clinicaltrials.gov Identifier: NCT02139930.

With respect to the compounds analyzed here, e-cigarettes have a more favorable toxicity profile than tobacco cigarettes.

We determined the persistence at various times (3,7,14,21,28,42 and 56 days) of eight tobacco smoke carcinogen and toxicant biomarkers in the urine of 17 smokers who stopped smoking. The biomarkers were 1-hydroxy-2-(N-acetylcysteinyl)-3-butene (1) and 1-(N-acetylcysteinyl)-2-hydroxy-3-butene (2) [collectively called MHBMA for monohydroxybutyl mercapturic acid] and 1,2-dihydroxy-4-(N-acetylcysteinyl)butane (3) [DHBMA for dihydroxybutyl mercapturic acid], metabolites of 1,3-butadiene; 1-(N-acetylcysteinyl)-propan-3-ol (4, HPMA for 3-hydroxypropyl mercapturic acid), a metabolite of acrolein; 2-(N-acetylcysteinyl)butan-4-ol (5, HBMA for 4-hydroxybut-2-yl mercapturic acid), a metabolite of crotonaldehyde; (N-acetylcysteinyl)benzene (6, SPMA for S-phenyl mercapturic acid), a metabolite of benzene; (N-acetylcysteinyl)ethanol (7, HEMA for 2-hydroxyethyl mercapturic acid), a metabolite of ethylene oxide; 1-hydroxypyrene (8) and its glucuronides (1-HOP), metabolites of pyrene; and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (9) and its glucuronides (total NNAL), a biomarker of exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These biomarkers represent some of the major carcinogens and toxicants in cigarette smoke: 1,3-butadiene, acrolein, crotonaldehyde, benzene, ethylene oxide, polycyclic aromatic hydrocarbons (PAH), and NNK. With the exception of DHBMA, levels of which did not change after cessation of smoking, all other biomarkers decreased significantly after 3 days of cessation (P<0.001). The decreases in MHBMA, HPMA, HBMA, SPMA, and HEMA were rapid, nearly reaching their ultimate levels (81 -91% reduction) after 3 days. The decrease in total NNAL was gradual, reaching 92% after 42 days, while reduction in 1-HOP was variable among subjects to about 50% of baseline. Since DHBMA did not change upon smoking cessation, there appear to be sources of this metabolite other than 1,3-butadiene. The results of this study demonstrate that the tobacco smoke carcinogen/toxicant biomarkers MHBMA, HPMA, HBMA, SPMA, HEMA, 1-HOP, and NNAL are related to smoking and are good indicators of the impact of smoking on human exposure to 1,3-butadiene, acrolein, crotonaldehyde, benzene, ethylene oxide, PAH and NNK.

Recently published data suggest that acrolein (1), a toxic but weakly carcinogenic constituent of cigarette smoke, may be involved as a causative factor for the mutations frequently observed in the p53 tumor suppressor gene in lung cancer in smokers. Biomarkers are needed to further assess the possible relationship between acrolein uptake and cancer. In this study, we analyzed 3-hydroxypropylmercapturic acid (3-HPMA, 2) in human urine. 3-HPMA is a major metabolite of acrolein in laboratory animals. The method employs [ 13 C 3 ]3-HPMA as internal standard, with analysis and quantitation by LC-APCI-MS/MS-SRM. Clean, readily quantifiable chromatograms were obtained. The method was accurate and precise and required only 0.1 mL of urine. Median levels of 3-HPMA were significantly higher (2900 pmol/mg creatinine, N = 35) in smokers than in non-smokers (683 pmol/mg creatinine, N = 21) (P = 0.0002). The effect of smoking was further assessed by determining levels of 3-HPMA before and after a 4 week smoking cessation period. There was a significant 78% decrease in median levels of urinary 3-HPMA after cessation (P < 0.0001). The relationship between levels of urinary 3-HPMA and those of acrolein-derived 1,N 2 -propanodeoxyguanosine (PdG) adducts in lung was investigated in 14 smokers. There was a significant inverse relationship between urinary 3-HPMA and α-hydroxy-PdG (3) but not γ-hydroxyPdG (4) or total adduct levels. The results of this study clearly demonstrate that acrolein uptake in smokers is significantly higher than in non-smokers, and underline the need for further investigation of the possible relationship of acrolein uptake to lung cancer.

Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydro-phenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case–control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00–2.88), 1.07 (0.62–1.84), 1.48 (0.86–2.53), and 2.34 (1.33–4.11), respectively, relative to the lowest quartile (Ptrend = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.