Lung Carcinogen Research Articles

Effect of Gene 33/Mig6/ERRFI1 on hexavalent chromium-induced transformation of human bronchial epithelial cells depends on the length of exposure

Hexavalent chromium (Cr(VI)) compounds are environmental and occupational lung carcinogens. The present study followed the chronic effect of Cr(VI) on the neoplastic transformation of BEAS-2B lung bronchial epithelial cells with or without deletion of Gene 33 (Mig6, EFFRI1), a multifunctional adaptor protein. We find that Gene 33-deleted cells exhibit increased anchorage-independent growth compared to control cells after transformed by 8-week but not 24-week Cr(VI) exposure. Gene 33-deleted cells show a higher level of cell proliferation and are more resistant to acute Cr(VI) toxicity compared to control cells after transformed by 8-week but not 24-week Cr(VI) exposure, despite that 24-week-transformed cells have increased resistance to acute Cr(VI) toxicity. However, Gene 33-deleted cells show increased migration after transformed by both 8-week and 24-week Cr(VI) exposures. Furthermore, only cells transformed by 24 weeks of Cr(VI) exposure can form subcutaneous tumors in nude mice. Although no significant difference in the size of tumors formed by the two cell types, there is a marked difference in the histological manifestation and more MMP3 expression in tumors from Gene 33-deleted cells. Our results demonstrate progressive neoplastic transformation of BEAS-2B cells and the adaptation of these cells to Gene 33 deletion during chronic exposure to Cr(VI).

Acrolein Increases the Pulmonary Tumorigenic Activity of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Tobacco smoke is a complex mixture of more than 7000 chemicals, of which many are toxic and/or carcinogenic. Many hazard assessments of tobacco have focused on individual chemical exposures without consideration of how the chemicals may interact with one another. Two chemicals, the human carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) and a possible human carcinogen, acrolein, were hypothesized to interact with one another, possibly owing to the additive effects of DNA adduct formation or influence on the repair of mutagenic DNA adducts. To test our hypothesis that coexposure to NNK and acrolein is more carcinogenic than either chemical alone, A/J mice were exposed to NNK (i.p., 0, 2.5, or 7.5 μmol in saline) in the presence or absence of inhaled acrolein (15 ppmV). While the single 3 h exposure to acrolein alone did not induce lung adenomas, it significantly enhanced NNK's lung carcinogenicity. In addition, mice receiving both NNK and acrolein had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that acrolein may also increase the severity of NNK-induced lung adenomas. To test the hypothesis that the interaction was due to effects on DNA adduct formation and repair, NNK- and acrolein pulmonary DNA adduct levels were assessed. There was no consistent effect of the coexposure on NNK-derived DNA adducts, and acrolein DNA adducts were not elevated above endogenous levels. This study supports the hypothesis that tobacco smoke chemicals combine to contribute to the carcinogenic potency of tobacco smoke, and the mechanism of interaction cannot be explained by alterations of DNA adduct levels.

Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY).

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates.

Exploration of occupations as risk factors for lung cancer in hierarchical and penalization penalized regression models accounting for multiple known exposures

Background and aim: Traditional occupational epidemiological analysis typically emphasize on disease risks associated with specific single exposures or single occupations. We used hierarchical and regularization models to explore occupational risks at the job-title level associated with lung cancer while accounting for exposures to multiple known lung carcinogens. Methods: We pooled lung cancer case-control study subjects from 14 European and Canadian studies. Associations between ever employment in 1,288 five-digit ISCO-68 occupations and lung cancer were screened using two approaches: Bayesian hierarchical and LASSO penalized regressions. Both modeling approaches account for age, smoking, sex, study, and fully quantitative exposures to six known occupational lung carcinogens: asbestos, chromium, diesel engine exhaust, nickel, PAHs, and silica. False positive findings in the Bayesian hierarchical and LASSO models were controlled using horseshoe priors and stability selection, respectively. Lung cancer odds ratios for selected occupations were estimated using unconditional logistic regression model with identical covariates. Results: Our final analyses included 16,901 lung cancer cases and 20,965 controls. There were notable overlaps in jobs selected by the hierarchical and penalization modeling approaches. Occupations selected by both modeling approaches with positive associations with lung cancer after controlling for known exposures include carpenters (OR: 1.77; 95CI: 1.36, 2.33) and construction bricklayers (OR: 1.40; 95CI: 1.17, 1.67). Similarly selected occupations but with negative associations with lung cancer include secondary school teachers (OR: 0.36; 95CI: 0.23, 0.55), production managers (OR: 0.65; 95CI: 0.53, 0.79), and government executive officials (OR: 0.7; 95% CI: 0.61, 0.79). Conclusion: We demonstrated viable agnostic approaches in identifying employment risk factors for lung cancer. Future work involves investigations of factors that contribute to the observed elevated or lower cancer risks, which may involve gaps in current exposure assessment and modeling framework, and/or exposures to other lung carcinogens yet to be elucidated.

Exposure to indoor wood-burning stoves and fireplaces and risk of lung cancer among Sister Study participants

Background and Aim: Epidemiological evidence from case-control studies has identified exposure to household combustion of biomass fuel (primarily wood) as a probable lung carcinogen. However, few studies have been conducted in the United States, where indoor wood-burning and usage patterns differ. We examined the association of exposure to indoor wood smoke from fireplaces and stoves with incident lung cancer in U.S. women. Methods: 50,399 women were studied in the U.S.-based prospective Sister Study cohort (recruited 2003-2009) who answered baseline exposure information and did not have lung cancer before enrollment. At baseline, women reported their frequency of use of wood-burning stoves and/or fireplaces in their longest-lived adult residence. Cox regression was used to estimate adjusted hazard ratios (HRadj) and 95% confidence intervals (CI) for the association between indoor wood-burning fireplace/stove use and incident lung cancer. Results: During an average of 11.3 years of follow-up, 520 lung cancer cases were diagnosed. Overall, 62.2% of the study population reported the presence of an indoor wood-burning fireplace/stove at their longest-lived adult residence. Compared to those without a wood-burning fireplace/stove, an elevated risk of lung cancer was observed in women who used their wood-burning fireplace/stove ≥30 days/year (HRadj = 1.20; 95% CI = 0.94, 1.52; p-for-trend=0.09). Associations were more pronounced in never smokers, with elevated HRs observed in women reporting use both 1-29 days/year (HRadj = 1.87; 95% CI = 1.07, 3.28) and ≥30 days/year (HRadj = 1.69; 95% CI = 0.92, 3.11). Findings were stronger among women who were younger, had less educational attainment and lived in urban settings. Conclusions: Our prospective analysis of a cohort of U.S. women found that frequent use of wood-burning indoor fireplaces/stoves was associated with incident lung cancer, consistent with earlier findings. Keywords: Wood Smoke; Lung Cancer; Women; Respiratory Diseases

OA13.06 Changing Patterns of Lung Cancer Histology in an Asbestos Exposed Population

Asbestos is a widely recognised lung carcinogen. Exposure to both asbestos and cigarette smoke has a synergistic effect on the risk of developing lung cancer. It is not known if the histology of asbestos-related lung cancer has changed over time, as has been observed with non-asbestos-related lung cancer.

Residents' perception and worldview about radon control policy in Canada: A pro-equity social justice lens.

Radon is a potent indoor air pollutant, especially in radon prone areas and in countries with long winters. As the second top lung carcinogen, radon is disproportionately affecting certain population subgroups. While many provinces have taken sporadic actions, the equity issue has remained unaddressed across all policy measures. Attempts to enforce radon guidelines and enact building regulations without considering residents' views have proved ineffective. Research linking residents' radon risk perception and worldviews regarding radon control policy is lacking in Canada. We applied mixed (quantitative and qualitative) methods in a pro-equity social justice lens to examine the variations in residents' risk perception, access to risk communication messages, and worldviews about risk management across the sociodemographic strata. Triangulation of the quantitative and qualitative findings strengthened the evidence base to identify challenges and potential solutions in addressing the health risk through upstream policy actions. Enacting radon control policy requires actions from all levels of governments and relevant stakeholders to ensure equal opportunities for all residents to take the preventive and adaptive measures. Small sample size limited the scope of findings for generalization. Future studies can examine the differential impacts of radon health risk as are determined by various sociodemographic variables in a representative national cohort.

Burden of Lung Cancer Attributable to Occupational Carcinogens from 1990 to 2019 and Projections until 2044 in China.

Simple SummaryThe disease burden trend of lung cancer that is attributable to occupational carcinogens in China remains unclear. We used the data from the Global Burden of Disease (GBD) study in 2019 to investigate the related disease burden from 1990 to 2019 and to project the disease burden for the next 25 years. The results indicate that the disease burden of lung cancer that can be attributed to occupational carcinogens significantly increased from 1990 to 2019 in China, and the absolute burden will continue to increase in the next 25 years.Background: Little is known about trends in the lung cancer burden from the disease that can be attributed to occupational carcinogens in China. Methods: Data regarding the lung cancer burden that can be attributed to occupational carcinogens in China were extracted from the Global Burden of Disease (GBD) study in 2019. Joinpoint regression analysis and an age-period-cohort (APC) analysis were conducted to estimate the trend of lung cancer burden as a result of occupational carcinogens from 1990 to 2019. A Bayesian APC model was used to predict the disease burden until 2044. Results: The average annual percentage changes of age-standardized summary exposure values (SEVs) of occupational lung carcinogens, as well as the age-standardized population attributable fraction (PAF) of lung cancer due to occupational carcinogens, were 0.5% (95% confidence interval (CI): 0.4–0.5%) and 0.1% (95% CI: 0–0.2%), respectively. In addition, both the joinpoint regression analysis and APC analysis demonstrated significantly increased trends of age-standardized lung cancer mortality (ASMR) and age-standardized disability-adjusted life years (ASDR) as a result of occupational carcinogens. Asbestos and silica accounted for the two most important occupational lung carcinogens in China. The absolute burden is expected to increase, mainly due to population aging and the age-specific rate of illness. Conclusions: The lung cancer burden that could be attributed to occupational carcinogens significantly increased from 1990 to 2019 in China, and the absolute burden will continue to increase in the next 25 years.

Occupational Exposure to Hexavalent Chromium, Nickel and PAHs: A Mixtures Risk Assessment Approach Based on Literature Exposure Data from European Countries.

Hexavalent chromium (Cr(VI)), nickel (Ni) and polycyclic aromatic hydrocarbons (PAHs) are genotoxic co-occurring lung carcinogens whose occupational health risk is still understudied. This study, conducted within the European Human Biomonitoring Initiative (HBM4EU), aimed at performing a mixtures risk assessment (MRA) based on published human biomonitoring (HBM) data from Cr(VI), Ni and/or PAHs occupational co-exposure in Europe. After data extraction, Risk Quotient (RQ) and Sum of Risk Quotients (SRQ) were calculated for binary and ternary mixtures to characterise the risk. Most selected articles measured urinary levels of Cr and Ni and a SRQ > 1 was obtained for co-exposure levels in welding activities, showing that there is concern regarding co-exposure to these substances. Similarly, co-exposure to mixtures of Cr(VI), Ni and PAHs in waste incineration settings resulted in SRQ > 1. In some studies, a low risk was estimated based on the single substances’ exposure level (RQ < 1), but the mixture was considered of concern (SRQ > 1), highlighting the relevance of considering exposure to the mixture rather than to its single components. Overall, this study points out the need of using a MRA based on HBM data as a more realistic approach to assess and manage the risk at the workplace, in order to protect workers’ health.

Grouping MWCNTs based on their similar potential to cause pulmonary hazard after inhalation: a case-study

BackgroundThe EU-project GRACIOUS developed an Integrated Approach to Testing and Assessment (IATA) to support grouping high aspect ratio nanomaterials (HARNs) presenting a similar inhalation hazard. Application of grouping reduces the need to assess toxicity on a case-by-case basis and supports read-across of hazard data from substances that have the data required for risk assessment (source) to those that lack such data (target). The HARN IATA, based on the fibre paradigm for pathogenic fibres, facilitates structured data gathering to propose groups of similar HARN and to support read-across by prompting users to address relevant questions regarding HARN morphology, biopersistence and inflammatory potential. The IATA is structured in tiers, allowing grouping decisions to be made using simple in vitro or in silico methods in Tier1 progressing to in vivo approaches at the highest Tier3. Here we present a case-study testing the applicability of GRACIOUS IATA to form an evidence-based group of multiwalled carbon nanotubes (MWCNT) posing a similar predicted fibre-hazard, to support read-across and reduce the burden of toxicity testing.ResultsThe case-study uses data on 15 different MWCNT, obtained from the published literature. By following the IATA, a group of 2 MWCNT was identified (NRCWE006 and NM-401) based on a high degree of similarity. A pairwise similarity assessment was subsequently conducted between the grouped MWCNT to evaluate the potential to conduct read-across and fill data gaps required for regulatory hazard assessment. The similarity assessment, based on expert judgement of Tier 1 assay results, predicts both MWCNT are likely to cause a similar acute in vivo hazard. This result supports the possibility for read-across of sub-chronic and chronic hazard endpoint data for lung fibrosis and carcinogenicity between the 2 grouped MWCNT. The implications of accepting the similarity assessment based on expert judgement of the MWCNT group are considered to stimulate future discussion on the level of similarity between group members considered sufficient to allow regulatory acceptance of a read-across argument.ConclusionThis proof-of-concept case-study demonstrates how a grouping hypothesis and IATA may be used to support a nuanced and evidence-based grouping of ‘similar’ MWCNT and the subsequent interpolation of data between group members to streamline the hazard assessment process.

Radon Level and Effects in Public and Residential Places in Nigeria

Reports from the World Health Organization (WHO) regarding radon as human lung carcinogen has generated a lot of research interest on the impacts of radon exposure to people all over the world. Radon concentration of different building types such as glass house, bricks and basement house structures at different locations geographically were reviewed to evaluate sustainable radon level as a strategic pathway for environmental sustainability in Nigeria. Volumes of expertises in research domain and their respective views were crystallized to forge status of Nigerians on the risk scale. Average mean radon concentration from cumulative survey suggested that dwelling and residential houses are within the recommended limit suggested by standard international and local organizations with little variations owing to several contributory factors. Research also shows that some buildings materials containing relative parent radionuclides of radon and its progenies can also contribute to indoor radon concentration, nevertheless, soil gas containing radon found in soils overlying basement rocks constitute the main source for indoor radon concentration within dwelling places. It is wholly to write that the delineated radon map will serve as a useful tool for determination of new building sites in Nigeria and as a guide for future radon remediation and monitory plan for the safest life in our dear Nation Nigeria.

Abstract 2251: Alu retroelement copy number, leukocyte telomere length, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial

Abstract Prospective cohort and genome-wide association studies have found consistent associations between longer leukocyte telomere length (LTL) and increased lung cancer risk. These findings present a paradox in the traditional expectations of telomere dynamics in cancer development, as longer telomeres are generally considered to be reflective of less advanced age and greater genomic stability. We posited that longer LTL may reflect or lead to delayed cellular senescence allowing cells to accumulate genomic abnormalities that drive lung carcinogenesis. Furthermore, increased copy number of Alu retroelements, repetitive mobile DNA sequences that are approximately 300 base pairs in length, could also reflect genomic instability. We previously found that exposure to diesel exhaust, a known lung carcinogen, was associated with increased Alu copy number and suspect that increased Alu retrotransposition could influence lung carcinogenesis. However, the interrelationship between Alu retroelements, LTL, and lung cancer is unknown. Therefore, we investigated associations between Alu copy number, LTL, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We conducted a nested case-control study of 410 confirmed incident lung cancer cases and 416 controls individually matched on age, sex, race/ethnicity, study center, and blood draw date. Quantitative PCR was used to measure Alu copy number and telomere length relative to albumin (Alb) copy number (Alu/Alb and T/S ratio, respectively) in pre-diagnostic leukocytes. Conditional logistic regression was used to estimate associations between quartiles (Q) of Alu/Alb ratio (reference=Q1) and lung cancer risk, adjusted for matching factors, smoking status and packyears, and LTL. Additionally, we dichotomized Alu/Alb ratio and LTL at their medians and created a cross-combination variable to assess combined effects. We found a positive dose-response relationship between Alu/Alb ratio and lung cancer risk (odds ratio (OR), 95% confidence intervals (CI): Q2: 1.34 (0.73, 2.48); Q3:1.89 (0.94, 3.84); Q4: 2.66 (1.03, 5.63); p-trendordinal=0.02). The association was apparent for lung adenocarcinoma (LUAD) (Q2: 1.32 (0.46, 3.77); Q3: 2.88 (0.90, 9.25); Q4: 5.07 (1.29, 19.87); p-trendordinal=0.02). We have previously reported that longer measured LTL was also associated with an increased risk of LUAD (Q4: 2.82 (1.16-6.85); p-trend=0.011). The combined effect of both a higher Alu/Alb ratio and longer LTL was 6.07 (1.75, 21.04; p=4.5x10-3) for LUAD compared with lower/shorter levels of both. Higher Alu copy number and longer LTL were associated with increased risk of lung cancer, especially LUAD. Our findings require replication. If confirmed, evaluation of Alu copy number and LTL in risk stratification and prediction analyses is warranted. Citation Format: Jason Yat-Yang Wong, Richard Cawthon, Wei Hu, Somayina Ezennia, Shahinaz Gadalla, Charles Breeze, Batel Blechter, Neal Freedman, Wen-Yi Huang, H. Dean Hosgood, Wei Jie Seow, Bryan Bassig, Mohammad Rahman, Richard Hayes, Nathaniel Rothman, Qing Lan. Alu retroelement copy number, leukocyte telomere length, and lung cancer risk in the prospective Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2251.

Military exposures and lung cancer in United States Veterans

Lung cancer screening begins at age 50, with yearly low dose computed tomography (LDCT) scans until age 80, for patients determined to be high risk due to tobacco smoking. Veterans serving from World War II to the Gulf War are now at the age where LDCT is recommended. This recommendation from the United States Preventative Service Task Force includes patients who have a 20-pack year tobacco history and currently smoke or quit within the last 15 years. This recommendation does not consider additional risk factors such as exposures to lung carcinogens. We discuss unique operational and occupational exposures encountered while serving in the armed forces, which may potentially increase the risk of lung cancers in the Veteran population. The additional risk of lung cancer due to military exposure history is unclear and more work is needed to identify and quantify risk at an individual level. Increasing awareness at the provider level regarding the carcinogenic exposures encountered may allow a larger population of Veterans, not meeting traditional LDCT criteria, to benefit from lung cancer screening.

Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: Results from a Pooled Analysis of Case-Control Studies (SYNERGY).

Exposure to polycyclic aromatic hydrocarbons (PAH) occurs widely in occupational settings. We investigated the association between occupational exposure to PAH and lung cancer risk and joint effects with smoking within the SYNERGY project. We pooled 14 case-control studies with information on lifetime occupational and smoking histories conducted between 1985 and 2010 in Europe and Canada. Exposure to benzo[a]pyrene (BaP) was used as a proxy of PAH and estimated from a quantitative general population job-exposure matrix. Multivariable unconditional logistic regression models, adjusted for smoking and exposure to other occupational lung carcinogens, estimated ORs, and 95% confidence intervals (CI). We included 16,901 lung cancer cases and 20,965 frequency-matched controls. Adjusted OR for PAH exposure (ever) was 1.08 (CI, 1.02-1.15) in men and 1.20 (CI, 1.04-1.38) in women. When stratified by smoking status and histologic subtype, the OR for cumulative exposure ≥0.24 BaP μg/m3-years in men was higher in never smokers overall [1.31 (CI, 0.98-1.75)], for small cell [2.53 (CI, 1.28-4.99)] and squamous cell cancers [1.33 (CI, 0.80-2.21)]. Joint effects between PAH and smoking were observed. Restricting analysis to the most recent studies showed no increased risk. Elevated lung cancer risk associated with PAH exposure was observed in both sexes, particularly for small cell and squamous cell cancers, after accounting for cigarette smoking and exposure to other occupational lung carcinogens. The lack of association between PAH and lung cancer in more recent studies merits further research under today's exposure conditions and worker protection measures.

Residential radon exposure and cancer.

Radon is an established human lung carcinogen naturally released as an odorless, colorless gas from soil and rocks. It is a major environmental source of ionizing radiation and can cause oxidative damage to DNA, increasing the risk of lung cancer. Although the association between radon and lung cancer is well established, the association between radon and other cancers is not. Based on reported studies, there is no consistent evidence indicating an association between radon and non-solid and solid cancers, but limited literature, heterogenous study design, and confounding variables preclude definitive conclusions. More research is needed to evaluate the association between residential radon and non-lung cancers, particularly with regard to skin cancer, central nervous system (CNS) cancer, renal, and stomach cancer, in which existing literature suggests potential associations with residential radon may exist. However, the literature largely demonstrates that lung cancer is the primary concern associated with residential radon exposure; the lack of association with nonlung cancers could reflect the lack of studies which have an adequate sample size, establish accurate levels of radon exposure, and control for confounders. These results should be considered in residential radon mitigation efforts which should focus on smokers with high radon exposures.

Exposure to Outdoor Particulate Matter Air Pollution and Risk of Gastrointestinal Cancers in Adults: A Systematic Review and Meta-Analysis of Epidemiologic Evidence.

Background:Outdoor air pollution is a known lung carcinogen, but research investigating the association between particulate matter (PM) and gastrointestinal (GI) cancers is limited.Objectives:We sought to review the epidemiologic literature on outdoor PM and GI cancers and to put the body of studies into context regarding potential for bias and overall strength of evidence.Methods:We conducted a systematic review and meta-analysis of epidemiologic studies that evaluated the association of fine PM [PM with an aerodynamic diameter of ()] and (aerodynamic diameter ) with GI cancer incidence or mortality in adults. We searched five databases for original research published from 1980 to 2021 in English and summarized findings for studies employing a quantitative estimate of exposure overall and by specific GI cancer subtypes. We evaluated the risk of bias of individual studies and the overall quality and strength of the evidence according to the Navigation Guide methodology, which is tailored for environmental health research.Results:Twenty studies met inclusion criteria and included participants from 14 countries; nearly all were of cohort design. All studies identified positive associations between PM exposure and risk of at least one GI cancer, although in 3 studies these relationships were not statistically significant. Three of 5 studies estimated associations with and satisfied inclusion criteria for meta-analysis, but each assessed a different GI cancer and were therefore excluded. In the random-effects meta-analysis of 13 studies, exposure was associated with an increased risk of GI cancer overall [; 95% CI: 1.01, 1.24]. The most robust associations were observed for liver cancer (; 95% CI: 1.07, 1.56) and colorectal cancer (; 95% CI: 1.08, 1.62), for which all studies identified an increased risk. We rated most studies with “probably low” risk of bias and the overall body of evidence as “moderate” quality with “limited” evidence for this association. We based this determination on the generally positive, but inconsistently statistically significant, effect estimates reported across a small number of studies.Conclusion:We concluded there is some evidence of associations between and GI cancers, with the strongest evidence for liver and colorectal cancers. Although there is biologic plausibility for these relationships, studies of any one cancer site were few and there remain only a small number overall. Studies in geographic areas with high GI cancer burden, evaluation of the impact of different PM exposure assessment approaches on observed associations, and investigation of cancer subtypes and specific chemical components of PM are important areas of interest for future research. https://doi.org/10.1289/EHP9620

Lung Cancer Screening in Asbestos-Exposed Populations.

Asbestos exposure is the most important cause of occupational lung cancer mortality. Two large randomized clinical trials in the U.S. and Europe conclusively demonstrate that annual low-dose chest CT (LDCT) scan screening reduces lung cancer mortality. Age and smoking are the chief risk factors tested in LDCT studies, but numerous risk prediction models that incorporate additional lung cancer risk factors have shown excellent performance. The studies of LDCT in asbestos-exposed populations shows favorable results but are variable in design and limited in size and generalizability. Outstanding questions include how to: (1) identify workers appropriate for screening, (2) organize screening programs, (3) inform and motivate people to screen, and (4) incorporate asbestos exposure into LDCT decision-making in clinical practice. Conclusion: Screening workers aged ≥50 years with a history of ≥5 years asbestos exposure (or fewer years given intense exposure) in combination with either (a) a history of smoking at least 10 pack-years with no limit on time since quitting, or (b) a history of asbestos-related fibrosis, chronic lung disease, family history of lung cancer, personal history of cancer, or exposure to multiple workplace lung carcinogens is a reasonable approach to LDCT eligibility, given current knowledge. The promotion of LDCT-based screening among asbestos-exposed workers is an urgent priority.

Particulate hexavalent chromium alters microRNAs in human lung cells that target key carcinogenic pathways

Hexavalent chromium [Cr(VI)] is a global environmental pollutant and human lung carcinogen. However, the mechanisms of Cr(VI) carcinogenesis are not well defined. Cr(VI)-altered gene expression has been reported in the literature and is implicated in numerous mechanisms of Cr(VI) carcinogenesis. MicroRNAs (miRNAs) play a key role in controlling gene expression and are associated with carcinogenic mechanisms. To date no studies have evaluated global changes in miRNA expression in human cells after Cr(VI) exposure. We used RNA sequencing to evaluate how a particulate Cr(VI) compound (zinc chromate), the most potent form of Cr(VI), alters global miRNA expression after acute (24 h) or prolonged (72 and 120 h) exposure to 0.1, 0.2 and 0.3 μg/cm2 zinc chromate in an immortalized, non-cancerous human lung cell line (WTHBF-6). Particulate Cr(VI) significantly affected expression of miRNAs at all time points and concentrations tested. We also found the number of significantly downregulated miRNAs increased in a time- and concentration-dependent manner and many miRNAs were upregulated after 24 h exposure at the intermediate concentration tested. Pathway analyses of the differentially expressed miRNAs predicted miRNAs target pathways of Cr(VI) carcinogenesis in a time- and concentration-dependent manner. These data are the first to evaluate global changes in miRNA expression in human lung cells after Cr(VI) exposure and indicate miRNAs may play a key role in pathways of Cr(VI) carcinogenesis.

The Carcinogenic Properties of Overlooked yet Prevalent Polycyclic Aromatic Hydrocarbons in Human Lung Epithelial Cells.

The WHO classified air pollution as a human lung carcinogen and polycyclic aromatic hydrocarbons (PAHs) are components of both indoor (e.g., tobacco smoke and cookstoves) and outdoor (e.g., wildfires and industrial and vehicle emissions) air pollution, thus a human health concern. However, few studies have evaluated the adverse effects of low molecular weight (LMW) PAHs, the most abundant PAHs in the environment. We hypothesized that LMW PAHs combined with the carcinogenic PAH benzo[a]pyrene (B[a]P) act as co-carcinogens in human lung epithelial cell lines (BEAS-2B and A549). Therefore, in this paper, we evaluate several endpoints, such as micronuclei, gap junctional intercellular communication (GJIC) activity, cell cycle analysis, anti-BPDE-DNA adduct formation, and cytotoxicity after mixed exposures of LMW PAHs with B[a]P. The individual PAH doses used for each endpoint did not elicit cytotoxicity nor cell death and were relevant to human exposures. The addition of a binary mixture of LMW PAHs (fluoranthene and 1-methylanthracene) to B[a]P treated cells resulted in significant increases in micronuclei formation, dysregulation of GJIC, and changes in cell cycle as compared to cells treated with either B[a]P or the binary mixture alone. In addition, anti-BPDE-DNA adducts were significantly increased in human lung cells treated with B[a]P combined with the binary mixture of LMW PAHs as compared to cells treated with B[a]P alone, further supporting the increased co-carcinogenic potential by LMW PAHs. Collectively, these novel studies using LMW PAHs provide evidence of adverse pulmonary effects that should warrant further investigation.

Characterization of adductomic totality of NNK, (R)-NNAL and (S)-NNAL in A/J mice, and their correlations with distinct lung carcinogenicity.

Lung cancer is the leading cause of cancer-related deaths. While tobacco use is the main cause, only 10-20% of smokers eventually develop clinical lung cancer. Thus, the ability of lung cancer risk prediction among smokers could transform lung cancer management with early preventive interventions. Given that DNA damage by tobacco carcinogens is the potential root cause of lung carcinogenesis, we characterized the adductomic totality of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (a potent lung carcinogen in tobacco, commonly known as NNK) in the target lung tissues, the liver tissues and the peripheral serum samples in a single-dose NNK-induced lung carcinogenesis A/J mouse model. We also characterized these adductomic totalities from the two enantiomers of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, the major in vivo metabolite of NNK) given their distinct carcinogenicity in A/J mice. With these adductomic data, we demonstrated that tissue protein adductomics have the highest abundance. We also identified that the adductomic levels at the 8h time point after carcinogen exposure were among the highest. More importantly, the relationships among these adductomics were characterized with overall strong positive linear correlations, demonstrating the potential of using peripheral serum protein adductomics to reflect DNA adductomics in the target lung tissues. Lastly, we explored the relationships of these adductomics with lung tumor status in A/J mice, providing preliminary but promising evidence of the feasibility of lung cancer risk prediction using peripheral adductomic profiling.