Search

Background: With the exception of lung cancer, the health effects associated with diesel exhaust for other cancers and nonmalignant health outcomes are not well understood., Objectives: We extended the mortality follow-up of the Diesel Exhaust in Miners Study, a cohort study of 12,315 workers, by 18 y (ending 31 December 2015), more than doubling the number of observed deaths to n = 4,887 , to evaluate associations between mortality and diesel exhaust exposure., Methods: Quantitative estimates of historical exposure to respirable elemental carbon (REC), a surrogate for diesel exhaust, were created for all jobs, by year and facility, using measurements collected from each mine, as well as historical measurements. Standardized mortality ratios (SMRs) and hazard ratios (HRs) were estimated for the entire cohort and by worker location (surface, underground)., Results: We observed an excess of death for cancers of the lung, trachea, and bronchus ( n = 409 ; SMR = 1.24 ; 95% CI: 1.13, 1.37). Among workers who ever worked underground, where the majority of diesel exposure occurred, excess deaths were evident for lung, trachea, and bronchus cancers ( n = 266 ; SMR = 1.26 ; 95% CI: 1.11, 1.42). Several nonmalignant diseases were associated with excess mortality among workers ever-employed underground, including ischemic heart disease ( SMR = 1.08 ; 95% CI: 1.00, 1.16), cerebrovascular disease ( SMR = 1.22 ; 95% CI: 1.04, 1.43), and nonmalignant diseases of the respiratory system ( SMR = 1.13 ; 95% CI: 1.01, 1.26). Continuous 15-y lagged cumulative REC exposure < 1,280   μ g / m 3 -y was associated with increased lung cancer risk ( HR = 1.93 ; 95% CI: 1.24, 3.03), but the risk declined at the highest exposures ( HR = 1.29 ; 95% CI: 0.74, 2.26). We also observed a significant trend in non-Hodgkin lymphoma (NHL) risk with increasing 20-y lagged cumulative REC ( HR Tertile 3  vs. Tertile 1 = 3.12 ; 95% CI: 1.00, 9.79; p -trend = 0.031 )., Discussion: Increased risks of lung cancer mortality observed in the original study were sustained. Observed associations between diesel exposure and risk of death from NHL and the excesses in deaths for diseases of the respiratory and cardiovascular system, including ischemic heart disease and cerebrovascular disease, warrant further study and provide evidence of the potential widespread public health impact of diesel exposure. https://doi.org/10.1289/EHP12840.

Background: The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths., Objective: Our purpose was to characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation., Methods: We conducted a case-control study of lung cancer nested in a cohort of 12,315 workers in eight nonmetal mines (376 lung cancer deaths, 718 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 y). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. To evaluate time windows of exposure, we evaluated the joint OR patterns for cumulative REC within each of four preselected exposure time windows, < 5 , 5-9, 10-19, and ≥ 20 y prior to death/reference date, and we evaluated the interaction of cumulative exposure across time windows under additive and multiplicative forms for the joint association., Results: ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of ∼ 950  to < 1,700   μ g / m 3 -y [ OR = 3.23 ; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed ( OR = 1.85 ; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows ( p homogeneity < 0.001 ), with ORs increasing for exposures accrued primarily 10-19 y prior to death ( p trend < 0.001 ). Results provided little support for a waning of risk among workers whose exposures ceased for ≥ 20 y., Conclusion: DEMS II findings provide insight into the exposure-response relationship between diesel exhaust and lung cancer mortality. The pronounced effect of exposures occurring in the window 10-19 y prior to death, the sustained risk 20 or more years after exposure ceases, and the plateau/decline in risk among the most heavily exposed provide direction for future research on the mechanism of diesel-induced carcinogenesis in addition to having important implications for the assessment of risk from diesel exhaust by regulatory agencies. https://doi.org/10.1289/EHP11980.

Objectives: Computer-assisted coding of job descriptions to standardized occupational classification codes facilitates evaluating occupational risk factors in epidemiologic studies by reducing the number of jobs needing expert coding. We evaluated the performance of the 2nd version of SOCcer, a computerized algorithm designed to code free-text job descriptions to US SOC-2010 system based on free-text job titles and work tasks, to evaluate its accuracy., Methods: SOCcer v2 was updated by expanding the training data to include jobs from several epidemiologic studies and revising the algorithm to account for nonlinearity and incorporate interactions. We evaluated the agreement between codes assigned by experts and the highest scoring code (a measure of confidence in the algorithm-predicted assignment) from SOCcer v1 and v2 in 14,714 jobs from three epidemiology studies. We also linked exposure estimates for 258 agents in the job-exposure matrix CANJEM to the expert and SOCcer v2-assigned codes and compared those estimates using kappa and intraclass correlation coefficients. Analyses were stratified by SOCcer score, score distance between the top two scoring codes from SOCcer, and features from CANJEM., Results: SOCcer's v2 agreement at the 6-digit level was 50%, compared to 44% in v1, and was similar for the three studies (38%-45%). Overall agreement for v2 at the 2-, 3-, and 5-digit was 73%, 63%, and 56%, respectively. For v2, median ICCs for the probability and intensity metrics were 0.67 (IQR 0.59-0.74) and 0.56 (IQR 0.50-0.60), respectively. The agreement between the expert and SOCcer assigned codes linearly increased with SOCcer score. The agreement also improved when the top two scoring codes had larger differences in score., Conclusions: Overall agreement with SOCcer v2 applied to job descriptions from North American epidemiologic studies was similar to the agreement usually observed between two experts. SOCcer's score predicted agreement with experts and can be used to prioritize jobs for expert review., (Published by Oxford University Press on behalf of The British Occupational Hygiene Society 2023.)

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent organic pollutants detectable in the serum of most U.S. adults. Some studies of highly-exposed individuals have suggested an association between PFAS and prostate cancer, but evidence from population-based studies is limited. We investigated the association between pre-diagnostic serum PFAS concentrations and aggressive prostate cancer risk in a large prospective study. We measured pre-diagnostic serum concentrations of eight PFAS, including perfluorooctanoate (PFOA), for 750 aggressive prostate cancer cases and 750 individually matched controls within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We assessed the reproducibility of PFAS concentrations in serial samples collected up to six years apart among 60 controls using intraclass correlation coefficients (ICCs). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with prostate cancer, adjusting for other PFAS and potential confounders. Concentrations of most PFAS were consistent (ICC>0.7) across the serial samples over time. We observed an inverse association between PFOA and aggressive prostate cancer (OR continuous  = 0.79, 95% CI = 0.63, 0.99), but the association was limited to cases diagnosed ≤3 years after blood collection and became statistically non-significant for cases diagnosed with later follow-up (>3 years, OR continuous  = 0.90, 95% CI = 0.79, 1.03). Other PFAS were not associated with aggressive prostate cancer risk. Although we cannot rule out an increased risk at higher levels, our findings from a population with PFAS serum concentrations comparable to the general population do not support an association with increased risk of aggressive prostate cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology., Objective: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data., Design, Setting, and Participants: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis., Outcome Measurements and Statistical Analyses: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking., Results and Limitations: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10 -8 ) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [p M-I ] = 0.004), 8q21.13 (PAG1; p M-I  = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; p M-I  = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers., Conclusions: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer., Patient Summary: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer., (Published by Elsevier B.V.)

Background: Diesel exhaust is a complex mixture, including polycyclic aromatic hydrocarbons (PAH) and nitrated PAHs (nitro-PAH), many of which are potent mutagens and possible bladder carcinogens. To explore the association between diesel exposure and bladder carcinogenesis, we examined the relationship between exposure and somatic mutations and mutational signatures in bladder tumors., Methods: Targeted sequencing was conducted in bladder tumors from the New England Bladder Cancer Study. Using data on 797 cases and 1,418 controls, two-stage polytomous logistic regression was used to evaluate etiologic heterogeneity between bladder cancer subtypes and quantitative, lifetime estimates of respirable elemental carbon (REC), a surrogate for diesel exposure. Poisson regression was used to evaluate associations between REC and mutational signatures., Results: We observed significant heterogeneity in the diesel-bladder cancer risk relationship, with a strong positive association among cases with high-grade, nonmuscle invasive TP53-mutated tumors compared with controls [ORTop Tertile vs.Unexposed, 4.8; 95% confidence interval (CI), 2.2-10.5; Ptrend < 0.001; Pheterogeneity = 0.002]. In muscle-invasive tumors, we observed a positive association between diesel exposure and the nitro-PAH signatures of 1,6-dintropyrene (RR, 1.93; 95% CI, 1.28-2.92) and 3-nitrobenzoic acid (RR, 1.97; 95% CI, 1.33-2.92)., Conclusions: The relationship between diesel exhaust and bladder cancer was heterogeneous based on the presence of TP53 mutations in tumors, further supporting the link between PAH exposure and TP53 mutations in carcinogenesis. Future studies that can identify nitro-PAH signatures in exposed tumors are warranted to add human data supporting the link between diesel and bladder cancer., Impact: This study provides additional insight into the etiology and possible mechanisms related to diesel exhaust-induced bladder cancer., (©2023 American Association for Cancer Research.)

Background: We previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear., Methods: In a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (<106 µg/m 3 ), below the European Union (EU) OEL (<50 µg/m 3 ) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (<20 µg/m 3 )., Results: Below the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1β (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (p trend =0.01, FDR=0.19) and gene expression (p trend =0.02, FDR=0.19)., Conclusions: DEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ethylene oxide (EtO) is a carcinogenic gas used in chemical production and to sterilize medical equipment that has been linked to risk of breast and lymphohematopoietic cancers in a small number of occupational studies. We investigated the relationship between environmental EtO exposure and risk of these cancers., Methods: Using the US Environmental Protection Agency's Toxics Release Inventory, we estimated historical exposures for National Institutes of Health-AARP Diet and Health Study participants enrolled in 1995-1996. We constructed 2 metrics at 3, 5, and 10 km: 1) distance between residences and EtO-emitting facilities, weighted by the proportion of time the home was downwind of each facility, and 2) distance-weighted, wind direction-adjusted average airborne emissions index (AEI=∑[lbs EtO/km2]). We estimated risk (hazard ratio [HR], 95% confidence interval [CI]) of incident breast cancer (in situ and invasive) among postmenopausal women (n = 173 670) overall and by tumor estrogen receptor status and non-Hodgkin lymphoma in the full cohort (n = 451 945)., Results: We observed an increased risk of breast cancer associated with EtO-emitting facilities within 10 km (HR[≤10vs>10] = 1.05, 95% CI = 1.00 to 1.10) that appeared stronger for in situ (HR[≤10vs>10] = 1.13, 95% CI = 1.00 to 1.27) than invasive (HR[≤10vs>10] = 1.03, 95% CI = 0.97 to 1.09) disease. Risk of breast cancer in situ was also increased in the top AEI quartiles, and associations weakened with larger distances (HR[Q4vs0] = 1.60, 95% CI = 0.98 to 2.61; HR[Q4vs0] = 1.28, 95% CI = 0.92 to 1.79; HR[Q4vs0] = 1.25, 95% CI = 1.02 to 1.53 at 3, 5, and 10 km, respectively). No differences in breast cancer risk were observed by estrogen receptor status. We found no clear pattern of increased non-Hodgkin lymphoma risk., Conclusions: A novel potential association between EtO emissions and risk of in situ, but not invasive, breast cancer warrants additional evaluation., (Published by Oxford University Press 2023.)

Background: Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study., Methods: This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker., Results: Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; Ptrend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; Ptrend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use., Conclusions: Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide., (© The Author(s) 2023. Published by Oxford University Press.)

Many low- and middle-income countries face challenges in attaining adequate levels of vaccination coverage, and the factors driving this under-coverage have not been completely elucidated. In this cross-sectional study, we investigated factors associated with vaccination coverage in Mopani District, Limpopo Province, South Africa. Between July and October 2017, we surveyed 317 caregivers (83% of whom were mothers) of seven-month-old infants in Mopani District about barriers faced when attaining vaccines and attitudes towards vaccination, and reviewed the infants' documented vaccination history. Caregiver and child demographic data were collected shortly after birth. We described the coverage for vaccines that should be received by age seven months, according to South Africa's Expanded Programme on Immunization schedule, and explored the relationship between coverage and caregiver characteristics, behavioral factors (e.g. attitudes towards vaccination), and structural factors (e.g. vaccination stock-outs at clinics). We found that caregivers reported positive attitudes towards vaccination, based on a seven-question survey of vaccination attitudes. Although coverage was high for most recommended vaccines, it was low for pneumococcal conjugate vaccine (PCV), with just 36% of children having received it by age seven months. This appears to have been due to PCV stock-outs at government clinics. For vaccines other than PCV, children were more likely to be up-to-date on vaccinations if a community health worker (CHW) had visited their home in the past month (adjusted odds ratio (OR) 1.24, confidence interval (CI) (1.10-1.41); p  < 0.001) and if the caregiver had more years of schooling (adjusted OR 1.03 (CI 1.01-1.05); p  = 0.012). We conclude that addressing PCV stock-outs at government clinics in Mopani District is necessary to ensure coverage reaches adequate levels. Additionally, supporting CHW programs may be a productive avenue for improving vaccination coverage.

Background: We previously showed that exposure to 5-methylchrysene (5MC) and other methylated polycyclic aromatic hydrocarbons (PAHs) best explains lung cancer risks in a case-control study among non-smoking women using smoky coal in China. Time-related factors (e.g., age at exposure) and non-linear relations were not explored., Objective: We investigated the relation between coal-derived air pollutants and lung cancer mortality using data from a large retrospective cohort., Methods: Participants were smoky (bituminous) or smokeless (anthracite) coal users from a cohort of 42,420 subjects from four communes in XuanWei. Follow-up was from 1976 to 2011, during which 4,827 deaths from lung-cancer occurred. Exposures were predicted for 43 different pollutants. Exposure clusters were identified using hierarchical clustering. Cox regression was used to estimate exposure-response relations for 5MC, while effect modification by age at exposure was investigated for cluster prototypes. A Bayesian penalized multi-pollutant model was fitted on a nested case-control sample, with more restricted models fitted to investigate non-linear exposure-response relations., Results: We confirmed the strong exposure-response relation for 5MC (Hazard Ratio [95% Confidence Interval] = 2.5 [2.4, 2.6] per standard-deviation (SD)). We identified four pollutant clusters, with all but two PAHs in a single cluster. Exposure to PAHs in the large cluster was associated with a higher lung cancer mortality rate (HR [95%CI] = 2.4 [2.2, 2.6] per SD), while exposure accrued before 18 years of age appeared more important than adulthood exposures. Results from the multi-pollutant model identified anthanthrene (ANT) and benzo(a)chrysene (BaC) as risk factors. 5MC remained strongly associated with lung cancer in models that included ANT and BaC and also benzo(a)pyrene (BaP)., Conclusion: We confirmed the link between PAH exposures and lung cancer in smoky coal users and found exposures before age 18 to be especially important. We found some evidence for the carcinogen 5MC and non-carcinogens ANT and BaC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diesel engine exhaust (DEE) is an established lung carcinogen, but the biological mechanisms of diesel-induced lung carcinogenesis are not well understood. MicroRNAs (miRNAs) are small noncoding RNAs that play a potentially important role in regulating gene expression related to lung cancer. We conducted a cross-sectional molecular epidemiology study to evaluate whether serum levels of miRNAs are altered in healthy workers occupationally exposed to DEE compared to unexposed controls. We conducted a two-stage study, first measuring 405 miRNAs in a pilot study of six DEE-exposed workers exposed and six controls. In the second stage, 44 selected miRNAs were measured using the Fireplex circulating miRNA assay that profiles miRNAs directly from biofluids of 45 workers exposed to a range of DEE (Elemental Carbon (EC), median, range: 47.7, 6.1-79.7 μg/m 3 ) and 46 controls. The relationship between exposure to DEE and EC with miRNA levels was analyzed using linear regression adjusted for potential confounders. Serum levels of four miRNAs were significantly lower (miR-191-5p, miR-93-5p, miR-423-3p, miR-122-5p) and one miRNA was significantly higher (miR-92a-3p) in DEE exposed workers compared to controls. Of these miRNAs, miR-191-5p (p trend  = .001, FDR = 0.04) and miR-93-5p (p trend  = .009, FDR = 0.18) showed evidence of an inverse exposure-response with increasing EC levels. Our findings suggest that occupational exposure to DEE may affect circulating miRNAs implicated in biological processes related to carcinogenesis, including immune function., (© 2023 Environmental Mutagen Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Despite the success of smoking cessation campaigns, lung cancer remains the leading cause of cancer death in the U.S. Variations in smoking behavior and lung cancer mortality are evident by sex and region., Methods: Applying geospatial methods to lung cancer mortality data from the National Vital Statistics System and county-level estimates of smoking prevalences from the NCI's Small Area Estimates of Cancer-Related Measures, we evaluated patterns in lung cancer mortality rates (2005-2018) in relation to patterns in ever cigarette smoking prevalences (1997-2003)., Results: Overall, ever smoking spatial patterns were generally associated with lung cancer mortality rates, which were elevated in the Appalachian region and lower in the West for both sexes. However, we also observed geographic variation in mortality rates that is not explained by smoking. Using Lee's L statistic for assessing bivariate spatial association, we identified counties where the ever smoking prevalence was low and lung cancer rates were high. We observed a significant cluster of counties (n = 25; P values ranging from 0.001 to 0.04) with low ever smoking prevalence and high mortality rates among females around the Mississippi River region south of St. Louis, Missouri and a similar and smaller cluster among males in Western Mississippi (n = 12; P values ranging from 0.002 to 0.03) that has not been previously described., Conclusions: Our analyses identified U.S. counties where factors other than smoking may be driving lung cancer mortality., Impact: These novel findings highlight areas where investigation of environmental and other risk factors for lung cancer is needed., (©2022 American Association for Cancer Research.)

Objectives: Diesel exhaust is an established human carcinogen, however the mechanisms by which it leads to cancer development are not fully understood. Mitochondrial dysfunction is an established contributor to carcinogenesis. Recent studies have improved our understanding of the role played by epigenetic modifications in the mitochondrial genome on tumorigenesis. In this study, we aim to evaluate the association between diesel engine exhaust (DEE) exposure with mitochondrial DNA (mtDNA) methylation levels in workers exposed to DEE., Methods: The study population consisted of 53 male workers employed at a diesel engine manufacturing facility in Northern China who were routinely exposed to diesel exhaust in their occupational setting, as well as 55 unexposed male control workers from other unrelated factories in the same geographic area. Exposure to DEE, elemental carbon, organic carbon, and particulate matter (PM2.5) were assessed. mtDNA methylation for CpG sites (CpGs) from seven mitochondrial genes (D-Loop, MT-RNR1, MT-CO2, MT-CO3, MT-ATP6, MT-ATP8, MT-ND5) was measured in blood samples. Linear regression models were used to estimate the associations between DEE, elemental carbon, organic carbon and PM2.5 exposures with mtDNA methylation levels, adjusting for potential confounders., Results: DEE exposure was associated with decreased MT-ATP6 (difference = -35.6%, P-value = 0.019) and MT-ATP8 methylation (difference = -30%, P-value = 0.029) compared to unexposed controls. Exposures to elemental carbon, organic carbon, and PM2.5 were also significantly and inversely associated with methylation in MT-ATP6 and MT-ATP8 genes (all P-values < 0.05)., Conclusions: Our findings suggest that DEE exposure perturbs mtDNA methylation, which may be of importance for tumorigenesis., (Published by Oxford University Press 2022.)

Purpose: We examined the interaction between common genetic bladder cancer variants, diet quality, and bladder cancer risk in a population-based case-control study conducted in New England., Methods: At the time of enrollment, 806 bladder cancer cases and 974 controls provided a DNA sample and completed a diet history questionnaire. Diet quality was assessed using the 2010 Alternate Healthy Eating Index (AHEI-2010) score. Single nucleotide polymorphisms (SNPs) reported in genome-wide association studies to be associated with bladder cancer risk were combined into a polygenic risk score and also examined individually for interaction with the AHEI-2010. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression., Results: A 1-standard deviation increase in polygenic risk score was associated with higher bladder cancer risk (OR, 1.34; 95% CI 1.21-1.49). Adherence to the AHEI-2010 was not associated with bladder cancer risk (OR, 0.99; 95% CI 0.98-1.00) and the polygenic risk score did not appear to modify the association between the AHEI-2010 and bladder cancer risk. In single-SNP analyses, rs8102137 (bladder cancer risk allele, C) modified the association between the AHEI-2010 total score and bladder cancer risk, with the strongest evidence for the AHEI-2010 long chain fat guideline (OR for TT, 0.92; 95% CI 0.87-0.98; OR for CT, 1.02; 95% CI 0.96-1.08; OR for CC, 1.03; 95% CI 0.93-1.14; p for interaction, 0.02)., Conclusions: In conclusion, rs8102137 near the cyclin E1 gene ( CCNE1 ) may be involved in gene-diet interactions for bladder cancer risk., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

We investigated whether exposure to carcinogenic diesel engine exhaust (DEE) was associated with altered adduct levels in human serum albumin (HSA) residues. Nano-liquid chromatography-high resolution mass spectrometry (nLC-HRMS) was used to measure adducts of Cys34 and Lys525 residues in plasma samples from 54 diesel engine factory workers and 55 unexposed controls. An untargeted adductomics and bioinformatics pipeline was used to find signatures of Cys34/Lys525 adductome modifications. To identify adducts that were altered between DEE-exposed and unexposed participants, we used an ensemble feature selection approach that ranks and combines findings from linear regression and penalized logistic regression, then aggregates the important findings with those determined by random forest. We detected 40 Cys34 and 9 Lys525 adducts. Among these findings, we found evidence that 6 Cys34 adducts were altered between DEE-exposed and unexposed participants (i.e., 841.75, 851.76, 856.10, 860.77, 870.43, and 913.45). These adducts were biologically related to antioxidant activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Introduction: Perfluorooctanoic acid (PFOA) has been associated with kidney cancer in human studies., Methods: We conducted a pooled analysis of two large studies of PFOA and renal cell carcinoma (RCC, the most common type of kidney cancer); one from the National Cancer Institute (NCI) (324 cases and controls), and a second from the C8 Science Panel (103 cases and 511 controls). Serum PFOA levels were estimated a median of 8 years before diagnosis. Analyses were conducted via conditional logistic regression. Lifetime risk of kidney cancer per unit serum PFOA concentration and per unit dose were calculated., Results: The 25th, 50th and 75th percentiles of serum PFOA levels were 4.8, 7.3, and 23.9 ng/ml for the pooled analysis. The preferred model for the pooled datawas a two-piece linear spline model (knot at 12.5 ng/ml serum PFOA); the log odds of RCC increased 0.1349 per 1 ng/ml increase in serum PFOA up to the knot (eg, an OR of 2.02 (1.45-2.80) from the median to the knot), and was flat thereafter. The estimated lifetime excess risk (cancer slope factor) with an exposure of 1 ng/ml was 0.0018, similar to the excess risk of 0.0026 recently reported by CalEPA based on different methods. Assuming a serum half-life of 2.3 years and a distribution volume of 170 ml/kg for PFOA, our results are equivalent to 0.0128 per ng/kg/d of PFOA intake. To limit excess lifetime kidney cancer risk to 1/1,000,000, our data suggest a limit of 0.0015 ng/L (0.0015 ppt) for PFOA in drinking water, similar to CalEPA's proposed Public Health Goal and the new US EPA Drinking Water Health Advisory., Conclusions: Our results correspond reasonably well with cancer slope factors developed by other investigators using published summary data, and suggest drinking water limits similar to new recommendations by the US EPA., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: By-products are formed when disinfectants react with organic matter in source water. The most common class of disinfection by-products, trihalomethanes (THMs), have been linked to bladder cancer. Several studies have shown exposure-response associations with THMs in drinking water and bladder cancer risk. Few epidemiologic studies have evaluated gene-environment interactions for total THMs (TTHMs) with known bladder cancer susceptibility variants., Objectives: In this study, we investigated the combined effect on bladder cancer risk contributed by TTHMs, bladder cancer susceptibility variants identified through genome-wide association studies, and variants in several candidate genes., Methods: We analyzed data from two large case-control studies-the New England Bladder Cancer Study ( n / n = 989 cases/1,162 controls), a population-based study, and the Spanish Bladder Cancer Study ( n / n = 706 cases/772 controls), a hospital-based study. Because of differences in exposure distributions and metrics, we estimated effects of THMs and genetic variants within each study separately using adjusted logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CI) with and without interaction terms, and then combined the results using meta-analysis., Results: Of the 16 loci showing strong evidence of association with bladder cancer, rs907611 at 11p15.5 [leukocyte-specific protein 1 ( LSP1 region)] showed the strongest associations in the highest exposure category in each study, with evidence of interaction in both studies and in meta-analysis. In the highest exposure category, we observed OR = 1.66 (95% CI: 1.17, 2.34, p -trend = 0.005 ) for those with the rs907611-GG genotype and p -interaction = 0.02 . No other genetic variants tested showed consistent evidence of interaction., Discussion: We found novel suggestive evidence for a multiplicative interaction between a putative bladder carcinogen, TTHMs, and genotypes of rs907611. Given the ubiquitous exposure to THMs, further work is needed to replicate and extend this finding and to understand potential molecular mechanisms. https://doi.org/10.1289/EHP9895.

Background: Prenatal exposure to drinking water with arsenic concentrations >50 μg/L is associated with adverse birth outcomes, with inconclusive evidence for concentrations ≤50 μg/L. In a collaborative effort by public health experts, hydrologists, and geologists, we used published machine learning model estimates to characterize arsenic concentrations in private wells-federally unregulated for drinking water contaminants-and evaluated associations with birth outcomes throughout the conterminous U.S., Methods: Using several machine learning models, including boosted regression trees (BRT) and random forest classification (RFC), developed from measured groundwater arsenic concentrations of ∼20,000 private wells, we characterized the probability that arsenic concentrations occurred within specific ranges in groundwater. Probabilistic model estimates and private well usage data were linked by county to all live birth certificates from 2016 (n = 3.6 million). We evaluated associations with gestational age and term birth weight using mixed-effects models, adjusted for potential confounders and incorporated random intercepts for spatial clustering., Results: We generally observed inverse associations with term birth weight. For instance, when using BRT estimates, a 10-percentage point increase in the probability that private well arsenic concentrations exceeded 5 μg/L was associated with a -1.83 g (95% CI: -3.30, -0.38) lower term birth weight after adjusting for covariates. Similarly, a 10-percentage point increase in the probability that private well arsenic concentrations exceeded 10 μg/L was associated with a -2.79 g (95% CI: -4.99, -0.58) lower term birth weight. Associations with gestational age were null., Conclusion: In this largest epidemiologic study of arsenic and birth outcomes to date, we did not observe associations of modeled arsenic estimates in private wells with gestational age and found modest inverse associations with term birth weight. Study limitations may have obscured true associations, including measurement error stemming from a lack of individual-level information on primary water sources, water arsenic concentrations, and water consumption patterns., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (Published by Oxford University Press on behalf of The British Occupational Hygiene Society 2021.)

Objectives: This study aimed to characterize patterns of worsening mental health during the postpartum period among women in rural areas of Limpopo Province, South Africa, and to identify correlates with household demographic factors., Methods: We collected data on maternal mental health symptoms shortly after birth and then again 7 months postpartum using the World Health Organization self-reporting questionnaire (SRQ-20) from December 2017 to November 2018. The absolute change in SRQ-20 symptom score was calculated to determine worsening mental health over the postpartum period. Linear regressions were performed to investigate factors associated with mental health symptom scores at varying postpartum time points., Results: We found increased reporting of poor mental health symptoms at 7 months postpartum as compared to shortly after birth (n = 224). Worsening maternal mental health over the postpartum period was associated with higher SRQ-20 symptom score shortly after birth (p < 0.001) and reported food insecurity at 7 months (p < 0.001). SRQ-20 symptom scores in the postpartum period were not associated with breastfeeding in the past 24 h reported at 7 months postpartum (p = 0.08)., Conclusions for Practice: Women in rural South Africa, like women in many settings, may be vulnerable to worsening postpartum mental health when they lack sufficient socioeconomic resources and when they have pre-existing depressive/anxiety symptoms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: This study examined the association between night shift work and risk of breast cancer, overall and by hormone receptor subtype, among females in the Norwegian Offshore Petroleum Workers (NOPW) cohort. We also examined the association of coexposure (chlorinated degreasers and benzene) and breast cancer risk, and possible interaction with work schedule., Design: Prospectively recruited case-cohort study within the NOPW cohort., Setting: Female offshore petroleum workers active on the Norwegian continental shelf., Participants: 600 female workers (86 cases and 514 non-cases) were included in the study. We excluded workers that died or emigrated before start of follow-up, had missing work history, were diagnosed with breast cancer or other prior malignancy (except non-melanoma skin cancer) before start of follow-up., Results: No overall association was found between breast cancer risk and work schedule (HR 0.87, 95% CI 0.52 to 1.46 for work schedule involving night shift vs day shift only). There was no significant association between work schedule and risk of any breast cancer subtype. No significant interactions were found between work schedule and chemical coexposures (breast cancer overall P interaction chlorinated degreasers =0.725 and P interaction benzene =0.175)., Conclusions: Our results did not provide supporting evidence that work schedule involving night shift affects breast cancer risk in female offshore petroleum workers, but should be considered cautiously due to few cases. Further studies with larger sample sizes are warranted., Competing Interests: Competing interests: JSS and TKG have received a grant from the Research Council of Norway (governmental agency) that awarded an industry-collaborative grant to the Cancer Registry of Norway (governmental agency) in 2019 to establish a cohort of offshore petroleum workers. A condition pertaining to industry-collaborative grants is that 20% (US$175 000) of the grant was provided by the petroleum industry and 80% (US$700 000) by the Research Council itself with the intention of joining forces for the common interest of occupational health among petroleum workers. The application process was governed by the Research Council without any involvement from the industry. The grant does not cover the PIs or any of the collaborators salary., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Diesel engine exhaust (DEE) is classified as a Group 1 human carcinogen. Using a targeted proteomics approach, we aimed to identify proteins associated with DEE and characterize these markers to understand the mechanisms of DEE-induced carcinogenicity. In this cross-sectional molecular epidemiology study, we measured elemental carbon (EC) using a personal air monitor and quantified 1317 targeted proteins in the serum using the SOMAScan assay (SOMALogic) among 19 diesel exposed factory workers and 19 unexposed controls. We used linear regressions to identify proteins associated with DEE and examined their exposure-response relationship across levels of EC using linear trend tests. We further examined pathway enrichment of DEE-related proteins using MetaCore. Occupational exposure to DEE was associated with altered levels of 22 serum proteins (permutation p < .01). Of these, 13 proteins (CXCL11, HAPLN1, FLT4, CD40LG, PES1, IGHE.IGK..IGL, TNFSF9, PGD, NAGK, CCL25, CCL4L1, PDXK, and PLA2G1B) showed an exposure-response relationship with EC (p trend < .01), with serum levels of all but PLA2G1B declining with increasing air levels of EC. For instance, C-X-C Motif Chemokine Ligand 11 (CXCL11) showed the most significant association with DEE (β = -0.25; permutation p = .00004), where mean serum levels were 4121.1, 2356.7, and 2298.8 relative fluorescent units among the unexposed, lower exposed (median, range : 56.9, 40.2-62.1 μg/m 3 EC), and higher exposed (median, range of EC: 72.9, 66.9-107.7 μg/m 3 EC) groups, respectively (p trend = .0005). Pathway analysis suggested that these proteins are enriched in pathways related to inflammation and immune regulation. Our study suggests that DEE exposure is associated with altered serum proteins, which play a role in inflammation and immune regulation., (© 2021 Environmental Mutagen Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Purpose: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete., Materials and Methods: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases., Results: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair ( MLH1 and MSH2 ) and cellular metabolism ( IDH1 and ME1 ). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls ( P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis ( P = .001). In addition, a pathogenic variant in CHEK2 (NM&#95;007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant., Conclusion: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology., Competing Interests: Talia Wegman-Ostrosky Travel, Accommodations, Expenses: Pfizer Bin Zhu Employment: GeneDx BioReference Douglas R. Stewart Employment: Genome Medical No other potential conflicts of interest were reported. Talia Wegman-Ostrosky Travel, Accommodations, Expenses: Pfizer Bin Zhu Employment: GeneDx BioReference Douglas R. Stewart Employment: Genome Medical No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

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 3 ) 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Published by Oxford University Press on behalf of the American Society for Nutrition 2021.)

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 2 ; 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 2 concentrations in 2005-2007 were estimated with land use regression. Multivariable Cox regression was used to estimate associations between commute patterns, NO 2 quartiles, and incident lung cancer. We conducted analyses stratified by NO 2 (>, ≤median = 28.3 µg/m 3 ) 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 2 (HR Q2  = 1.21, 95 %CI: 0.90-1.62; HR Q3  = 1.48, 95 %CI: 1.10-1.99; HR Q4  = 1.58, 95 %CI: 1.13-2.23; p-trend = 3.1 × 10 -3 ). The public transportation association was observed among those with higher NO 2 (p-interaction = 0.02). Other commute categories were not associated with risk., Conclusions: Commuters residing in high-NO 2 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., (Published by Elsevier Ltd.)

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 -5 ) and a significant exposure-response relationship with 5MC (p = 7 × 10 -4 ). 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 -3 ). 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., (© 2021 Environmental Mutagen Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

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 KDM6A 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 ERCC2- Signature mutations compared with former ( P = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; P = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( P = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; P = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with ERCC2- Signature mutations and APOBEC-Signature13 mutations among current ( P trend = 0.005) and former smokers ( P = 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., (©2021 American Association for Cancer Research.)

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., (© 2021 UICC.)

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., (Published by Elsevier Inc.)

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 P < 5 × 10 -8 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, P interaction = 3.08 × 10 -9 ). 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 ( r 2 = 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., (©2021 American Association for Cancer Research.)

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., (Published by Oxford University Press 2020.)

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.

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.

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., (©2020 American Association for Cancer Research.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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 P values < 0.05 (0.0040, 0.0057, 0.011, and 3.4 × 10 -6 , 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 ( P = 0.0029, 0.0057, and 0.0098, respectively). Genomic regions for celiac disease ( P = 0.22) and primary sclerosing cholangitis ( P = 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., (©2020 American Association for Cancer Research.)

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 2 ) 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 FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10 -6 ) was observed in the meta-analysis ( P GxE = 1.2 ×10 -6 , P Joint = 4.2 ×10 -7 )., 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., (©2020 American Association for Cancer Research.)

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., (Published by Oxford University Press on behalf of The British Occupational Hygiene Society 2020.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Ambient air pollution is a modifiable risk factor for cardiovascular disease, yet uncertainty remains about the size of risks at lower levels of fine particulate matter (PM2.5) exposure which now occur in the USA and elsewhere., Methods: We investigated the relationship of ambient PM2.5 exposure with cause-specific cardiovascular disease mortality in 565 477 men and women, aged 50 to 71 years, from the National Institutes of Health-AARP Diet and Health Study. During 7.5 x 106 person-years of follow up, 41 286 cardiovascular disease deaths, including 23 328 ischaemic heart disease (IHD) and 5894 stroke deaths, were ascertained using the National Death Index. PM2.5 was estimated using a hybrid land use regression (LUR) geostatistical model. Multivariate Cox regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CI)., Results: Each increase of 10  μg/m3 PM2.5 (overall range, 2.9-28.0  μg/m3) was associated, in fully adjusted models, with a 16% increase in mortality from ischaemic heart disease [hazard ratio (HR) 1.16; 95% CI 1.09-1.22] and a 14% increase in mortality from stroke (HR 1.14; CI 1.02-1.27). Compared with PM2.5 exposure <8  μg/m3 (referent), risks for CVD were increased in relation to PM2.5 exposures in the range of 8-12  μg/m3 (CVD: HR 1.04; 95% CI 1.00-1.08), in the range 12-20  μg/m3 (CVD: HR 1.08; 95% CI 1.03-1.13) and in the range 20+ μg/m3 (CVD: HR 1.19; 95% CI 1.10-1.28). Results were robust to alternative approaches to PM2.5 exposure assessment and statistical analysis., Conclusions: Long-term exposure to fine particulate air pollution is associated with ischaemic heart disease and stroke mortality, with excess risks occurring in the range of and below the present US long-term standard for ambient exposure to PM2.5 (12  µg/m3), indicating the need for continued improvements in air pollution abatement for CVD prevention., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., (Published by Oxford University Press on behalf of the International Epidemiological Association 2019. This work is written by US Government employees and is in the public domain in the US.)

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 3 -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 3 -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., (Published by Elsevier Ltd.)

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 (<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 2.5 , 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 2.5 measurements (r = 0.001) and predictions (r = 0.05) were uncorrelated at the sites. UFP model explained variance was robust (R 2  = 0.66) and 10-fold cross-validation indicated good performance (R 2  = 0.59). Explained variation was moderate for PM 2.5 (R 2  = 0.47) and BC (R 2  = 0.38). In the cohort, we predicted a 2.3-fold exposure contrast from the 5 th to 95 th percentiles for all three pollutants. The correlation between modeled UFP and PM 2.5 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., (Copyright © 2019. Published by Elsevier B.V.)

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 3 -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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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).

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.