Established Lung Carcinogen Research Articles

Integrated environmental and health assessment from hydrogeochemistry and radiogeology parameters of hydrothermal spring attractions in Southern Thailand.

The present study aimed to investigate the hydrogeochemical patterns and contamination of the radiogeology, especially radon activity, related to geothermal aquifer properties and to perform a risk assessment of annual effective doses covering all hydrothermal spring attractions in Southern Thailand. Radon is an established lung carcinogen; especially longer term exposure to radioactive radon through inhalation could be a cause of lung cancer risk. Altogether 22 hydrothermal spring samples were collected from the six hydrothermal provinces in Southern Thailand in early November of 2023. Geochemical data represented by calcium chloride and sodium chloride type, most of which were influenced by seawater intrusion. In addition, the hydrothermal springs that located along local fault zones were mainly controlled by water‒rock interactions, indicating that hydrothermal spring quality was influenced by weathering. Hydrothermal springs located along the coastlines of the Gulf of Thailand and Andaman Sea were dominated by evaporation. Radon activity concentrations show value levels from 9Bq/L (PG1) to 7,070Bq/L (SR3), with an average of 580Bq/L. Radon levels of hydrothermal spring attractions can be divided into three categories: (a) low radon levels below 100Bq/L, (b) moderate to high radon levels between 100 and 580Bq/L, and (c) very high radon levels greater than 580Bq/L. The total annual effective doses for adults due to ingestion and dominantly inhalation of radon at hydrothermal spring attractions varied from 0.01 to 19.30mSv/year. These results highlight the usefulness of this method as an essential tool for delineating radon concentrations, which could be used to introduce guidelines for health risk assessment.

Occupational exposure to diesel engine exhaust and serum levels of microRNAs in a cross-sectional molecular epidemiology study in China.

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, 6.1-79.7μg/m3 ) 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 (ptrend =.001, FDR=0.04) and miR-93-5p (ptrend =.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.

Characterizing occupational radon exposure greater than 100Bq/m3 in a highly exposed country.

Radon is an established lung carcinogen concentrating in indoor environments with importance for many workers worldwide. However, a systematic assessment of radon levels faced by all workers, not just those with direct uranium or radon exposure, has not previously been completed. The objective of this study was to estimate the prevalence of workers exposed to radon, and the level of exposure (> 100-200Bq/m3, 200-400Bq/m3, 400-800Bq/m3, and > 800Bq/m3) in a highly exposed country (Canada). Exposures among underground workers were assessed using the CAREX Canada approach. Radon concentrations in indoor workplaces, obtained from two Canadian surveys, were modelled using lognormal distributions. Distributions were then applied to the susceptible indoor worker population to yield the number of exposed workers, by occupation, industry, province, and sex. In total, an estimated 603,000 out of Canada's 18,268,120 workers are exposed to radon in Canada. An estimated52% of exposed workers are women, even though they comprise only 48% of the labour force. The majority (68%) are exposed at a level of > 100-200Bq/m3. Workers are primarily exposed in educational services, professional, scientific and technical services, and health care and social assistance, but workers in mining, quarrying, and oil and gas extraction have the largest number of exposed workers at high levels (> 800Bq/m3). Overall, a significant number of workers are exposed to radon, many of whom are not adequately protected by existing guidelines. Radon surveys across multiple industries and occupations are needed to better characterize occupational exposure. These results can be used to identify exposed workers, and to support lung cancer prevention programs within these groups.

Air pollution with NO2, PM2.5, and elemental carbon in relation to risk of breast cancer– a nationwide case-control study from Denmark

Air pollution with particulate matter is an established lung carcinogen. Studies have suggested an association with breast cancer, but the evidence is inconsistent. MethodsFrom nationwide registers, we identified all breast cancer cases (n = 55 745) in Denmark between 2000 and 2014. We matched one control for each case on age and year of birth. We used a multi-scale dispersion model to estimate outdoor concentrations of particulate matter <2.5 μm (PM2.5), elemental carbon (EC) and nitrogen dioxide (NO2) as time-weighted average over all addresses up to 20 years prior to diagnosis. We calculated odds ratios (OR) and 95% confidence intervals (CI) by conditional logistic regression with adjustment for marital status, educational level, occupational status, personal income, region of origin, medication and area-level socio-economic indicators. ResultsA 10 μg/m3 higher PM2.5 was associated with an OR for breast cancer of 1.21 (95% CI: 1.11–1.33). The corresponding ORs for EC (per 1 μg/m3) and NO2 (per 10 μg/m3) were 1.03 (95% CI: 1.00–1.07) and 1.03 (95% CI: 1.01–1.06), respectively. In multi–pollutant models, the OR for PM2.5 changed only little, whereas ORs for EC or NO2 approached the null. In an analysis of persons below 55 years, PM2.5 was associated with an OR of 1.32 (95% CI: 1.09–1.60) per 10 μg/m3 increase. ConclusionWe found evidence of an association between the investigated air pollutants and breast cancer, especially PM2.5. There were indications that the association differed by age at diagnosis. We were not able to include all potential confounders and thus, results should be interpreted with caution.

Low-moderate arsenic exposure and respiratory in American Indian communities in the Strong Heart Study

BackgroundArsenic exposure through drinking water is an established lung carcinogen. Evidence on non-malignant lung outcomes is less conclusive and suggests arsenic is associated with lower lung function. Studies examining low-moderate arsenic (< 50 μg/L), the level relevant for most populations, are limited. We evaluated the association of arsenic exposure with respiratory health in American Indians from the Northern Plains, the Southern Plains and the Southwest United States, communities with environmental exposure to inorganic arsenic through drinking water.MethodsThe Strong Heart Study is a prospective study of American Indian adults. This analysis used urinary arsenic measurements at baseline (1989–1991) and spirometry at Visit 2 (1993–1995) from 2132 participants to evaluate associations of arsenic exposure with airflow obstruction, restrictive pattern, self-reported respiratory disease, and symptoms.ResultsAirflow obstruction was present in 21.5% and restrictive pattern was present in 14.4%. The odds ratio (95% confidence interval) for obstruction and restrictive patterns, based on the fixed ratio definition, comparing the 75th to 25th percentile of arsenic, was 1.17 (0.99, 1.38) and 1.27 (1.01, 1.60), respectively, after adjustments, and 1.28 (1.02, 1.60) and 1.33 (0.90, 1.50), respectively, based on the lower limit of normal definition. Arsenic was associated with lower percent predicted FEV1 and FVC, self-reported emphysema and stopping for breath.ConclusionLow-moderate arsenic exposure was positively associated with restrictive pattern, airflow obstruction, lower lung function, self-reported emphysema and stopping for breath, independent of smoking and other lung disease risk factors. Findings suggest that low-moderate arsenic exposure may contribute to restrictive lung disease.

Genomic instability reflected by elevated Alu retroelement copy-number among workers exposed to diesel engine exhaust

OPS 44: Occupational health studies with environmental implications, Room 411, Floor 4, August 27, 2019, 4:30 PM - 5:30 PM Background/Aim: Millions of transportation and industrial workers worldwide are exposed to diesel engine exhaust (DEE), an established lung carcinogen that contains DNA-damaging constituents. Alu retroelements are repetitive DNA sequences that can multiply, insert throughout the genome, and disrupt gene expression and genomic architecture. Site-specific DNA strand breaks activate Alu retrotransposition and altered Alu repeats have been linked to cancer and mortality risk. However, whether Alu retroelements are influenced by environmental pollutants is largely unexplored. In an occupational setting with high levels of DEE, we investigated associations between personal exposure and Alu copy-number. Methods: A cross-sectional study was conducted in China with 54 DEE-exposed male workers from an engine testing facility and 55 unexposed male controls. Personal air samples were measured for elemental carbon (EC), a DEE surrogate, using NIOSH Method 5040. Leukocyte DNA was extracted from blood samples and quantitative polymerase chain reaction was used to measure Alu copy-number relative to albumin (Alb) single gene copy-number. The unitless Alu/Alb ratio reflects the average Alu copy-number. Linear regression models were used to test for differences in Alu/Alb ratio between controls and DEE-exposed workers, and to evaluate exposure–response relationships across DEE-exposure groups (i.e., controls and EC-tertiles: 6.1–39.0, 39.1–54.5, and 54.6–107.7 µg/m3) adjusted for age and smoking status. Results: DEE-exposed workers had a higher Alu/Alb ratio than unexposed controls (p=0.03). Further, we found a positive exposure-response relationship with EC (p-trend=0.02). The Alu/Alb ratio was largest among DEE-exposed workers in the highest EC-tertile versus controls (1.12+/-0.08 SD versus 1.06+/-0.07 SD, p=0.01). Age, body mass index, smoking, and work years were not associated with Alu/Alb ratio. Conclusions: Our findings suggest that increased levels of DEE exposure may contribute to genomic instability, possibly reflected by Alu copy-number. Further studies are needed to evaluate the influence of environmental pollutants on Alu copy-number in relation to carcinogenesis.

Air pollution from traffic and risk for brain tumors: a nationwide study in Denmark.

Air pollution is an established lung carcinogen, and there is increasing evidence that air pollution also negatively affects the brain. We have previously reported an association between air pollution and risk of brain tumors in a cohort study based on only 95 cases. We set out to replicate that finding in a large nationwide case-control study. We identified all 4,183 adult brain tumor cases in Denmark in the years 2000-2009 and 8,018 risk set sampled population controls matched on gender and year of birth. We extracted residential address histories and estimated mean residential nitrogen oxides (NO x ) concentrations since 1971 with a validated dispersion model. Categorical and linear odds ratios (OR) and confidence intervals (CI) were calculated with conditional logistic regression models. The highest risk estimates for any brain cancer were observed among subjects with the highest average exposure levels (80-99 µg/m(3): OR 1.27, 95% CI 0.82-1.96; ≥100 µg/m(3): 1.40, 95 % CI 0.87-2.26 as compared to <20 µg/m(3) NO x ), but there was no increased OR at NO x levels below 80 µg/m(3) and when modeled linearly there was no significant association with risk of brain cancer (OR 1.11, 95% CI 0.84-1.46 per 100 µg/m(3) NO x ). In sub-analysis the OR associated with exposures ≥100 µg/m(3) was 2.30 (95% CI 1.15-4.59) for non-glioma and 0.89 (95% CI 0.44-1.77) for glioma. This study did not support the relatively strong linear association between air pollution and risk of brain tumors which was found in our previous study. The suggestion of an increased brain tumor risk at high exposures merits further attention as does the differing results according to tumor morphology.

A Population-Based Study Of Occupational Asbestos Exposure And The Risk Of Colon And Rectal Cancer In Canadian Men

Background: Asbestos is an established lung carcinogen, however, its effects on cancers at other sites are not well understood. We addressed this research gap by examining associations between diff...

Household air pollution and cancers other than lung: a meta-analysis.

Household air pollution (HAP) from solid fuel combustion contributes to 2.6% of the global burden of disease. HAP emissions are an established lung carcinogen; however, associations with other cancer sites have not been fully explored. We conducted a meta-analysis of 18 case–control studies. Using fixed-effects models, utilizing the adjusted odds ratios (OR) and 95% confidence intervals (95% CI) from each study, we evaluated the association between HAP and cervical neoplasia (663 cases and 1747 controls) and upper aero-digestive tract cancers (6022 cases and 15 325 controls). We found that HAP was associated with cervical neoplasia (OR = 6.46; 95% CI = 3.12-13.36; 4 studies); oral (OR = 2.44; 95% CI = 1.87-3.19; 4 studies; 1000 cases/3450 controls); nasopharyngeal (OR = 1.80; 95% CI = 1.42-2.29; 6 studies; 2231 cases/2160 controls); pharyngeal (OR = 3.56; 95% CI = 2.22-5.70; 4 studies; 1036 cases/3746 controls); and laryngeal (OR = 2.35; 95% CI = 1.72- 3.21; 5 studies; 1416 cases/4514 controls) cancers. The elevated risk for esophageal cancer (OR = 1.92; 95% CI = 0.82-4.49; 2 studies; 339 cases/1455 controls) was non-significant. HAP was associated with cervical neoplasia among studies that accounted for HPV infection (OR = 9.60; 95% CI = 3.79-24.32) and smoking (OR = 4.72; 95% CI = 1.84-12.07). Similarly, our observed associations between HAP and upper aero-digestive tract cancers remained significantly elevated when analyses were restricted to studies that controlled for smoking. No significant publication bias was detected. Our results suggest that the carcinogenic effect of HAP observed for lung cancer may extend to other cancers, including those of the cervix and the upper aero-digestive tract. Further research is needed to confirm these associations in prospective studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-015-0001-3) contains supplementary material, which is available to authorized users.

Mitochondrial DNA Copy Number and Exposure to Polycyclic Aromatic Hydrocarbons

Increased mitochondrial DNA copy number (mtDNAcn) is a biologic response to mtDNA damage and dysfunction, predictive of lung cancer risk. Polycyclic aromatic hydrocarbons (PAHs) are established lung carcinogens and may cause mitochondrial toxicity. Whether PAH exposure and PAH-related nuclear DNA (nDNA) genotoxic effects are linked with increased mtDNAcn has never been evaluated. We investigated the effect of chronic exposure to PAHs on mtDNAcn in peripheral blood lymphocytes (PBLs) of 46 Polish male noncurrent smoking coke-oven workers and 44 matched controls, who were part of a group of 94 study individuals examined in our previous work. Subjects' PAH exposure and genetic alterations were characterized through measures of internal dose (urinary 1-pyrenol), target dose [anti-benzo[a]pyrene diolepoxide (anti-BPDE)-DNA adduct], genetic instability (micronuclei and telomere length), and DNA methylation (p53 promoter) in PBLs. mtDNAcn (MT/S) was measured using a validated real-time PCR method. Workers with PAH exposure above the median value (>3 μmol 1-pyrenol/mol creatinine) showed higher mtDNAcn [geometric means (GM) of 1.06 (unadjusted) and 1.07 (age-adjusted)] compared with controls [GM 0.89 (unadjusted); 0.89 (age-adjusted); (P = 0.029 and 0.016)], as well as higher levels of genetic and chromosomal [i.e., anti-BPDE-DNA adducts (P < 0.001), micronuclei (P < 0.001), and telomere length (P = 0.053)] and epigenetic [i.e., p53 gene-specific promoter methylation (P < 0.001)] alterations in the nDNA. In the whole study population, unadjusted and age-adjusted mtDNAcn was positively correlated with 1-pyrenol (P = 0.043 and 0.032) and anti-BPDE-DNA adducts (P = 0.046 and 0.049). PAH exposure and PAH-related nDNA genotoxicity are associated with increased mtDNAcn. The present study is suggestive of potential roles of mtDNAcn in PAH-induced carcinogenesis.

Use of the Cytokinesis-Blocked Micronucleus Assay to Detect Gender Differences and Genetic Instability in a Lung Cancer Case–Control Study

Although tobacco exposure is the predominant risk factor for lung cancer, other environmental agents are established lung carcinogens. Measuring the genotoxic effect of environmental exposures remains equivocal, as increases in morbidity and mortality may be attributed to coexposures such as smoking. We evaluated genetic instability and risk of lung cancer associated with exposure to environmental agents (e.g., exhaust) and smoking among 500 lung cancer cases and 500 controls using the cytokinesis-blocked micronucleus (CBMN) assay. Linear regression was applied to estimate the adjusted means of the CBMN endpoints (micronuclei and nucleoplasmic bridges). Logistic regression analyses were used to estimate lung cancer risk and to control for potential confounding by age, gender, and smoking. Cases showed significantly higher levels of micronuclei and nucleoplasmic bridges as compared with controls (mean ± SEM = 3.54 ± 0.04 vs. 1.81 ± 0.04 and mean ± SEM = 4.26 ± 0.03 vs. 0.99 ± 0.03, respectively; P < 0.001) with no differences among participants with or without reported environmental exposure. No differences were observed when stratified by smoking or environmental exposure among cases or controls. A difference in lung cancer risk was observed between nonexposed male and female heavy smokers, although it was not statistically significant (I(2) = 64.9%; P value for Q statistic = 0.09). Our study confirms that the CBMN assay is an accurate predictor of lung cancer and supports the premise that heavy smoking may have an effect on DNA repair capacity and in turn modulate the risk of lung cancer. Identifying factors that increase lung cancer risk may lead to more effective prevention measures.

Urinary levels of volatile organic carcinogen and toxicant biomarkers in relation to lung cancer development in smokers.

Besides polycyclic aromatic hydrocarbons (PAH) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which are established lung carcinogens, tobacco smoke also contains relatively large quantities of volatile organic carcinogens and toxicants, including 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde. Although animal experiments showed that some of these compounds can induce tumors in multiple organs including the lung, epidemiological studies of their relationship with lung cancer in smokers have not been reported. Therefore, in this study, we quantified urinary mercapturic acid metabolites of 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde in addition to urinary biomarkers for PAH, NNK and nicotine in 343 lung cancer cases and 392 matched controls among a cohort of 18,244 Chinese men in Shanghai, China, followed from 1986 to 2006. Compared with the lowest quartiles, highest quartiles of all measured mercapturic acids were associated with statistically significantly ~2-fold increased risk for lung cancer (all P's for trend <0.01) after adjustment for smoking intensity and duration. The positive associations between biomarkers of ethylene oxide, benzene or acrolein and lung cancer risk remained statistically significant after adjustment for biomarkers of PAH and NNK, whereas urinary total cotinine completely explained the mercapturic acid metabolites and lung cancer associations (all P's for trend ≥ 0.39). We conclude that mercapturic acid metabolites of 1,3-butadiene, ethylene oxide, benzene, acrolein and crotonaldehyde may not be independent risk predictors of lung cancer among Shanghai smokers, in contrast to biomarkers of PAH, NNK and nicotine exposure.

TOENAIL ARSENIC CONCENTRATIONS AMONG RESIDENTS OF A COAL MINING AREA OF THE APPALACHIAN MOUNTAINS OF THE UNITED STATES: A PILOT STUDY.

Background and Aims: Arsenic is an established lung carcinogen. Lung cancer rates in the Appalachian region of Kentucky are about twice the national rates in the U.S.A. The high rates of smoking in the area do not explain all the elevation in lung cancer risk. This area is also characterized by extensive coal mining activity. This pilot study explored a comparison of toenail arsenic concentrations in Appalachian Kentucky and another distant region of the state. Methods:Toenail samples were collected for a population - based case-control study in Kentucky. A sub-group of the samples were selected and analyzed for trace elements, based on location of the study participants, who were included if they lived in the East Kentucky Coal counties in Appalachian Kentucky, or in the largest urban center of Jefferson County. For the assessment of population-based exposure, only the controls of the original study were included. Total elemental analyses were performed using inductively-coupled plasma-mass spectrometry. There were a considerable number of samples with arsenic concentrations below the method detection limit, due in part to inadequate sample mass. Therefore, a reverse Kaplan-Meier method was used for the statistical analysis of the left-censored data. Results: A total of 88 toenail samples from Appalachian Kentucky and 155 from Jefferson County were analyzed for arsenic concentrations. The reverse Kaplan-Meier estimation indicated that the arsenic concentrations in the Appalachian counties were significantly higher than in Jefferson (75th and 90th percentiles were 0.13 vs. 0.03 and 0.29 vs. 0.04 ug/g, respectively). Conclusions: The results of this study suggest that residents of the selected Appalachian Kentucky counties with high coal mining activity have higher exposure to arsenic than those in an urban, non-coal mining region of the same state. However, further studies are needed to elucidate the source of the arsenic exposure.

Exposure Assessment for a Nested Case–Control Study of Lung Cancer among European Asphalt Workers

Development of a method for retrospective assessment of exposure to bitumen fume, bitumen condensate, organic vapour, polycyclic aromatic hydrocarbons, and co-exposures to known or suspected lung carcinogens for a nested case-control study of lung cancer mortality among European asphalt workers. Company questionnaires and structured questionnaires used in interviews and industry-specific job-exposure matrices (JEMs) were elaborated and applied. Three sources of information were eventually used for exposure assessment and assignment: (i) data obtained in cohort phase, (ii) data from living subjects, next-of-kin, and fellow-workers questionnaires, and (iii) JEMs for bitumen exposure by inhalation and via skin and co-exposures to known or suspected lung carcinogens within and outside cohort companies. Inhalation and dermal exposure estimates for bitumen were adjusted for time trends, time spent in a job, and other determinants of exposure (e.g. oil gravel paving). Clothing patterns, personal protective devices, and personal hygiene were taken into consideration while estimating dermal exposure. Occupational exposures could be assessed for 433 cases and 1253 controls for relevant time periods. Only 43% of work histories were spent inside original asphalt and construction companies. A total of 95.8% of job periods in cohort companies could be coded at a more detailed level. Imputation of work time and 'hygienic behaviour' multipliers was needed for <10% of work history years. Overall, downward trends in exposure were present and differences existed between countries and companies. As expected, correlations were strongest (r > 0.7) among bitumen-related agents, while correlations between coal tar, bitumen-related agents, and established lung carcinogens were weaker (r < 0.4). A systematic and detailed approach was developed to estimate inhalation and dermal exposure for a nested case-control study among asphalt workers.

Shorter telomere length in peripheral blood lymphocytes of workers exposed to polycyclic aromatic hydrocarbons

Shorter telomere length (TL) in peripheral blood lymphocytes (PBLs) is predictive of lung cancer risk. Polycyclic aromatic hydrocarbons (PAHs) are established lung carcinogens that cause chromosome instability. Whether PAH exposure and its molecular effects are linked with shorter TL has never been evaluated. In the present study, we investigated the effect of chronic exposure to PAHs on TL measured in PBLs of Polish male non-current smoking cokeoven workers and matched controls. PAH exposure and molecular effects were characterized using measures of internal dose (urinary 1-pyrenol), effective dose [anti-benzo[a]pyrene diolepoxide (anti-BPDE)-DNA adduct], genetic instability (micronuclei, MN) and DNA methylation [p53 promoter and Alu and long interspersed nuclear element-1 (LINE-1) repetitive elements, as surrogate measures of global methylation] in PBLs. TL was measured by real-time polymerase chain reaction. Cokeoven workers were heavily exposed to PAHs (79% exceeded the urinary 1-pyrenol biological exposure index) and exhibited lower TL (P = 0.038) than controls, as well as higher levels of genetic and chromosomal alterations [i.e. anti-BPDE-DNA adduct and MN (P < 0.0001)] and epigenetic changes [i.e. p53 gene-specific promoter and global methylation (P <or= 0.001)]. TL decreased with longer duration of work as cokeoven worker (P = 0.039) and in all subjects with higher levels of anti-BPDE-DNA adduct (P = 0.042), p53 hypomethylation (P = 0.005) and MN (P = 0.009). In multivariate analysis, years of work in cokery (P = 0.008) and p53 hypomethylation (P = 0.001) were the principal determinants of shorter TL. Our results indicate that shorter TL is associated with chronic PAH exposure. The interrelations with other genetic and epigenetic mechanisms in our data suggest that shorter TL could be a central event in PAH carcinogenesis.

Arsenic activates EGFR pathway signaling in the lung.

Arsenic is an established lung carcinogen, however, the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell cycle progression, tumor invasion, and angiogenesis. We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-EGF, and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor, Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95% confidence interval 1.1–15.6) (p = 0.04). These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic-exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.

Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and meta-analysis.

Typical polycyclic aromatic hydrocarbon mixtures are established lung carcinogens, but the quantitative exposure–response relationship is less clear. To clarify this relationship we conducted a review and meta-analysis of published reports of occupational epidemiologic studies. Thirty-nine cohorts were included. The average estimated unit relative risk (URR) at 100 μg/m3 years benzo[a]pyrene was 1.20 [95% confidence interval (CI), 1.11–1.29] and was not sensitive to particular studies or analytic methods. However, the URR varied by industry. The estimated means in coke ovens, gasworks, and aluminum production works were similar (1.15–1.17). Average URRs in other industries were higher but imprecisely estimated, with those for asphalt (17.5; CI, 4.21–72.78) and chimney sweeps (16.2; CI, 1.64–160.7) significantly higher than the three above. There was no statistically significant variation of URRs within industry or in relation to study design (including whether adjusted for smoking), or source of exposure information. Limited information on total dust exposure did not suggest that dust exposure was an important confounder or modified the effect. These results provide a more secure basis for risk assessment than was previously available.

Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary...

Radon measurements in underground dwellings from two prefectures in China.

Radon, an established lung carcinogen, remains the single most important environmental radiation exposure. Yet, an excess of lung cancer from breathing radon in homes has not been consistently demonstrated in studies conducted to date. To address several major problems that have hindered previous studies of lung cancer and radon in homes, we have embarked upon a lung cancer case-control study in Gansu Province, China, where a substantial proportion of the population live in underground dwellings. In this paper, we report on results of a pilot study in which radon measurements were made for 3 days in the summer in 40 homes under normal occupancy conditions using short-term E-PERM detectors and for 6 months from February through August in 49 homes using long-term alpha-track detectors. Useable E-PERM data were obtained from 38 homes and useable alpha-track data from 47 homes. For both types of detectors, measurements were approximately log-normally distributed. Arithmetic and geometric means were 233 and 185 Bq m-3 (range 74-1,590 Bq m-3) for E-PERM measurements and 165 and 158 Bq m-3 (range 74-592 Bq m-3) for alpha-track measurements, respectively; 68% of E-PERM measured homes and 55% of alpha-track measured homes exceeded 148 Bq m-3. Alpha-track measurements made at the entry, middle, and rear areas of the underground dwellings did not differ significantly (arithmetic means of 168, 162, and 165 Bq m-3 with standard deviations 63, 73, and 48, respectively), which suggests that air circulation may be minimal. The underground dwellings measured in the pilot study had high radon levels and the underground dwellers may provide an excellent population for studying indoor radon and risk of lung cancer.

Metal Toxicity and the Respiratory Tract

The type of lung disease caused by metal compounds depends on the nature of the offending agent, its physicochemical form, the dose, exposure conditions and host factors. The fumes or gaseous forms of several metals, e.g. cadmium (Cd), manganese (Mn), mercury (Hg), nickel carbonyl (Nl(CO)4, zinc chloride (ZnCl2), vanadium pentoxide (V2O5), may lead to acute chemical pneumonitis and pulmonary oedema or to acute tracheobronchitis. Metal fume fever, which may follow the inhalation of metal fumes e.g. zinc (Zn), copper (Cu) and many others, is a poorly understood influenza-like reaction, accompanied by an acute self-limiting neutrophil alveolitis. Chronic obstructive lung disease may result from occupational exposure to mineral dusts, including probably some metallic dusts, or from jobs involving the working of metal compounds, such as welding. Exposure to cadmium may lead to emphysema. Bronchial asthma may be caused by complex platinum salts, nickel, chromium or cobalt, presumably on the basis of allergic sensitization. The cause of asthma in aluminium workers is unknown. It is remarkable that asthma induced by nickel (Ni) or chromium (Cr) is apparently infrequent, considering their potency and frequent involvement as dermal sensitizers. Metallic dusts deposited in the lung may give rise to pulmonary fibrosis and functional impairment, depending on the fibrogenic potential of the agent and on poorly understood host factors. Inhalation of iron compounds causes siderosis, a pneumoconiosis with little or no fibrosis. Hard metal lung disease is a fibrosis characterized by desquamative and giant cell interstitial pneumonitis and is probably caused by cobalt, since a similar disease has been observed in workers exposed to cobalt in the absence of tungsten carbide. Chronic beryllium disease is a fibrosis with sarcoid-like epitheloid granulomas and is presumably due to a cell-mediated immune response to beryllium. Such a mechanism may be responsible for the pulmonary fibrosis occasionally found in subjects exposed to other metals e.g. aluminium (Al), titanium (Ti), rare earths. The proportion of lung cancer attributable to occupation is around 15%, with exposure to metals being frequently incriminated. Underground mining of e.g. uranium or iron is associated with a high incidence of lung cancer, as a result of exposure to radon. At least some forms of arsenic, chromium and nickel are well established lung carcinogens in humans. There is also evidence for increased lung cancer mortality in cadmium workers and in iron or steel workers.