BACKGROUND:Banning cigarette filter ventilation has been raised by some public health researchers and organisations because it has misled people who smoke to believe they are smoking a safer cigarette. AIM:To examine the potential effects of banning ventilated filters on smoking behaviour and biomarkers of toxicant exposures. TRIAL DESIGN:Randomised controlled trial with parallel semi-blind study design. METHODS:People who smoke (n=164) ventilated cigarettes daily were randomised to smoke 'ventilated' (≈27% ventilation) or 'unventilated' (≈0.11% ventilation) study cigarettes for 6 weeks. Non-inferiority testing was conducted on the changes in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL) and cigarettes per day (CPD) between the two cigarette groups. Superiority testing was conducted for differences in smoking intensity (amount of nicotine in cigarette butts), other exposure biomarkers and subjective responses. RESULTS:The unventilated condition was generally non-inferior to the ventilated condition for change in total NNAL (3% greater for unventilated vs ventilated, less than the non-inferiority 15% margin but with wide variability with an upper bound of 95% CI of 16%, p=0.064) and in CPD (0.22 cigarettes greater for unventilated vs ventilated, lower than the non-inferiority margin of 2, p<0.001). There were no significant differences between the two groups in other biomarkers (p>0.05). Less intensity of smoking was observed with unventilated cigarettes (difference of changes=-0.04 mg nicotine, p=0.002), aligning with higher self-reported ratings of nicotine strength (p=0.005) and aversion (p=0.028). CONCLUSIONS:Overall, banning filter ventilation is unlikely to lead to greater toxicant exposures but certain subgroups might experience greater exposures.

Among cigarette smokers, higher internal smoking dose is associated with elevated lung cancer risk and mortality, independent of smoking pack-years. Some measures of epigenetic age acceleration (EAA) are associated with cigarette smoking status and exposure, as well as lung cancer risk and overall mortality. No study has examined the association between EAA measures and internal smoking dose (total nicotine equivalents (TNE; nmol/mL)), and their shared relationship with lung cancer incidence and mortality in a multiethnic population. From a subgroup of Multiethnic Cohort Study participants who smoked cigarettes at the time of biospecimen collection (n = 1969), six epigenetic clocks were computed using blood-based DNA methylation (DNAm) array data. EAA measures were computed by calculating the residuals that results from regressing an epigenetic clock on chronological age. The association of urinary TNE with EAA measures were assessed using linear regression models, adjusted for age, sex, body mass index (BMI; kg/m2), DNAm-based estimates of blood cell composition, population stratification, and self-reported pack-years of cigarette smoking. To evaluate the associations of EAA with incident lung cancer risk (n = 176 cases) and all-cause mortality (n = 780 deaths) (from 13 years of follow-up), Cox proportional hazard models, with age as the time metric, adjusted for decade of birth, sex, BMI, years of education, creatinine, DNAm-based estimates of blood cell composition, population stratification, self-reported pack-years, and urinary TNE, were used. A standard deviation (SD) increase of log-TNE was statistically significantly associated with increased AgeAccelPheno (beta = 0.416, 95

Human exposure to toxicants and carcinogens occurs via polluted air, the diet, occupational settings, endogenous processes, and tobacco products. The glutathione-S-transferase detoxification pathway resulting in the excretion of mercapturic acids is one of the most important human systems for processing and excreting toxicants and carcinogens. Maximizing effectiveness of this pathway through dietary modifications can potentially decrease the impact of such exposures. We conducted a two-site clinical trial with a crossover, single blind (to participants) design, randomized to order of product receipt comparing levels of selected urinary mercapturic acids when participants consumed a drink made from freeze-dried watercress (3× daily, 2 weeks) naturally containing 2-phenethyl isothiocyanate (PEITC) vs. a placebo drink containing maltodextrin (3× daily, 2 weeks) with a 4-week washout between the treatment periods. Two hundred forty participants (157 F) were recruited and 188 (125 F, 152 non-smokers) were compliant and completed the study. Among compliant subjects, urinary mercapturic acid detoxification products of acrolein, acrylonitrile, benzene, crotonaldehyde, methacrolein, and methyl vinyl ketone increased significantly (P ≤ 0.002), with the largest increases being observed for the mercapturic acids of acrolein (65.6%) and benzene (37.3%), both P < 0.001. Consumption of a drink, three times daily, prepared from freeze-dried watercress containing PEITC (total of approximately 40 mg/day) significantly increased the detoxification of 6 of 7 environmental toxicants and carcinogens monitored. The results indicate that watercress consumption can ameliorate exposure to environmental toxicants and carcinogens. These results are particularly timely and relevant to exposures to atmospheric pyrolysis products resulting from wildfires. Clinical trial registration number: NCT03978117.

Smoking is the leading cause of lung cancer. Differences in CYP2A6-catalyzed nicotine metabolism affect smoking dose and intensity, which, in turn, can affect lung cancer risk. CYP2A6 also catalyzes the bioactivation of the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). To determine the contribution of CYP2A6 to the metabolic activation of NNK, a group of Japanese American and Native Hawaiian smokers with little or no CYP2A6 activity was recruited to smoke [pyridyl-D4]-NNK-containing cigarettes for a week. [Pyridyl-D4]-4-hydroxy-4-(3-pyridyl)butanoic acid (D4-hydroxy acid), the urinary product of NNK α-hydroxylation, the major bioactivation pathway, was quantified in these individuals and in an equal number of smokers with "normal" CYP2A6 activity. In expectation of low D4-hydroxy acid levels, a sensitive nanoflow LC-MS/MS assay was developed. CYP2A6 activity was measured as the plasma ratio of 3'-hydroxycotinine to cotinine, which is the nicotine metabolite ratio (NMR). The average concentration of D4-hydroxy acid in 24 h urine samples over 3 days was 20 ± 14 fmol/mL in low NMR (<0.05) smokers (n = 8) versus 33 ± 18 fmol/mL (p = 0.056) in "normal" NMR (>0.3) smokers (n = 8). The total D4-hydroxy acid excreted by the low NMR group was half that of the higher NMR group (29.1 ± 16.8 versus 59.7 ± 45.3 pmol/24h, p = 0.048). These data support the role of CYP2A6 in the metabolic activation of NNK. However, it is unlikely that more modest differences in CYP2A6 activity, for example, as might be seen across smokers of European ancestry, would significantly impact NNK bioactivation. The influence of CYP2A6 activity on nicotine metabolism and the associated carcinogen uptake is likely the primary influence of CYP2A6 activity on a smoker's risk of lung cancer, not a modest effect on the metabolic activation of NNK, one of several lung carcinogens in tobacco smoke.

Age-standardized incidence rates (ASIR) and 95% confidence intervals (CI) for lung cancer among a subcohort of Multiethnic Cohort (MEC) Study current smokers - overall and by race/ethnicity

Limit of detection, proportion missing, median, 25-75% interquartile range, and standard deviation of the log distribution for urinary biomarkers of smoking-related toxicants among the Multiethnic Cohort (MEC) subcohort of current smokers and incident lung cancer cases.

Pearson's correlations between measures of urinary biomarkers of smoking-related toxicants among the Multiethnic Cohort (MEC) subcohort of current smokers and incident lung cancer cases a

BACKGROUND:Cadmium (Cd), classified as an International Agency for Research on Cancer (IARC) Group 1 human carcinogen, is present in cigarette smoke. Recent studies have illustrated the potential role of genetics in influencing Cd biomarker levels. METHODS:We conducted a genome-wide association study (GWAS) of urinary Cd levels in 1977 current smokers from the Multiethnic Cohort Study, comprising participants from five different racial and ethnic groups. Linear regression models were adjusted for age at urine collection, sex, self-reported race/ethnicity, and the top ten leading principal components. RESULTS:Among the 11 710 497 single nucleotide polymorphisms (SNP) analyzed, no associations with urinary Cd reached genome-wide significance (P < 5.0 × 10-8). Notably, five variants demonstrated suggestive associations with urinary Cd levels (P < 1.0 × 10-6). Lead variants included: rs10097646 in the SCARA gene at 8q13.2 (P = 2.62 × 10-7); rs7444817 in the NIPBL gene at 5p13.2 (P = 3.10 × 10-7), rs830422 in the SPINK4 gene at 9q13.2 (P = 4.89 × 10-7); chrX:145489901 in the SLC9A7 gene at Xq121.1 (P = 5.38 × 10-7); and rs73074456 at 5p13.3 (P = 5.86 × 10-7). CONCLUSIONS:Our GWAS of urinary Cd levels in a diverse population of people who smoke, revealed suggestive associations with variants in SCARA5, NIPBL, SPINK4, SLC9A7, and 5p13.3. These findings underscore the potential role of genetic factors in understanding and mitigating the health risks associated with internal dose of carcinogens, particularly in the context of tobacco-related carcinogens.

Histologic cell-type by race/ethnicity of the Multiethnic Cohort (MEC) smokers with lung cancer (N=140 cases only) identified during study follow-up.

Distribution plot of pack-years and urinary biomarkers of smoking-related toxicants both without and with transformation for the Multiethnic Cohort (MEC) subcohort of current smokers at time of urine collection. Figure A. Distribution plot of pack-years without transformation; Figure B. Distribution plot of pack-years divided by the overall population standard deviation (with transformation); Figure C. Distribution plot of total nicotine equivalents (TNE) without transformation; Figure D. Distribution plot of TNE with transformation; Figure E. Distribution plot of the ratio of total trans 3’-hydroxycotinine (3-HCOT)/cotinine (Total 3-HCOT/cotinine) without transformation; Figure F. Distribution plot of Total 3-HCOT/cotinine with transformation; Figure H. Distribution plot of 4-(methylnitrosamino)-1-3-pyridyl)-1-butanol (Total NNAL) without transformation; Figure I. Distribution plot of Total NNAL with transformation; Figure J. Distribution plot of S-phenylmercapturicacid (SPMA) without transformation; Figure J. Distribution plot of SPMA with transformation; Figure K. Distribution plot of 3-hydroxypropyl mercapturic acid (3-HPMA) without transformation; Figure L. Distribution plot of 3-HPMA with transformation; Figure M. Distribution plot of phenanthrene tetraol(PheT) without transformation; Figure N. Distribution plot of PheTwith transformation; Figure O. Distribution plot of 3-hydroxyphenanthrene (PheOH) without transformation; Figure P. Distribution plot of PheOH with transformation; Figure Q. Distribution plot of PheT/PheOH (a proposed biomarker of metabolic activiation of polycyclic aromatic hydrocarbons) without transformation; Figure R. Distribution plot of PheT/PheOH with transformation; Figure S. Distribution plot of cadmium (Cd) without transformation; Figure T. Distribution plot of Cd with transformation; Plot U. Distribution plot of (Z)-7-[1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid (8-iso-PGF2α) without transformation; Figure V. Distribution plot of 8-iso-PGF2α with transformation.

[This corrects the article DOI: 10.1016/j.lana.2024.100796.].

Association of urinary biomarkers of smoking-related toxicants with lung cancer incidence - Multiethnic Cohort Study (MEC), by low total nicotine equivalents (TNE) and high TNE.

Geometric mean and 95% confidence intervals for urinary biomarkers of smoking-related toxicants among the Multiethnic Cohort (MEC) subcohort of current smokers and incident lung cancer cases

Association of various characteristics at time of urine collection with lung cancer incidence in the Multiethnic Cohort (MEC) subcohort of current smokers (n=140 cases).

Supplemental Table 1. Coefficients of Variation for Biomarker analysis

Supplemental Table 7. Association of urinary biomarkers and lung cancer risk in Southern Community Cohort participants stratified by histologic cell-type

Supplemental Table 3. Pearson Correlation Coefficients (R) for smoking-related urinary biomarkers

The U.S. Food and Drug Administration has stated its intention to reduce the nicotine content of combustible cigarettes to render them less addictive. This study evaluated the impact of providing adults who smoke with both very low nicotine content cigarettes (VLNCCs) and electronic cigarettes (ECs) of varying nicotine content on measures of human abuse potential. Participants (n = 213) were adult combustible cigarette users. They smoked their usual brand cigarettes (UBCs) during Phase 1 (baseline; week 1) and were provided with and encouraged to exclusively use VLNCCs during Phase 2 (weeks 2-4). During dual-product Phases 3 (weeks 5-7) and 4 (weeks 8-10), participants received both VLNCCs and ECs (assigned to one of two EC devices in higher or lower nicotine concentrations and choice of flavor), with instructions to use them freely in Phases 3 and 4. Assessments included product use, exposure, acceptability, risk perception, and withdrawal-related measures. Results indicated that participants used significantly fewer UBCs during the VLNCC and dual-product phases and smoked fewer VLNCCs during the dual-product phases than the VLNCC-only phase. Neither EC liquid nicotine concentration nor flavor influenced product use. The three study product phases resulted in less product liking and more withdrawal symptoms than the UBC phase. These results suggest that adults who smoke are able to switch much of their tobacco product use from UBCs to VLNCCs and will substitute combustible UBCs and VLNCCs with noncombustible nicotine-containing ECs, but most remain dual users, at least in the short term.

Supplemental Table 2. Median and SD of the log distribution for smoking-related urinary biomarkers overall

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 x 10(-8)). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 x 10(-4)). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.