by applying an embedded calibration (EC), derived from the reported peak areas for the LU test samples, somewhat improved the CVR values (range: 9.6–28.8%, mean: 16.7%). It is concluded that the intra-laboratory variation (repeatability) in the determination of 3-HPMA in urine is in general acceptable in the participating laboratories, while the inter-laboratory variability requires further improvement. The relatively small reduction in the inter-laboratory variability (sR and CVR) by applying an EC suggests that other methodological factors than the standard reference material for 3-HPMA have to be addressed to achieve further improvement in reproducibility.

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Urinary excretion of the acrylonitrile metabolite 2-cyanoethylmercapturic acid is correlated with a variety of biomarkers of tobacco smoke exposure and consumption

Cited by 38 publications

References 19 publications

Urinary biomarkers of smokers’ exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach

Urinary biomarkers of smokers’ exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach

A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers

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