Effect of reducing the nicotine content of cigarettes on cigarette smoking behavior and tobacco smoke toxicant exposure: 2-year follow up.

BACKGROUND AND AIMS: A broadly mandated reduction of the nicotine content (RNC) of cigarettes has been proposed in the United States to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted and to facilitate quitting in established smokers. The primary aim of this study was to determine whether following 7 months of smoking very low nicotine content cigarettes (VLNC), and then returning to their own cigarettes, smokers would demonstrate persistently reduced nicotine intake compared with baseline or quit smoking. METHODS: In a community-based clinic 135 smokers not interested in quitting were randomized to one of two groups. A research group smoked their usual brand of cigarettes, followed by five types of research cigarettes with progressively lower nicotine content, each for 1 month, followed by 6 months at the lowest nicotine level (0.5 mg/cigarette) (53 subjects) and then 12 months with no intervention (30 subjects completed). A control group smoked their usual brand for the same period of time (50 subjects at 6 months, 38 completed). Smoking behavior, biomarkers of nicotine intake and smoke toxicant exposure were measured. RESULTS: After 7 months smoking VLNC, nicotine intake remained below baseline (plasma cotinine 149 versus 250 ng/ml, P<0.005) with no significant change in cigarettes per day or expired carbon monoxide (CO). During the 12-month follow-up, cotinine levels in RNC smokers rose to baseline levels and to those of control smokers. Quit rates among RNC smokers were very low [7.5 versus 2% in controls, not significant). CONCLUSIONS: In smokers not interested in quitting, reducing the nicotine content in cigarettes over 12 months does not appear to result in extinction of nicotine dependence, assessed by persistently reduced nicotine intake or quitting smoking over the subsequent 12 months.

Nicotine and carcinogen exposure after water pipe smoking in hookah bars.

BACKGROUND: Water pipe tobacco smoking is spreading globally and is increasingly becoming popular in the United States, particularly among young people. Although many perceive water pipe smoking to be relatively safe, clinical experimental studies indicate significant exposures to tobacco smoke carcinogens following water pipe use. We investigated biomarkers of nicotine intake and carcinogen exposure from water pipe smoking in the naturalistic setting of hookah bars. METHODS: Fifty-five experienced water pipe users were studied before and after smoking water pipe in their customary way in a hookah bar. Urine samples were analyzed for nicotine, cotinine, the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and mercapturic acid metabolites of volatile organic compounds (VOC). RESULTS: We found an average 73-fold increase in nicotine, 4-fold increase in cotinine, 2-fold increase in NNAL, and 14% to 91% increase in VOC mercapturic acid metabolites immediately following water pipe smoking. We saw moderate to high correlations between changes in tobacco-specific biomarkers (nicotine, cotinine, and NNAL) and several mercapturic acid metabolites of VOCs. CONCLUSION: Water pipe smoking in a hookah bar is associated with significant nicotine intake and carcinogen exposure. IMPACT: Given the significant intake of nicotine and carcinogens, chronic water pipe use could place users at increased risk of cancer and other chronic diseases. Cancer Epidemiol Biomarkers Prev; 23(6); 1055-66. ©2014 AACR.

Smoking behavior and exposure to tobacco toxicants during 6 months of smoking progressively reduced nicotine content cigarettes.

BACKGROUND: Recent federal legislation gives the U.S. Food and Drug Administration authority to regulate the nicotine content of cigarettes. A nationwide strategy for progressive reduction of the nicotine content of cigarettes is a potential way to reduce the addictiveness of cigarettes, to prevent new smokers from becoming addicted, and to facilitate quitting in established smokers. We conducted a trial of progressive nicotine content tapering over 6 months to determine the effects on smoking behaviors and biomarkers of tobacco smoke exposure and cardiovascular effects. METHODS: One hundred and thirty-five healthy smokers were randomly assigned to one of two groups. A research group smoked their usual brand of cigarettes followed by five types of research cigarettes with progressively lower nicotine content, each smoked for one month. A control group smoked their own brand of cigarettes for the same period of time. RESULTS: Nicotine intake, as indicated by plasma cotinine concentration, declined progressively as the nicotine content of cigarettes was reduced. Cigarette consumption and markers of exposure to carbon monoxide and polycyclic aromatic hydrocarbons, as well as cardiovascular biomarkers remained stable, whereas urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) excretion decreased. No significant changes in biomarkers of exposure or cardiovascular effects were observed in controls. CONCLUSIONS: Our data support the proposition that the intake of nicotine from cigarettes of smokers can be substantially lowered without increasing exposure to other tobacco smoke toxins. IMPACT: These findings support the feasibility and safety of gradual reduction of the nicotine content in cigarettes.

Racial differences in the relationship between number of cigarettes smoked and nicotine and carcinogen exposure.

INTRODUCTION: Black smokers are reported to have higher lung cancer rates and greater tobacco dependence at lower levels of cigarette consumption compared to non-Hispanic White smokers. We studied the relationship between cigarettes per day (CPD) and biomarkers of nicotine and carcinogen exposure in Black and White smokers. METHODS: In 128 Black and White smokers, we measured plasma nicotine and its main proximate metabolite cotinine, urine nicotine equivalents, 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites. RESULTS: The dose-response between CPD and nicotine equivalents, and NNAL and PAH was flat for Black but positive for White smokers (Race × CPD interaction, all ps < .05). Regression estimates for the Race × CPD interactions were 0.042 (95% CI 0.013-0.070), 0.054 (0.023-0.086), and 0.028 (0.004-0.052) for urine nicotine equivalents, NNAL, and PAHs, respectively. In contrast there was a strong correlation between nicotine equivalents and NNAL and PAH independent of race. Nicotine and carcinogen exposure per individual cigarette was inversely related to CPD. This inverse correlation was stronger in Black compared to White smokers and stronger in menthol compared to regular cigarette smokers (not mutually adjusted). CONCLUSIONS: Our data indicate that Blacks on average smoke cigarettes differently than White smokers such that CPD predicts smoke intake more poorly in Black than in White smokers.

Urine menthol as a biomarker of mentholated cigarette smoking.

OBJECTIVES: Menthol cigarettes are smoked by 27% of U.S. smokers, and there are concerns that menthol might enhance toxicity of cigarette smoking by increasing systemic absorption of smoke toxins. We measured urine menthol concentrations in relation to biomarkers of exposure to nicotine and tobacco carcinogens. METHODS: Concentrations of menthol glucuronide (using a novel analytical method), nicotine plus metabolites (nicotine equivalents, NE), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in the urine of 60 menthol and 67 regular cigarette smokers. RESULTS: Urine menthol was measurable in 82% of menthol and 54% in regular cigarette smokers. Among menthol smokers, urine menthol was highly correlated with NE, NNAL, and PAHs. In a multiple regression model NE but not menthol was significantly associated with NNAL and PAHs. CONCLUSIONS: Urine menthol concentration is a novel biomarker of exposure in menthol cigarette smokers, and is highly correlated with exposure to nicotine and carcinogens. Menthol is not independently associated with carcinogen exposure when nicotine intake is considered.

Estimation of nicotine dose after low-level exposure using plasma and urine nicotine metabolites.

BACKGROUND: We sought to determine the optimal plasma and urine nicotine metabolites, alone or in combination, to estimate the systemic dose of nicotine after low-level exposure. METHODS: We dosed 36 nonsmokers with 100, 200, or 400 microg p.o. of deuterium-labeled nicotine (doses similar to exposure to secondhand smoke) daily for 5 days and then measured plasma and urine nicotine metabolites at various intervals over 24 hours. RESULTS: The strongest correlations with nicotine dose were seen for the sum of four (cotinine+cotinine-glucuronide+trans-3'-hydroxycotinine+3HC-glucuronide) or six (including also nicotine+nicotine-glucuronide) of the major nicotine metabolites in 24-hour urine collection (r=0.96), with lesser correlations for these metabolites using spot urines corrected for creatinine at various times of day (r=0.72-0.80). The sum of plasma cotinine+trans-3'-hydroxycotine was more highly correlated with nicotine dose than plasma cotinine alone (r=0.82 versus 0.75). CONCLUSIONS: Our results provide guidance for the selection of biomarkers to estimate the dose of nicotine taken in low-level (secondhand smoke) tobacco exposure. IMPACT: This is probably relevant to active smoking as well.

Prevalence of smoking assessed biochemically in an urban public hospital: a rationale for routine cotinine screening.

Cotinine, a metabolite of nicotine, has been used to study tobacco smoke exposure in population studies, but the authors are unaware of its use to screen hospitalized patients. The authors measured serum cotinine levels in 948 patients admitted to an urban public hospital in San Francisco, California, between September 2005 and July 2006. On the basis of cotinine levels, they classified patients as active smokers (cotinine > or = 14 ng/mL), recent smokers or significantly exposed to secondhand smoke (SHS) (0.5-13.9 ng/mL), lightly exposed to SHS (0.05-0.49 ng/mL), or unexposed (<0.05 ng/mL). In contrast to the 13% prevalence of smoking in the general population of San Francisco, 40% of patients were active smokers; 15% were recent smokers or heavily exposed to SHS; 25% had low-level exposure to SHS; and 20% were unexposed. Active smoking or heavy SHS exposure was particularly high among African Americans (77%), the uninsured (65%), self-reported alcohol drinkers (77%), and illicit drug users (90%). Of people who denied smoking, 32% were found to have had significant exposure. If serum cotinine measurement became part of routine screening at urban public hospitals, cotinine levels would be abnormal in many patients and would provide objective evidence of tobacco smoke exposure, probably resulting in more intensive intervention to encourage patients to stop smoking and avoid SHS.

Urine nicotine metabolite concentrations in relation to plasma cotinine during low-level nicotine exposure.

INTRODUCTION: Plasma or saliva cotinine concentrations are used widely as biomarkers of secondhand smoke (SHS) exposure and have been associated with the risk of SHS-related disease. Concentrations of cotinine and other nicotine metabolites are considerably higher in urine than in plasma or saliva, making chemical analysis easier. In addition, urine is often more convenient to collect in some SHS exposure studies. The optimal use of nicotine metabolites in urine, singly or in combination, with or without correction for urine creatinine concentration, to estimate plasma cotinine concentration with low-level nicotine exposure has not been determined. METHODS: We dosed 36 nonsmokers with 100, 200, or 400 microg deuterium-labeled nicotine (simulating exposure to SHS) by mouth daily for 5 days and then measured plasma and urine cotinine and metabolites at various intervals over 24 hr. RESULTS: A plasma cotinine concentration of 1 ng/ml corresponds on average to a daily intake of 100 microg nicotine. Cotinine concentrations in urine averaged four to five times those in plasma. Correction of urine cotinine for creatinine concentration improved the correlation between urine and plasma cotinine. Measuring multiple cotinine metabolites in urine did not improve the correlation with plasma cotinine, compared with the use of urine cotinine alone. DISCUSSION: Measurement of urine cotinine corrected for creatinine concentration appears to be the best predictor of plasma cotinine.

Progressive commercial cigarette yield reduction: biochemical exposure and behavioral assessment.

BACKGROUND: Mandated reduction of exposure to nicotine and other cigarette toxins has been proposed as a possible national regulatory strategy. However, tapering using lower yield commercial cigarettes may not be effective in reducing nicotine or tar exposure due to compensatory smoking behavior. We examined the effects of gradual reduction of nicotine yield in commercial cigarettes on smoking behavior, with an assessment of nicotine intake and exposure to tobacco smoke toxins. METHODS: This 10-week longitudinal study of 20 smokers involved smoking the usual brand followed by different brands with progressively lower machine-determined yields, ranging from 0.9 to 0.1 mg nicotine, each smoked for 1 week. Subjects were followed for 4 weeks after returning to smoking the usual brand (or quitting). Smoking behaviors, biomarkers of tobacco smoke exposure, and cardiovascular effects were measured. FINDINGS: Cotinine and other biomarkers of smoke exposure remained unchanged comparing the usual brand with the 0.4 mg nicotine brands. A 30% to 40% decrease in nicotine, carbon monoxide, and carcinogen exposure comparing 0.1 mg nicotine cigarettes with baseline was observed. Self-efficacy was significantly increased and dependence decreased after tapering. IMPLICATIONS: We confirm prior cross-sectional population and experimental studies showing complete compensation for cigarettes down to the 0.4 mg nicotine range. Nicotine and tobacco toxin exposure were substantially reduced while smoking 0.1 mg nicotine cigarettes. Our data suggest that the degree of nicotine dependence of smokers may be lowered with progressive yield tapering. Gradual tapering of smokers from regular to ultralow nicotine yield commercial cigarettes might facilitate smoking cessation and warrants future research.

Comprehensive evaluation of the association between prostate cancer and genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2.

Genes involved in the testosterone biosynthetic pathway - such as CYP17A1, CYP3A4, and SRD5A2 - represent strong candidates for affecting prostate cancer. Previous work has detected associations between individual variants in these three genes and prostate cancer risk and aggressiveness. To more comprehensively evaluate CYP17A1, CYP3A4, and SRD5A2, we undertook a two-phase study of the relationship between their genotypes/haplotypes and prostate cancer. Phase I of the study first searched for single-nucleotide polymorphisms (SNPs) in these genes by resequencing 24 individuals from the Coriell Polymorphism Discovery Resource, 92-110 men from prostate cancer case-control sibships, and by leveraging public databases. In all, 87 SNPs were discovered and genotyped in 276 men from case-control sibships. Those SNPs exhibiting preliminary case-control allele frequency differences, or distinguishing (ie, 'tagging') common haplotypes across the genes, were identified for further study (24 SNPs in total). In Phase II of the study, the 24 SNPs were genotyped in an additional 841 men from case-control sibships. Finally, associations between genotypes/haplotypes in CYP17A1, CYP3A4, and SRD5A2 and prostate cancer were evaluated in the total case-control sample of 1117 brothers from 506 sibships. Family-based analyses detected associations between prostate cancer risk or aggressiveness and a number of CYP3A4 SNPs (P-values between 0.006 and 0.05), a CYP3A4 haplotype (P-values 0.05 and 0.009 in nonstratified and stratified analysis, respectively), and two SRD5A2 SNPs in strong linkage disequilibrium (P=0.02). Undertaking a two-phase study comprising SNP discovery, haplotype tagging, and association analyses allowed us to more fully decipher the relation between CYP17A1, CYP3A4, and SRD5A2 and prostate cancer.

Positional cloning of the combined hyperlipidemia gene Hyplip1.

Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We fine-mapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO2 production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism.