Publications by authors named "Debra Silverman"

221 Publications

Adapting Decision Rules to Estimate Occupational Metalworking Fluid Exposure in a Case-Control Study of Bladder Cancer in Spain.

Ann Work Expo Health 2021 Oct 9. Epub 2021 Oct 9.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Objectives: We adapted previously developed decision rules from the New England Bladder Cancer Study (NEBCS) to assign occupational exposure to straight, soluble, and synthetic metalworking fluids (MWFs) to participants of the Spanish Bladder Cancer Study (SBCS).

Methods: The SBCS and NEBCS are case-control studies that used the same lifetime occupational history and job module questionnaires. We adapted published decision rules from the NEBCS that linked questionnaire responses to estimates of the probability (<5, ≥5 to <50, ≥50 to <100, and 100%), frequency (in h week-1), and intensity (in mg m-3) of exposure to each of the three broad classes of MWFs to assign exposure to 10 182 reported jobs in the SBCS. The decision rules used the participant's module responses to MWF questions wherever possible. We then used these SBCS module responses to calculate job-, industry-, and time-specific patterns in the prevalence and frequency of MWF exposure. These estimates replaced the NEBCS-specific estimates in decision rules applied to jobs without MWF module responses. Intensity estimates were predicted using a previously developed statistical model that used the decade, industry (three categories), operation (grinding versus machining), and MWF type extracted from the SBCS questionnaire responses. We also developed new decision rules to assess mineral oil exposure from non-machining sources (possibly exposed versus not exposed). The decision rules for MWF and mineral oil identified questionnaire response patterns that required job-by-job expert review.

Results: To assign MWF exposure, we applied decision rules that incorporated participant's responses and job group patterns for 99% of the jobs and conducted expert review of the remaining 1% (145) jobs. Overall, 14% of the jobs were assessed as having ≥5% probability of exposure to at least one of the three MWFs. Probability of exposure of ≥50% to soluble, straight, and synthetic MWFs was identified in 2.5, 1.7, and 0.5% of the jobs, respectively. To assign mineral oil from non-machining sources, we used module responses for 49% of jobs, a job-exposure matrix for 41% of jobs, and expert review for the remaining 10%. We identified 24% of jobs as possibly exposed to mineral oil from non-machining sources.

Conclusions: We demonstrated that we could adapt existing decision rules to assess exposure in a new population by deriving population-specific job group patterns.
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http://dx.doi.org/10.1093/annweh/wxab084DOI Listing
October 2021

Elevated urinary mutagenicity among those exposed to bituminous coal combustion emissions or diesel engine exhaust.

Environ Mol Mutagen 2021 Oct 16;62(8):458-470. Epub 2021 Aug 16.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Urinary mutagenicity reflects systemic exposure to complex mixtures of genotoxic/carcinogenic agents and is linked to tumor development. Coal combustion emissions (CCE) and diesel engine exhaust (DEE) are associated with cancers of the lung and other sites, but their influence on urinary mutagenicity is unclear. We investigated associations between exposure to CCE or DEE and urinary mutagenicity. In two separate cross-sectional studies of nonsmokers, organic extracts of urine were evaluated for mutagenicity levels using strain YG1041 in the Salmonella (Ames) mutagenicity assay. First, we compared levels among 10 female bituminous (smoky) coal users from Laibin, Xuanwei, China, and 10 female anthracite (smokeless) coal users. We estimated exposure-response relationships using indoor air concentrations of two carcinogens in CCE relevant to lung cancer, 5-methylchrysene (5MC), and benzo[a]pyrene (B[a]P). Second, we compared levels among 20 highly exposed male diesel factory workers and 15 unexposed male controls; we evaluated exposure-response relationships using elemental carbon (EC) as a DEE-surrogate. Age-adjusted linear regression was used to estimate associations. Laibin smoky coal users had significantly higher average urinary mutagenicity levels compared to smokeless coal users (28.4 ± 14.0 SD vs. 0.9 ± 2.8 SD rev/ml-eq, p = 2 × 10 ) and a significant exposure-response relationship with 5MC (p = 7 × 10 ). DEE-exposed workers had significantly higher urinary mutagenicity levels compared to unexposed controls (13.0 ± 10.1 SD vs. 5.6 ± 4.4 SD rev/ml-eq, p = .02) and a significant exposure-response relationship with EC (p-trend = 2 × 10 ). Exposure to CCE and DEE is associated with urinary mutagenicity, suggesting systemic exposure to mutagens, potentially contributing to cancer risk and development at various sites.
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http://dx.doi.org/10.1002/em.22455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511344PMC
October 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 10;114(4):1408-1417

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488877PMC
October 2021

Commute patterns, residential traffic-related air pollution, and lung cancer risk in the prospective UK Biobank cohort study.

Environ Int 2021 10 15;155:106698. Epub 2021 Jun 15.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20850, USA.

Introduction: Commuting exposes millions of people to carcinogens from traffic-related air pollution (TRAP) but is seldomly considered in epidemiologic studies of lung cancer. In the prospective United Kingdom (UK) Biobank cohort study, we investigated associations between commute patterns, residential nitrogen dioxide concentrations (NO; a surrogate for TRAP), and lung cancer risk.

Methods: We analyzed 234,124 employed participants at baseline (2006-2010). There were 493 incident lung cancer cases diagnosed over an average 7-year follow-up. Subjects were cross-classified into exclusive categories of commute mode (automobile, public transportation, walking, cycling, active mixture, and other mixture) and frequency (regular: 1-4, often: ≥5 work-bound trips/week). Annual average residential NO concentrations in 2005-2007 were estimated with land use regression. Multivariable Cox regression was used to estimate associations between commute patterns, NO quartiles, and incident lung cancer. We conducted analyses stratified by NO (>, ≤median = 28.3 µg/m) and potential confounders such as sex and smoking.

Results: Compared to regular automobile use, commuting often by public transportation was associated with increased lung cancer risk (hazard ratio (HR) = 1.58, 95% confidence intervals (CI):1.08-2.33). Additionally, we found a positive exposure-response relationship with residential NO (HR = 1.21, 95 %CI: 0.90-1.62; HR = 1.48, 95 %CI: 1.10-1.99; HR = 1.58, 95 %CI: 1.13-2.23; p-trend = 3.1 × 10). The public transportation association was observed among those with higher NO (p-interaction = 0.02). Other commute categories were not associated with risk.

Conclusions: Commuters residing in high-NO areas who often use public transportation could have elevated lung cancer risk compared to regular automobile users. These results warrant investigations into which component(s) of public transportation contribute to the observed association with increased lung cancer risk.
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http://dx.doi.org/10.1016/j.envint.2021.106698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292218PMC
October 2021

Elevated Alu retroelement copy number among workers exposed to diesel engine exhaust.

Occup Environ Med 2021 Nov 26;78(11):823-828. Epub 2021 May 26.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: Millions of workers worldwide are exposed to diesel engine exhaust (DEE), a known genotoxic carcinogen. Alu retroelements are repetitive DNA sequences that can multiply and compromise genomic stability. There is some evidence linking altered Alu repeats to cancer and elevated mortality risks. However, whether Alu repeats are influenced by environmental pollutants is unexplored. In an occupational setting with high DEE exposure levels, we investigated associations with Alu repeat copy number.

Methods: A cross-sectional study of 54 male DEE-exposed workers from an engine testing facility and a comparison group of 55 male unexposed controls was conducted in China. Personal air samples were assessed for elemental carbon, a DEE surrogate, using NIOSH Method 5040. Quantitative PCR (qPCR) was used to measure Alu repeat copy number relative to albumin (Alb) single-gene copy number in leucocyte DNA. The unitless Alu/Alb ratio reflects the average quantity of Alu repeats per cell. Linear regression models adjusted for age and smoking status were used to estimate relations between DEE-exposed workers versus unexposed controls, DEE tertiles (6.1-39.0, 39.1-54.5 and 54.6-107.7 µg/m) and Alu/Alb ratio.

Results: DEE-exposed workers had a higher average Alu/Alb ratio than the unexposed controls (p=0.03). Further, we found a positive exposure-response relationship (p=0.02). The Alu/Alb ratio was highest among workers exposed to the top tertile of DEE versus the unexposed controls (1.12±0.08 SD vs 1.06±0.07 SD, p=0.01).

Conclusion: Our findings suggest that DEE exposure may contribute to genomic instability. Further investigations of environmental pollutants, Alu copy number and carcinogenesis are warranted.
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http://dx.doi.org/10.1136/oemed-2021-107462DOI Listing
November 2021

Targeted Deep Sequencing of Bladder Tumors Reveals Novel Associations between Cancer Gene Mutations and Mutational Signatures with Major Risk Factors.

Clin Cancer Res 2021 Jul 13;27(13):3725-3733. Epub 2021 Apr 13.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Purpose: Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.

Experimental Design: We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.

Results: Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.

Conclusions: These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254772PMC
July 2021

Machine Learning Models of Arsenic in Private Wells Throughout the Conterminous United States As a Tool for Exposure Assessment in Human Health Studies.

Environ Sci Technol 2021 04 17;55(8):5012-5023. Epub 2021 Mar 17.

New England Water Science Center, U.S. Geological Survey, 331 Commerce Way, Pembroke, New Hampshire 03275, United States.

Arsenic from geologic sources is widespread in groundwater within the United States (U.S.). In several areas, groundwater arsenic concentrations exceed the U.S. Environmental Protection Agency maximum contaminant level of 10 μg per liter (μg/L). However, this standard applies only to public-supply drinking water and not to private-supply, which is not federally regulated and is rarely monitored. As a result, arsenic exposure from private wells is a potentially substantial, but largely hidden, public health concern. Machine learning models using boosted regression trees (BRT) and random forest classification (RFC) techniques were developed to estimate probabilities and concentration ranges of arsenic in private wells throughout the conterminous U.S. Three BRT models were fit separately to estimate the probability of private well arsenic concentrations exceeding 1, 5, or 10 μg/L whereas the RFC model estimates the most probable category (≤5, >5 to ≤10, or >10 μg/L). Overall, the models perform best at identifying areas with low concentrations of arsenic in private wells. The BRT 10 μg/L model estimates for testing data have an overall accuracy of 91.2%, sensitivity of 33.9%, and specificity of 98.2%. Influential variables identified across all models included average annual precipitation and soil geochemistry. Models were developed in collaboration with public health experts to support U.S.-based studies focused on health effects from arsenic exposure.
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http://dx.doi.org/10.1021/acs.est.0c05239DOI Listing
April 2021

Evaluation of a commercial database to estimate residence histories in the los angeles ultrafines study.

Environ Res 2021 06 6;197:110986. Epub 2021 Mar 6.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Background: Commercial databases can be used to identify participant addresses over time, but their quality and impact on environmental exposure assessment is uncertain.

Objective: To evaluate the performance of a commercial database to find residences and estimate environmental exposures for study participants.

Methods: We searched LexisNexis® for participant addresses in the Los Angeles Ultrafines Study, a prospective cohort of men and women aged 50-71 years. At enrollment (1995-1996) and follow-up (2004-2005), we evaluated attainment (address found for the corresponding time period) and match rates to survey addresses by participant characteristics. We compared geographically-referenced predictors and estimates of ultrafine particulate matter (UFP) exposure from a land use regression model using LexisNexis and survey addresses at enrollment.

Results: LexisNexis identified an address for 69% of participants at enrollment (N = 50,320) and 95% of participants at follow-up (N = 24,432). Attainment rate at enrollment modestly differed (≥5%) by age, smoking status, education, and residential mobility between surveys. The match rate at both survey periods was high (82-86%) and similar across characteristics. When using LexisNexis versus survey addresses, correlations were high for continuous values of UFP exposure and its predictors (rho = 0.86-0.92).

Significance: Time period and population characteristics influenced the attainment of addresses from a commercial database, but accuracy and subsequent estimation of specific air pollution exposures were high in our older study population.
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http://dx.doi.org/10.1016/j.envres.2021.110986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187285PMC
June 2021

Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3.

Cancer Res 2021 06 11;81(11):3134-3143. Epub 2021 Feb 11.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and < 5 × 10 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, = 3.08 × 10). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178175PMC
June 2021

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome Med 2021 02 1;13(1):15. Epub 2021 Feb 1.

CIBERONC, Madrid, Spain.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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http://dx.doi.org/10.1186/s13073-020-00816-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849104PMC
February 2021

Bladder cancer risk associated with family history of cancer.

Int J Cancer 2021 06 5;148(12):2915-2923. Epub 2021 Mar 5.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Twin studies suggest a familial aggregation of bladder cancer, but elements of this increased familial risk of bladder cancer are not well understood. To characterize familial risk of bladder cancer, we examined the relationship between family history of bladder and other types of cancer among first-degree relatives and risk of bladder cancer in 1193 bladder cancer cases and 1418 controls in a large population-based case-control study. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between family history of bladder cancer (defined as at least one first-degree family member with bladder cancer or a cancer of any other site). We also evaluated cancer aggregation of specific sites in family members. Participants with a first-degree relative with bladder cancer had nearly double the risk of bladder cancer (OR = 1.8, 95% CI 1.2-2.9) as those without a family history of bladder cancer. Risk was increased for having a sibling with bladder cancer (OR = 2.6, 95% CI 1.3-5.3) compared to no siblings with cancer. Bladder cancer risk was elevated when participants reported a first-degree relative with a history of female genital cancer (OR = 1.5, 95% CI 1.1-2.1), melanoma (OR = 1.9, 95% CI 1.02-3.6), and tobacco-associated cancer (OR = 1.3, 95% CI 1.06-1.6). These findings add to evidence of a familial predisposition to bladder cancer. Clarification of the aggregation of bladder cancer in families and with other cancer sites will be of interest as many loci and common polymorphisms related to bladder cancer have yet to be identified in large genomic studies.
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http://dx.doi.org/10.1002/ijc.33486DOI Listing
June 2021

White Blood Cell Count and Risk of Incident Lung Cancer in the UK Biobank.

JNCI Cancer Spectr 2020 Apr 12;4(2):pkz102. Epub 2019 Dec 12.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK).

Methods: We evaluated 424 407 adults aged 37-73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006-2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference.

Results: There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HR = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers ( /  = 244 / 19 464, HR = 2.15, 95% CI = 1.46 to 3.16), former smokers ( /  = 280 / 69 198, HR = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (n / n = 108 / 111 294, HR = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (n /  = 329 / 22 934, HR = 2.95, 95% CI = 2.04 to 4.26) and former smokers ( /  = 358/71 616, HR = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions.

Conclusions: Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men.
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http://dx.doi.org/10.1093/jncics/pkz102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083262PMC
April 2020

Mesothelioma risk among those exposed to chrysotile asbestos only and mixtures that include amphibole: a case-control study in the USA, 1975-1980.

Occup Environ Med 2020 Oct 21. Epub 2020 Oct 21.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Objectives: Occupational asbestos exposure is causally linked to mesothelioma. However, whether exposure to only chrysotile asbestos is associated with mesothelioma risk, and the heterogeneity in risk by different fibre types/lengths remains unclear. We investigated whether mesothelioma risk differs among workers exposed to only chrysotile asbestos compared with chrysotile and ≥1 amphibole (ie, amosite, tremolite, anthophyllite and crocidolite) over the working lifetime.

Methods: We analysed next-of-kin interview data including occupational histories for 580 white men (176 cases and 404 controls) from a case-control study of mesothelioma conducted in the USA in 1975-1980. Asbestos exposure was determined by an occupational hygienist using a job-exposure matrix and exposure categories included chrysotile only and nine chrysotile-amphibole mixtures. Logistic regression models were used to estimate the ORs and 95% CIs of mesothelioma, comparing each asbestos category to the unexposed group, adjusted for age at death and data source. Analysis of contrasts was used to assess overall heterogeneity and pair-wise differences in risk.

Results: Exposure to long and short chrysotile only was associated with increased mesothelioma risk compared with the unexposed (OR=3.8 (95% CI 1.3 to 11.2)). The complex mixture of extra-long amosite, short and long chrysotile, tremolite and anthophyllite was associated with the highest risk (OR=12.8 (95% CI 4.1 to 40.2)). There was evidence for overall heterogeneity among the asbestos exposure categories (p heterogeneity=0.02). However, the lower risk observed for exposure to chrysotile only compared with the complex mixture was not significant (p difference=0.10).

Conclusions: Our findings suggest that policies aimed at regulating asbestos should target both pure chrysotile and mixtures that include amphibole.
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http://dx.doi.org/10.1136/oemed-2020-106665DOI Listing
October 2020

Mendelian Randomization Analysis of n-6 Polyunsaturated Fatty Acid Levels and Pancreatic Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 12 23;29(12):2735-2739. Epub 2020 Sep 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex.

Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710600PMC
December 2020

Serum Concentrations of Per- and Polyfluoroalkyl Substances and Risk of Renal Cell Carcinoma.

J Natl Cancer Inst 2021 May;113(5):580-587

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.

Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.

Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.

Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.
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http://dx.doi.org/10.1093/jnci/djaa143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096365PMC
May 2021

Genome-Wide Association Study Data Reveal Genetic Susceptibility to Chronic Inflammatory Intestinal Diseases and Pancreatic Ductal Adenocarcinoma Risk.

Cancer Res 2020 09 8;80(18):4004-4013. Epub 2020 Jul 8.

Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

Registry-based epidemiologic studies suggest associations between chronic inflammatory intestinal diseases and pancreatic ductal adenocarcinoma (PDAC). As genetic susceptibility contributes to a large proportion of chronic inflammatory intestinal diseases, we hypothesize that the genomic regions surrounding established genome-wide associated variants for these chronic inflammatory diseases are associated with PDAC. We examined the association between PDAC and genomic regions (±500 kb) surrounding established common susceptibility variants for ulcerative colitis, Crohn's disease, inflammatory bowel disease, celiac disease, chronic pancreatitis, and primary sclerosing cholangitis. We analyzed summary statistics from genome-wide association studies data for 8,384 cases and 11,955 controls of European descent from two large consortium studies using the summary data-based adaptive rank truncated product method to examine the overall association of combined genomic regions for each inflammatory disease group. Combined genomic susceptibility regions for ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis were associated with PDAC at values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10, respectively). After excluding the 20 PDAC susceptibility regions (±500 kb) previously identified by GWAS, the genomic regions for ulcerative colitis, Crohn disease, and inflammatory bowel disease remained associated with PDAC ( = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( = 0.22) and primary sclerosing cholangitis ( = 0.078) were not associated with PDAC. Our results support the hypothesis that genomic regions surrounding variants associated with inflammatory intestinal diseases, particularly, ulcerative colitis, Crohn disease, inflammatory bowel disease, and chronic pancreatitis are associated with PDAC. SIGNIFICANCE: The joint effects of common variants in genomic regions containing susceptibility loci for inflammatory bowel disease and chronic pancreatitis are associated with PDAC and may provide insights to understanding pancreatic cancer etiology.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7861352PMC
September 2020

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Cancer Epidemiol Biomarkers Prev 2020 09 16;29(9):1784-1791. Epub 2020 Jun 16.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the (family with sequence similarity 63 member A) gene (significance threshold < 1.25 × 10) was observed in the meta-analysis ( = 1.2 ×10, = 4.2 ×10).

Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483330PMC
September 2020

Diesel Exhaust Exposure during Farming Activities: Statistical Modeling of Continuous Black Carbon Concentrations.

Ann Work Expo Health 2020 06;64(5):503-513

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Objectives: Daily driving of diesel-powered tractors has been linked to increased lung cancer risk in farmers, yet few studies have quantified exposure levels to diesel exhaust during tractor driving or during other farm activities. We expanded an earlier task-based descriptive investigation of factors associated with real-time exposure levels to black carbon (BC, a surrogate of diesel exhaust) in Iowa farmers by increasing the sample size, collecting repeated measurements, and applying statistical models adapted to continuous measurements.

Methods: The expanded study added 43 days of sampling, for a total of 63 sample days conducted in 2015 and 2016 on 31 Iowa farmers. Real-time, continuous monitoring (30-s intervals) of personal BC concentrations was performed using a MicroAeth AE51 microaethelometer affixed with a micro-cyclone. A field researcher recorded information on tasks, fuel type, farmer location, and proximity to burning biomass. We evaluated the influence of these variables on log-transformed BC concentrations using a linear mixed-effect model with random effects for farmer and day and a first-order autoregressive structure for within-day correlation.

Results: Proximity to diesel-powered equipment was observed for 42.5% of the overall sampling time and on 61 of the 63 sample days. Predicted geometric mean BC concentrations were highest during grain bin work, loading, and harvesting, and lower for soil preparation and planting. A 68% increase in BC concentrations was predicted for close proximity to a diesel-powered vehicle, relative to far proximity, while BC concentrations were 44% higher in diesel vehicles with open cabins compared with closed cabins. Task, farmer location, fuel type, and proximity to burning biomass explained 8% of within-day variance in BC concentrations, 2% of between-day variance, and no between-farmer variance.

Conclusion: Our findings showed that farmers worked frequently near diesel equipment and that BC concentrations varied between tasks and by fuel type, farmer location, and proximity to burning biomass. These results could support the development of exposure models applicable to investigations of health effects in farmers associated with exposure to diesel engine exhaust.
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http://dx.doi.org/10.1093/annweh/wxaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313260PMC
June 2020

A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.

J Natl Cancer Inst 2020 10;112(10):1003-1012

Yale Cancer Center, New Haven, CT, USA.

Background: Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown.

Methods: To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74-421 samples).

Results: We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction.

Conclusions: By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
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http://dx.doi.org/10.1093/jnci/djz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566474PMC
October 2020

Diesel exhaust and bladder cancer risk by pathologic stage and grade subtypes.

Environ Int 2020 02 18;135:105346. Epub 2019 Dec 18.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. Electronic address:

Background: The International Agency for Research on Cancer (IARC) classifies diesel engine exhaust as carcinogenic to humans based on sufficient evidence for lung cancer. IARC noted, however, an increased risk of bladder cancer (based on limited evidence).

Objective: To evaluate the association between quantitative, lifetime occupational diesel exhaust exposure and risk of urothelial cell carcinoma of the bladder (UBC) overall and according to pathological subtypes.

Methods: Data from personal interviews with 1944 UBC cases, as well as formalin-fixed paraffin-embedded tumor tissue blocks, and 2135 controls were pooled from two case-control studies conducted in the U.S. and Spain. Lifetime occupational histories combined with exposure-oriented questions were used to estimate cumulative exposure to respirable elemental carbon (REC), a primary surrogate for diesel exhaust. Unconditional logistic regression and two-stage polytomous logistic regression were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for smoking and other risk factors.

Results: Exposure to cumulative REC was associated with an increased risk of UBC; workers with cumulative REC >396 μg/m-years had an OR of 1.61 (95% CI, 1.08-2.40). At this level of cumulative exposure, similar results were observed in the U.S. and Spain, OR = 1.75 (95% CI, 0.97-3.15) and OR = 1.54 (95% CI, 0.89-2.68), respectively. In lagged analysis, we also observed a consistent increased risk among workers with cumulative REC >396 μg/m-years (range of ORs = 1.52-1.93) for all lag intervals evaluated (5-40 years). When we accounted for tumor subtypes defined by stage and grade, a significant association between diesel exhaust exposure and UBC was apparent (global test for association p = 0.0019).

Conclusions: Combining data from two large epidemiologic studies, our results provide further evidence that diesel exhaust exposure increases the risk of UBC.
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http://dx.doi.org/10.1016/j.envint.2019.105346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237313PMC
February 2020

Land use regression models for ultrafine particles, fine particles, and black carbon in Southern California.

Sci Total Environ 2020 Jan 2;699:134234. Epub 2019 Sep 2.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States.

Exposure models are needed to evaluate health effects of long-term exposure to ambient ultrafine particles (UFP; <0.1 μm) and to disentangle their association from other pollutants, particularly PM (<2.5 μm). We developed land use regression (LUR) models to support UFP exposure assessment in the Los Angeles Ultrafines Study, a cohort in Southern California. We conducted a short-term measurement campaign in Los Angeles and parts of Riverside and Orange counties to measure UFP, PM, and black carbon (BC), collecting three 30-minute average measurements at 215 sites across three seasons. We averaged concentrations for each site and evaluated geographic predictors including traffic intensity, distance to airports, land use, and population and building density by supervised stepwise selection to develop models. UFP and PM measurements (r = 0.001) and predictions (r = 0.05) were uncorrelated at the sites. UFP model explained variance was robust (R = 0.66) and 10-fold cross-validation indicated good performance (R = 0.59). Explained variation was moderate for PM (R = 0.47) and BC (R = 0.38). In the cohort, we predicted a 2.3-fold exposure contrast from the 5 to 95 percentiles for all three pollutants. The correlation between modeled UFP and PM at cohort residences was weak (r = 0.28), although higher than between measured levels. LUR models, particularly for UFP, were successfully developed and predicted reasonable exposure contrasts.
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http://dx.doi.org/10.1016/j.scitotenv.2019.134234DOI Listing
January 2020

Understanding racial disparities in renal cell carcinoma incidence: estimates of population attributable risk in two US populations.

Cancer Causes Control 2020 Jan 28;31(1):85-93. Epub 2019 Nov 28.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD, 20850, USA.

Purpose: Renal cell carcinoma (RCC) incidence is higher among black than white Americans. The reasons for this disparity remain unclear.

Methods: We calculated race- and sex-specific population attributable risk percentages (PAR%) and their 95% confidence intervals (CI) for hypertension and chronic kidney disease (CKD) among black and white subjects ≥  50 years of age from the US Kidney Cancer Study (USKC; 965 cases, 953 controls), a case-control study in Chicago and Detroit, and a nested case-control study in the Kaiser Permanente Northern California health care network (KPNC; 2,162 cases, 21,484 controls). We also estimated PAR% for other modifiable RCC risk factors (cigarette smoking, obesity) in USKC.

Results: In USKC, the PAR% for hypertension was 50% (95% CI 24-77%) and 44% (95% CI 25-64%) among black women and men, respectively, and 29% (95% CI 13-44%) and 27% (95% CI 14-39%) for white women and men, respectively. In KPNC, the hypertension PAR% was 40% (95% CI 18-62%) and 23% (95% CI 2-44%) among black women and men, and 27% (95% CI 20-35%) and 19% (95% CI 14-24%) among white women and men, respectively. The PAR% for CKD in both studies ranged from 7 to 10% for black women and men but was negligible (<1%) for white subjects. In USKC, the PAR% for current smoking was 20% and 8% among black and white men, respectively, and negligible and 8.6% for black and white women, respectively. The obesity PAR% ranged from 12 to 24% across all race/sex strata.

Conclusions: If the associations found are causal, interventions that prevent hypertension and CKD among black Americans could potentially eliminate the racial disparity in RCC incidence (hypothetical black:white RCC incidence ratio of 0.5).
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http://dx.doi.org/10.1007/s10552-019-01248-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717618PMC
January 2020

Chronic obstructive pulmonary disease mortality: The Diesel Exhaust in Miners Study (DEMS).

Environ Res 2020 01 1;180:108876. Epub 2019 Nov 1.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, USA.

Background: Miners are highly exposed to diesel exhaust emissions from powered equipment. Although biologically plausible, there is little evidence based on quantitative exposure assessment, that long-term diesel exposure increases risk of chronic obstructive pulmonary disease (COPD). To fill this gap, we examined COPD mortality and diesel exhaust exposure in the Diesel Exhaust in Miners Study (DEMS).

Methods: We fit Cox models to estimate hazard ratios (HRs) for COPD mortality and cumulative exposure (μg/m-years) to respirable elemental carbon (REC), a key metric for diesel exhaust exposure. Separate models were fit for ever-underground and surface-only miners to allow for effect modification. Exposure was lagged by 0, 10 and 15 years. In a secondary analysis, we addressed the healthy worker survivor effect by applying the parametric g-formula to handle time-varying confounding affected by prior exposure among ever-underground workers.

Results: Based on 140 cases, the HRs for COPD mortality increased as categories of lagged REC exposure increased for all workers. Among surface-only workers, those in the middle exposure category (0 lag) had a significantly elevated hazard ratio of 2.34 (95% CI: 1.11-4.61) relative to those in the lowest category. Among the ever-underground, that ratio was 1.35, with wide confidence intervals. Using the g-formula, we estimated that the lifetime cumulative risk of COPD mortality would have been reduced from the observed 5.0%-3.1% under a hypothetical intervention where all ever-underground workers were always unexposed.

Conclusions: Our results suggest long term exposure to diesel exhaust may increase risk of COPD in miners, though power was limited.
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http://dx.doi.org/10.1016/j.envres.2019.108876DOI Listing
January 2020

Ingested Nitrate and Nitrite and Bladder Cancer in Northern New England.

Epidemiology 2020 01;31(1):136-144

From the Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Background: N-nitroso compounds are hypothesized human bladder carcinogens. We investigated ingestion of N-nitroso compound precursors nitrate and nitrite from drinking water and diet and bladder cancer in the New England Bladder Cancer Study.

Methods: Using historical nitrate measurements for public water supplies and measured and modeled values for private wells, as well as self-reported water intake, we estimated average nitrate concentrations (mg/L NO3-N) and average daily nitrate intake (mg/d) from 1970 to diagnosis/reference date (987 cases and 1,180 controls). We estimated overall and source-specific dietary nitrate and nitrite intakes using a food frequency questionnaire (1,037 cases and 1,225 controls). We used unconditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). We evaluated interactions with factors that may affect N-nitroso compound formation (i.e., red meat, vitamin C, smoking), and with water intake.

Results: Average drinking water nitrate concentration above the 95th percentile (>2.07 mg/L) compared with the lowest quartile (≤0.21 mg/L) was associated with bladder cancer (OR = 1.5, 95% CI = 0.97, 2.3; P trend = 0.01); the association was similar for average daily drinking water nitrate intake. We observed positive associations for dietary nitrate and nitrite intakes from processed meat (highest versus lowest quintile OR for nitrate = 1.4, 95% CI = 1.0, 2.0; P trend = 0.04; OR for nitrite = 1.5, 95% CI = 1.0, 2.1; P trend = 0.04, respectively), but not other dietary sources. We observed positive interactions between drinking water nitrate and red meat (P-interaction 0.05) and processed red meat (0.07).

Conclusions: Our results suggest the importance of both drinking water and dietary nitrate sources as risk factors for bladder cancer.
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http://dx.doi.org/10.1097/EDE.0000000000001112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927574PMC
January 2020

SIX AUTHORS REPLY.

Am J Epidemiol 2020 04;189(4):361-362

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

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http://dx.doi.org/10.1093/aje/kwz205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305792PMC
April 2020

The impact of alternative historical extrapolations of diesel exhaust exposure and radon in the Diesel Exhaust in Miners Study (DEMS).

Int J Epidemiol 2020 04;49(2):459-466

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Previous results from the Diesel Exhaust in Miners Study (DEMS) demonstrated a positive exposure-response relation between lung cancer and respirable elemental carbon (REC), a key surrogate for diesel exhaust exposure. Two issues have been raised regarding DEMS: (i) the use of historical carbon monoxide (CO) measurements to calibrate models used for estimating historical exposures to REC in the DEMS exposure assessment; and (ii) potential confounding by radon.

Methods: We developed alternative REC estimates using models that did not rely on CO for calibration, but instead relied on estimated use of diesel equipment, mine ventilation rates and changes in diesel engine emission rates over time. These new REC estimates were used to quantify cumulative REC exposure for each subject in the nested case-control study. We conducted conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals for lung cancer. To evaluate the impact of including radon as a potential confounder, we estimated ORs for average REC intensity adjusted for cumulative radon exposure in underground miners.

Results: Validation of the new REC exposure estimates indicated that they overestimated historical REC by 200-400%, compared with only 10% for the original estimates. Effect estimates for lung cancer using these alternative REC exposures or adjusting for radon typically changed by <10% when compared with the original estimates.

Conclusions: These results emphasize the robustness of the DEMS findings, support the use of CO for model calibration and confirm that radon did not confound the DEMS estimates of the effect of diesel exposure on lung cancer mortality.
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http://dx.doi.org/10.1093/ije/dyz189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266543PMC
April 2020

Constituents of Household Air Pollution and Risk of Lung Cancer among Never-Smoking Women in Xuanwei and Fuyuan, China.

Environ Health Perspect 2019 09 5;127(9):97001. Epub 2019 Sep 5.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

Background: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified.

Objectives: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer.

Methods: Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables.

Results: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide ([Formula: see text]) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]) were associated with lung cancer in the multipollutant models.

Conclusions: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913.
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http://dx.doi.org/10.1289/EHP4913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792381PMC
September 2019

Ischaemic heart disease and stroke mortality by specific coal type among non-smoking women with substantial indoor air pollution exposure in China.

Int J Epidemiol 2020 02;49(1):56-68

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Background: Lifetime use of bituminous ('smoky') coal is associated with nearly a 100-fold higher risk of lung cancer mortality compared with anthracite ('smokeless') coal use in rural Xuanwei, China, among women. Risk of mortality from ischaemic heart disease (IHD) and stroke for these coal types has not been evaluated.

Methods: A cohort of 16 323 non-smoking women in Xuanwei, who were lifetime users of either smoky or smokeless coal, were followed up from 1976 to 2011. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) to evaluate lifetime use of coal types and stoves in the home in relation to risk of IHD and stroke mortality.

Results: Among lifetime users of smokeless coal, higher average exposure intensity (≥4 tons/year vs <2.5 tons/year, HR = 7.9, 95% CI = 3.5-17.8; Ptrend =<0.0001) and cumulative exposure (>64 ton-years vs ≤28 ton-years, HR = 6.5, 95% CI = 1.5-28.3; Ptrend =0.003) during follow-up and over their lifetime was associated with increased IHD mortality, and ventilated stove use dramatically reduced this risk (HR = 0.2, 95% CI 0.1-0.5). Higher cumulative exposure to smoky coal during follow-up showed positive associations with IHD mortality, but the evidence for other metrics was less consistent compared with associations with smokeless coal use.

Conclusions: Higher use of smokeless coal, which is burned throughout China and is generally regarded to be a cleaner fuel type, is associated with IHD mortality. Use of cleaner fuels or stove interventions may be effective in reducing the increasing burden of IHD in developing regions that currently rely on smokeless coal for cooking and heating.
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http://dx.doi.org/10.1093/ije/dyz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124484PMC
February 2020
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