Chemical carcinogenesis involves a complex series of events, the earliest of which typically include DNA damage and the fixation of DNA mutations. Sophisticated new techniques have been developed to quantify DNA damage and to correlate the amount of damage with cancer risk. Approaches such as these are underway in Linxian, China, where food contains high levels of DNA-damaging, carcinogenic polycyclic aromatic hydrocarbons (PAHs), and where there is high mortality from oesophageal cancer. Gaining better insight into the mechanisms by which PAH exposure might increase oesophageal cancer risk could lead to new strategies for cancer prevention.

Chemical-induced DNA damage and human cancer risk

Simultaneous analysis of 28 urinary VOC metabolites using ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS)

Cytogenetic biomarkers and genetic polymorphisms.

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.

/pdf/effects-of-smoking-cessation-on-eight-urinary-tobacco-dbp0id7h23.pdf

Effects of Smoking Cessation on Eight Urinary Tobacco Carcinogen and Toxicant Biomarkers

Tobacco carcinogen and toxicant biomarkers, quantitative measurements of exposure and fate of specific tobacco carcinogens and toxicants, could in principle become an important part of a risk algorithm to identify smokers susceptible to lung cancer and are also important for the evaluation and potentially the regulation of new and existing tobacco products. Our goal is to develop a panel of tobacco carcinogen and toxicant biomarkers applicable in these activities. One validation criterion for a tobacco carcinogen or toxicant biomarker is its relationship to tobacco use. This can be determined by assessing the decrease in a biomarker level when people stop using the product. Therefore, in this study, we evaluated the relationship to cigarette smoking of eight tobacco carcinogen and toxicant biomarkers: 1-hydroxypyrene (1-HOP), a metabolite of pyrene and a widely accepted biomarker of exposure to carcinogenic polycyclic aromatic hydrocarbons; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), an established biomarker of exposure to the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and 6 mercapturic acids (MA) derived from: 1,3 butadiene (MHBMA and DHBMA), acrolein (HPMA), crotonaldehyde (HBMA), benzene (SPMA), and ethylene oxide (HEMA) . Smokers provided 24h urine samples twice while still smoking and then on days 3, 7, 14, 21, 28, 42, and 56 after quitting. Seventeen subjects (11 female) completed the study. Their mean age (± S.D.) was 43.9 ± 11.0 years (range 23 - 58). Sixteen were Caucasian and one was of mixed racial heritage. They had been smoking an average of 17.3 ± 12.3 years and smoked 21.8 ± 6.7 cigarettes per day. MAs were quantified by a newly developed combined LC-negative ion-APCI-MS/MS method, total NNAL by GC-nitrosamine selective detection, and 1-HOP by LC-fluorescence. Baseline values of the biomarkers could be split into three groups: low, medium, and high. NNAL, 1-HOP, and SPMA comprised the low group (1-3 nmol/24h), HEMA and MHBMA the medium group (30 - 50 nmol/24h), and DHBMA, HPMA, and HBMA the high group (2600 - 11,000 nmol/24h). Levels of all MAs except DHBMA decreased rapidly after smoking cessation. In each case, the mean reduction of the MA from baseline was approximately 80% (P Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3014.

Abstract #3014: Effects of smoking cessation on eight urinary tobacco carcinogen and toxicant biomarkers

Biomarkers for assessing occupational exposures to 1,3-butadiene.

A multiinstitutional, transitional epidemiologic study was conducted with a worker population in the Czech Republic to evaluate the utility of a continuum of non-disease biological responses as biomarkers of exposure to 1,3-butadiene (BD)* in an industrial setting. The study site included two BD facilities in the Czech Republic. Institutions that collaborated in the study were the University of Vermont (Burlington, Vermont, USA); the Laboratory of Genetic Ecotoxicology (Prague, the Czech Republic); Shell International Chemicals, BV (Amsterdam, The Netherlands); the University of North Carolina at Chapel Hill (Chapel Hill, North Carolina, USA); University of Texas Medical Branch at Galveston (Galveston, Texas, USA); Leiden University (Leiden, The Netherlands); and the Health and Safety Laboratory (Sheffield, United Kingdom). Male volunteer workers (83) participated in the study: 24 were engaged in BD monomer production, 34 in polymerization activities, and 25 plant administrative workers served as unexposed control subjects. The BD concentrations experienced by each exposed worker were measured by personal monitor on approximately ten separate occasions for 8-hour workshifts over a 60-day exposure assessment period before biological samples were collected. Coexposures to styrene, benzene, and toluene were also measured. The administrative control workers were considered to be a homogeneous, unexposed group for whom a series of 28 random BD measurements were taken during the exposure assessment period. Questionnaires were administered in Czech to all participants. At the end of the exposure assessment period, blood and urine samples were collected at the plant; samples were. fractionated, cryopreserved, and kept frozen in Prague until they were shipped to the appropriate laboratories for specific biomarker analysis. The following biomarkers were analyzed: * polymorphisms in genes involved in BD metabolism (Prague and Burlington); * urinary concentrations of 1-hydroxy-2-(N-acetylcysteinyl)-3-butene and 2-hydroxy-1-(N-acetylcysteinyl)-3-butene (M2 [refers to an isomeric mixture of both forms]) (Amsterdam); * urinary concentrations of 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (M1) (Amsterdam); * concentrations of the hemoglobin (Hb) adducts N-(1-[hydroxymethyl]-2-propenyl)valine and N-(2-hydroxy-3-butenyl)valine (HBVal [refers to an isomeric mixture of both forms]) (Amsterdam); * concentrations of the Hb adduct N-(2,3,4-trihydroxybutyl)valine (THBVal) (Chapel Hill); * T cell mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene (autoradiographic assay in Galveston with slide review in Burlington; cloning assay in Leiden with mutational spectra determined in Burlington); and * chromosomal aberrations by the conventional method and by fluorescence in situ hybridization [FISH]), and cytogenetic changes (sister chromatid exchanges [SCEs] (Prague). All assay analysts were blinded to worker and sample identity and remained so until all work in that laboratory had been completed and reported. Assay results were sent to the Biometry Facility in Burlington for statistical analyses. Analysis of questionnaire data revealed that the three exposure groups were balanced with respect to age and years of residence in the district, but the control group had significantly more education than the other two groups and included fewer smokers. Group average BD exposures were 0.023 mg/m3 (0.010 ppm) for the control group, 0.642 mg/m3 (0.290 ppm) for the monomer group, and 1.794 mg/m3 (0.812 ppm) for the polymer group; exposure levels showed considerable variability between and within individuals. Styrene exposures were significantly higher in the polymer group than in the other two groups. We found no statistically significant differences in the distributions of metabolic genotypes over the three exposure groups; genotype frequencies were consistent with those previously reported for this ethnic and national population. Although some specific genotypes were associated with quantitative differences in urinary metabolite concentrations or Hb adduct dose-response characteristics, none indicated a heightened susceptibility to BD. Concentrations of both the M2 and M1 urinary metabolites and both the HBVal and THBVal Hb adducts were significantly correlated with group and individual mean BD exposure levels; the Hb adducts were more strongly correlated than the urinary metabolites. By contrast, no significant relations were observed between BD exposures and HPRT gene mutations (whether determined by the auto-radiographic or the cloning method) or any of the cytogenetic biomarkers (whether determined by the conventional method or FISH analysis). Neither the mutational nor the cytogenetic responses showed any association with genotypes. The molecular spectrum of HPRT mutations in BD-exposed workers showed a high frequency of deletions; but the same result was found in the unexposed control subjects, which suggests that these were not due to BD exposure. This lack of association between BD exposures and genetic effects persisted even when control subjects were excluded from the analyses or when we conducted regression analyses of individual workers exposed to different levels of BD.

/pdf/biomarkers-in-czech-workers-exposed-to-1-3-butadiene-a-3dks6hzm4e.pdf

Biomarkers in Czech workers exposed to 1,3-butadiene: a transitional epidemiologic study.

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Biomarkers for assessing occupational exposures to 1,3-butadiene.

Biomarkers in Czech workers exposed to 1,3-butadiene: a transitional epidemiologic study.