Particulate matter air pollution components and risk for lung cancer.

BACKGROUND: Particulate matter (PM) air pollution is a human lung carcinogen; however, the components responsible have not been identified. We assessed the associations between PM components and lung cancer incidence. METHODS: We used data from 14 cohort studies in eight European countries. We geocoded baseline addresses and assessed air pollution with land-use regression models for eight elements (Cu, Fe, K, Ni, S, Si, V and Zn) in size fractions of PM2.5 and PM10. We used Cox regression models with adjustment for potential confounders for cohort-specific analyses and random effect models for meta-analysis. RESULTS: The 245,782 cohort members contributed 3,229,220 person-years at risk. During follow-up (mean, 13.1 years), 1878 incident cases of lung cancer were diagnosed. In the meta-analyses, elevated hazard ratios (HRs) for lung cancer were associated with all elements except V; none was statistically significant. In analyses restricted to participants who did not change residence during follow-up, statistically significant associations were found for PM2.5 Cu (HR, 1.25; 95% CI, 1.01-1.53 per 5 ng/m(3)), PM10 Zn (1.28; 1.02-1.59 per 20 ng/m(3)), PM10 S (1.58; 1.03-2.44 per 200 ng/m(3)), PM10 Ni (1.59; 1.12-2.26 per 2 ng/m(3)) and PM10 K (1.17; 1.02-1.33 per 100 ng/m(3)). In two-pollutant models, associations between PM10 and PM2.5 and lung cancer were largely explained by PM2.5 S. CONCLUSIONS: This study indicates that the association between PM in air pollution and lung cancer can be attributed to various PM components and sources. PM containing S and Ni might be particularly important.

Long-term exposure to traffic-related air pollution and diabetes-associated mortality: a cohort study.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether air pollution from traffic at a residence is associated with mortality related to type 1 or type 2 diabetes. METHODS: We followed up 52,061 participants in the Danish Diet, Cancer and Health cohort for diabetes-related mortality in the nationwide Register of Causes of Death, from baseline in 1993-1997 up to the end of 2009, and traced their residential addresses since 1971 in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO2) since 1971 and amount of traffic at the baseline residence as indicators of traffic-related air pollution and used Cox regression models to estimate mortality-rate ratios (MRRs) with adjustment for potential confounders. RESULTS: Mean levels of NO2 at the residence since 1971 were significantly associated with mortality from diabetes. Exposure above 19.4 µg/m³ (upper quartile) was associated with a MRR of 2.15 (95% CI 1.21, 3.83) when compared with below 13.6 µg/m³ (lower quartile), corresponding to an MRR of 1.31 (95% CI 0.98, 1.76) per 10 µg/m³ NO2 after adjustment for potential confounders. CONCLUSIONS/INTERPRETATION: This study suggests that traffic-related air pollution is associated with mortality from diabetes. If confirmed, reduction in population exposure to traffic-related air pollution could be an additional strategy against the global public health burden of diabetes.

Effects of a 17q21 chromosome gene variant, tobacco smoke and furred pets on infant wheeze.

The first common genetic factor identified for pediatric asthma by genome-wide association is the chromosome 17q21 locus, harbouring the ORMDL3 gene. ORMDL3 is involved in facilitation of endoplasmic reticulum-mediated inflammatory responses, believed to underlie its asthma association. We investigated associations between the rs7216389 polymorphism in the 17q21 locus affecting ORMDL3 expression and the risk for recurrent wheeze and interactions with exposure to tobacco smoke and furred pets during pregnancy and infancy using a birth cohort of 101,042 infants. Rs7216389 was significantly associated with recurrent wheeze risk among 18-month-old infants. There was a 1.35-fold higher risk of recurrent wheeze among homozygous variant allele carriers compared with homozygous wild-type allele carriers. There was significant interaction between rs7216389 and domestic furred pets, with a positive association between pets and wheeze among homozygous wild-type carriers and a negative association among homozygous variant allele carriers. There was no interaction between rs7216389 and tobacco smoke exposure.

Long-term exposure to indoor air pollution and wheezing symptoms in infants.

Long-term exposure to air pollution is suspected to cause recurrent wheeze in infants. The few previous studies have had ambiguous results. The objective of this study was to estimate the impact of measured long-term exposure to indoor air pollution on wheezing symptoms in infants. We monitored wheezing symptoms in diaries for a birth cohort of 411 infants. We measured long-term exposure to nitrogen oxides (NO(x)), NO(2), formaldehyde, PM(2.5) and black smoke in the infants' bedrooms and analyzed risk associations during the first 18 months of life by logistic regression with the dichotomous end-point 'any symptom-day' (yes/no) and by standard linear regression with the end-point 'number of symptom-days'. The results showed no systematic association between risk for wheezing symptoms and the levels of these air pollutants with various indoor and outdoor sources. In conclusion, we found no evidence of an association between long-term exposure to indoor air pollution and wheezing symptoms in infants, suggesting that indoor air pollution is not causally related to the underlying disease. Practical Implications Nitrogen oxides, formaldehyde and fine particles were measured in the air in infants' bedrooms. The results showed no evidence of an association between long-term exposure and wheezing symptoms in the COPSAC birth cohort.

Fruits and vegetables consumption and the risk of histological subtypes of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

OBJECTIVE: To examine the association between fruit and vegetable consumption and risk of different histological subtypes of lung cancer among participants of the European Prospective Investigation into Cancer and Nutrition study. METHODS: Multivariable Cox proportional hazard models were used to analyze the data. A calibration study in a subsample was used to reduce dietary measurement errors. RESULTS: During a mean follow-up of 8.7 years, 1,830 incident cases of lung cancer (574 adenocarcinoma, 286 small cell, 137 large cell, 363 squamous cell, 470 other histologies) were identified. In line with our previous conclusions, we found that after calibration a 100 g/day increase in fruit and vegetables consumption was associated with a reduced lung cancer risk (HR 0.94; 95% CI 0.89-0.99). This was also seen among current smokers (HR 0.93; 95% CI 0.90-0.97). Risks of squamous cell carcinomas in current smokers were reduced for an increase of 100 g/day of fruit and vegetables combined (HR 0.85; 95% CI 0.76-0.94), while no clear effects were seen for the other histological subtypes. CONCLUSION: We observed inverse associations between the consumption of vegetables and fruits and risk of lung cancer without a clear effect on specific histological subtypes of lung cancer. In current smokers, consumption of vegetables and fruits may reduce lung cancer risk, in particular the risk of squamous cell carcinomas.

Size distribution and total number concentration of ultrafine and accumulation mode particles and hospital admissions in children and the elderly in Copenhagen, Denmark.

OBJECTIVES: To study the association between short-term exposure to ultrafine particles and morbidity in Copenhagen, Denmark. METHODS: We studied the association between urban background levels of the total number concentration of particles (NC(tot), 6-700 nm in diameter) measured at a single site (15 May 2001 to 31 December 2004) and hospital admissions due to cardiovascular (CVD) and respiratory disease (RD) in the elderly (age >or=65 years), and due to asthma in children (age 5-18 years). We examined these associations in the presence of PM(10), PM(2.5) (particulate matter <10 and 2.5 microm in diameter, respectively) and ambient gasses. We utilised data on size distribution to calculate NC(tot) for four modes with median diameters 12, 23, 57 and 212 nm, and NC(100) (number concentration of particles <100 nm in diameter) and examined their associations with health outcomes. We used a time series Poisson generalised additive model adjusted for overdispersion, season, day of the week, public holidays, school holidays, influenza, pollen and meteorology, with up to 5 days' lagged exposure. RESULTS AND CONCLUSIONS: The adverse health effects of particulate matter on CVD and RD hospital admissions in the elderly were mainly mediated by PM(10) and accumulation mode particles with lack of effects for NC(100). For paediatric asthma, accumulation mode particles, NC(100) and nitrogen oxides (mainly from traffic related sources) were relevant, whereas PM(10) appeared to have little effect. Our results suggest that particle volume/mass from long-range transported air pollution is relevant for CVD and RD admissions in the elderly, and possibly particle numbers from traffic sources for paediatric asthma.

Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers.

BACKGROUND: We chose a set of candidate single nucleotide polymorphisms (SNPs) to investigate gene-environment interactions in three types of cancer that have been related to air pollution (lung, bladder and myeloid leukemia). PATIENTS AND METHODS: The study has been conducted as a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (409 cancer cases and 757 matched controls). We included never and ex-smokers. SNPs were in genes involved in oxidative stress, phase I metabolizing genes, phase II metabolizing genes and methylenetetrahydrofolate reductase (MTHFR). RESULTS: The most notable findings are: GSTM1 deletion and bladder cancer risk [odds ratio (OR) = 1.60; 95% confidence interval 1.00-2.56]; CYP1A1 and leukemia (2.22, 1.33-3.70; heterozygotes); CYP1B1 and leukemia (0.47, 0.27-0.84; homozygotes); MnSOD and leukemia (1.91, 1.08-3.38; homozygotes) and NQO1 and lung cancer (8.03, 1.73-37.3; homozygotes). Other statistically significant associations were found in subgroups defined by smoking habits (never or ex-smokers), environmental tobacco smoke or gender, with no obvious pattern. When gene variants were organized according to the three main pathways, the emerging picture was of a strong involvement of combined phase I enzymes in leukemia, with an OR of 5 (1.63-15.4) for those having three or more variant alleles. The association was considerably stronger for leukemias arising before the age of 55.

Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions.

It is becoming increasingly evident that single-locus effects cannot explain complex multifactorial human diseases like cancer. We applied the multi-factor dimensionality reduction (MDR) method to a large cohort study on gene-environment and gene-gene interactions. The study (case-control nested in the EPIC cohort) was established to investigate molecular changes and genetic susceptibility in relation to air pollution and environmental tobacco smoke (ETS) in non-smokers. We have analyzed 757 controls and 409 cases with bladder cancer (n=124), lung cancer (n=116) and myeloid leukemia (n=169). Thirty-six gene variants (DNA repair and metabolic genes) and three environmental exposure variables (measures of air pollution and ETS at home and at work) were analyzed. Interactions were assessed by prediction error percentage and cross-validation consistency (CVC) frequency. For lung cancer, the best model was given by a significant gene-environment association between the base excision repair (BER) XRCC1-Arg399Gln polymorphism, the double-strand break repair (DSBR) BRCA2-Asn372His polymorphism and the exposure variable 'distance from heavy traffic road', an indirect and robust indicator of air pollution (mean prediction error of 26%, P<0.001, mean CVC of 6.60, P=0.02). For bladder cancer, we found a significant 4-loci association between the BER APE1-Asp148Glu polymorphism, the DSBR RAD52-3'-untranslated region (3'-UTR) polymorphism and the metabolic gene polymorphisms COMT-Val158Met and MTHFR-677C>T (mean prediction error of 22%, P<0.001, mean CVC consistency of 7.40, P<0.037). For leukemia, a 3-loci model including RAD52-2259C>T, MnSOD-Ala9Val and CYP1A1-Ile462Val had a minimum prediction error of 31% (P<0.001) and a maximum CVC of 4.40 (P=0.086). The MDR method seems promising, because it provides a limited number of statistically stable interactions; however, the biological interpretation remains to be understood.

Increasing incidence of childhood tumours of the central nervous system in Denmark, 1980-1996.

The registered incidence rate of childhood central nervous system (CNS) tumours has increased in several countries. It is uncertain whether these increases are biologically real or owing to improved diagnostic methods. We explored the medical records of 626 CNS tumours diagnosed in Danish children between 1980 and 1996. Population-based registers were used to extract data on mortality and background population. Temporal patterns were analysed by regression techniques. Most tumours were verified by computed tomography (78%) or magnetic resonance imaging (14%). Overall, the incidence rate increased by 2.9% per year (95% confidence interval (CI): 1.3;4.5) and the mortality rate increased by 1.4% per year (95% CI: -0.4;3.3). Among children aged 0-4 years, the survival rate after diagnosis remained almost unchanged, whereas among children aged 5-14 years, the 10-year survival rate improved from 59 to 74%. These data suggest that the incidence rate of CNS tumours among Danish children has truly increased, although alternative explanations cannot be excluded.

DNA repair polymorphisms and cancer risk in non-smokers in a cohort study.

Environmental carcinogens contained in air pollution, such as polycyclic aromatic hydrocarbons, aromatic amines or N-nitroso compounds, predominantly form DNA adducts but can also generate interstrand cross-links and reactive oxygen species. If unrepaired, such lesions increase the risk of somatic mutations and cancer. Our study investigated the relationships between 22 polymorphisms (and their haplotypes) in 16 DNA repair genes belonging to different repair pathways in 1094 controls and 567 cancer cases (bladder cancer, 131; lung cancer, 134; oral-pharyngeal cancer, 41; laryngeal cancer, 47; leukaemia, 179; death from emphysema and chronic obstructive pulmonary disease, 84). The design was a case-control study nested within a prospective investigation. Among the many comparisons, few polymorphisms were associated with the diseases at the univariate analysis: XRCC1-399 Gln/Gln variant homozygotes [odds ratios (OR) = 2.20, 95% confidence intervals (CI) = 1.16-4.17] and XRCC3-241 Met/Met homozygotes (OR = 0.51, 95% CI = 0.27-0.96) and leukaemia. The recessive model in the stepwise multivariate analysis revealed a possible protective effect of XRCC1-399Gln/Gln in lung cancer (OR = 0.22, 95% CI = 0.05-0.98), and confirmed an opposite effect (OR = 2.47, 95% CI = 1.02-6.02) in the leukaemia group. Our results also suggest that the XPD/ERCC1-GAT haplotype may modulate leukaemia (OR = 1.28, 95% CI = 1.02-1.61), bladder cancer (OR = 1.38, 95% CI = 1.06-1.79) and possibly other cancer risks. Further investigations of the combined effects of polymorphisms within these DNA repair genes, smoking and other risk factors may help to clarify the influence of genetic variation in the carcinogenic process.

Urinary concentrations of trichloroacetic acid in Danish workers exposed to trichloroethylene, 1947-1985.

BACKGROUND: Since 1947, the National Labour Inspection Service in Denmark has relied upon urinary measurements of trichloroacetic acid (TCA) in surveys of the occupational exposure to trichloroethylene (TCE). METHODS: We examined the paper files relating to 2397 TCA measurements to extract information about the year, the company, the work process and the worker. We used multiple regression models to analyze the effects of various factors on the urinary concentration of TCA. RESULTS: The regression analyses showed that (1) a four-fold decrease in TCA concentrations occurred from 1947 to 1985; (2) the highest concentrations were observed in the iron and metal, chemical, and dry cleaning industries; (3) TCA levels were two times higher among men compared with women in the iron and metal and dry cleaning industries; (4) TCA concentrations were higher among younger compared with older workers; and (5) persons working in an area in which TCE was used, but not working with TCE themselves, also showed urinary TCA levels indicative of exposure. CONCLUSIONS: Calendar year, type of industry, degree of contact with TCE, sex and age were predictors of TCA concentration in the urine of Danish workers.

Cancer incidence among Danish workers exposed to trichloroethylene.

Human evidence regarding the carcinogenicity of the animal carcinogen trichloroethylene (TCE) is limited. We evaluated cancer occurrence among 803 Danish workers exposed to TCE, using historical files of individual air and urinary measurements of TCE-exposure. The standardized incidence ratio (SIR) for cancer overall was close to unity for both men and women who were exposed to TCE. Men had significantly elevated SIRs for non-Hodgkin's lymphoma (SIR = 3.5; n = 8) and cancer of the esophagus (SIR = 4.2; n = 6). Among women, the SIR for cervical cancer was significantly increased (SIR = 3.8; n = 4). No clear dose-response relationship appeared for any of these cancers. We found no increased risk for kidney cancer. In summary, we found no overall increase in cancer risk among TCE-exposed workers in Denmark. For those cancer sites where excesses were noted, the small numbers of observed cases and the lack of dose-related effects hinder etiological conclusions.

Air pollution from traffic at the residence of children with cancer.

The hypothesis that exposure to traffic-related air pollution increases the risk of developing cancer during childhood was investigated. The authors enrolled 1,989 children reported to the Danish Cancer Registry with a diagnosis of leukemia, tumor of the central nervous system, or malignant lymphoma during 1968-1991 and 5,506 control children selected at random from the entire childhood population. The residential histories of the children were traced from 9 months before birth until the time of diagnosis of the cases and a similar period for the controls. For each of the 18,440 identified addresses, information on traffic and the configuration of streets and buildings was collected. Average concentrations of benzene and nitrogen dioxide (indicators of traffic-related air pollution) were calculated for the relevant period, and exposures to air pollution during pregnancy and during childhood were calculated separately. The risks of leukemia, central nervous system tumors, and all selected cancers combined were not linked to exposure to benzene or nitrogen dioxide during either period. The risk of lymphomas increased by 25% (p for trend = 0.06) and 51% (p for trend = 0.05) for a doubling of the concentration of benzene and nitrogen dioxide, respectively, during the pregnancy. The association was restricted to Hodgkin's disease.

An air pollution model for use in epidemiological studies: evaluation with measured levels of nitrogen dioxide and benzene.

The aim of the study was to evaluate the predictions derived from the Danish Operational Street Pollution Model (OSPM) when the input data are obtained by simple methods that could be used in large-scale epidemiological studies. The model calculations were thus compared with passive sampler measurements of nitrogen dioxide and benzene at 103 street locations in Copenhagen, Denmark, and at 101 locations in rural areas. Data on traffic and street configuration were collected by means of a simple registration scheme in which forms were filled out by local municipal authorities. Meteorological data were derived from routine measurements at Copenhagen airport, and data on background air pollution were based on a simple empirical model. Differences in air pollution levels between rural areas and Copenhagen and differences in nitrogen dioxide concentrations at various locations in Copenhagen were well reproduced by the OSPM. The correlation coefficients (r) between the measured and the predicted half-year average concentrations of nitrogen dioxide in Copenhagen were between 0.75 and 0.80 for various degrees of precision of the input data for the model. The results indicate that the OSPM used with the presented methods for generation of input data might be useful in assessing long-term exposure to air pollutants in epidemiological studies.

Increased risk of lung cancer among different types of professional drivers in Denmark.

OBJECTIVES: To study risk of lung cancer among groups of professional drivers probably exposed to different levels of traffic exhaust fumes. METHODS: A nationwide case-control study (1970-89) based on employees comprising 28,744 men with primary lung cancer and incidence density sampled matched controls (1:1). Employment histories were reconstructed back to 1964 for each study subject from the records of a nationwide pension scheme with compulsory membership. Socioeconomic status was derived from the individual job title taken from the national population registry. Information on tobacco smoking habits was available from historical surveys. Relative risks were estimated by odds ratios (ORs) based on conditional logistic regression analyses. RESULTS: In total 2251 of the male lung cancer cases had been employed as bus, lorry, taxi, or unspecified drivers. No significant difference in tobacco smoking habits was found among professional male Danish drivers and the total employed population. The OR for lung cancer adjusted for socioeconomic status was 1.6 (95% confidence interval (95% CI) 1.2 to 2.2) among taxi drivers, who were considered to be exposed to the highest concentrations of vehicle exhaust fumes, and 1.3 (1.2 to 1.5) for bus and lorry drivers. The OR was 1.4 (1.3 to 1.5) for unspecified drivers. The adjusted risk of lung cancer increased significantly with increasing duration of employment as a driver, and the risk was highest for long term taxi drivers with 10 years of lag time (OR 3.0; 1.2 to 6.8). CONCLUSION: Occupational factors, probably exposure to vehicle exhaust, seems to play an important part in the development of lung cancer among drivers.

Front-door concentrations and personal exposures of Danish children to nitrogen dioxide.

The aims of the study were to evaluate the front-door concentration of traffic exhaust fumes as a surrogate for the personal exposure of children and to study factors in the behavior and the environment of children that affect their personal exposure to nitrogen dioxide (NO(2)). The exposure to NO(2) of 103 children living in Copenhagen and 101 children living in rural areas of Denmark was studied by measuring average concentrations over 1 week with diffusive badge samplers placed outside the front door of the home, inside the child's bedroom, and on each child. Detailed information about the activities of the children involving potential exposure to NO(2) was noted in diaries. The results indicated that the front-door concentration of traffic pollution might be used to classify the personal exposure of urban children, although misclassification would be introduced. Multiple regression analysis showed several factors that affected the personal NO(2) exposure of the children independently, including the front-door concentration, the bedroom concentration, time spent outdoors, gas appliances used at home, passive smoking, and burning candles.

Ambient air levels and the exposure of children to benzene, toluene, and xylenes in Denmark.

The aims of the study were to evaluate if the front-door concentrations of benzene, toluene, and xylenes can be used to classify the personal exposures of Danish children and to identify factors that affect their personal exposure. Average concentrations were measured over 1 week with diffusive samplers, and the personal exposures of 98 children and the concentrations outside the front doors of their homes were measured simultaneously. Time and activity patterns were noted in diaries. The front-door concentrations were significantly higher in Copenhagen than in rural areas (all P < 0.0001), but the personal exposures were only slightly higher. Even though the personal exposures were highly significantly associated with front-door concentrations in urban areas (all P < 0.004), use of the residential front-door concentration as an exposure surrogate would imply misclassification, as it cannot be used for rural children. Multiple regression analyses brought to light several factors that affect the exposure of children independently, including front-door concentration, riding in cars, and activities involving potential exposure to gasoline vapors like motocross, moped driving, and refueling of cars.

Exposure of Danish children to traffic exhaust fumes.

This exposure study addresses the validity of the exposure assessment method of an epidemiological study of traffic-related air pollution and childhood cancer. In particular, this paper concerns the question of whether the concentration of nitrogen dioxide (NO2) outside the front door is a valid marker of the exposure of the child living at the address. The study includes 100 children living on streets with dense traffic in central parts of Copenhagen and 100 children living in rural areas. Preliminary results, based on 25% of the study subjects, suggest that both the outdoor NO2-concentration and the exposure of the children are two to three times higher in Copenhagen than in the rural districts. Moreover, the results suggest that the NO2-concentration outside the front door is a poor marker of the exposure of the children in Copenhagen, but a marker of some relevance for the exposure of the children in rural districts. The preliminary results must be treated with caution, as among other things, the analysis did not consider seasonal changes and indoor NO2-sources such as passive smoking, candles, and gas appliances.

Traffic-related air pollution: exposure and health effects in Copenhagen street cleaners and cemetery workers.

This questionnaire-based study found a significantly higher prevalence of chronic bronchitis, asthma, and several other symptoms in 116 Copenhagen street cleaners who were exposed to traffic-related air pollution at levels that were slightly lower than the 1987 World Health Organization-recommended threshold values, compared with 115 Copenhagen cemetery workers exposed to lower pollution levels. Logistic regression analysis, controlling for age and smoking, was conducted, and odds ratios and 95% confidence intervals were calculated to be 2.5 for chronic bronchitis (95% confidence interval = 1.2-5.1), 2.3 for asthma (95% confidence interval = 1.0-5.1), and 1.8-7.9 for other symptoms (95% confidence interval = 1.0-28.2). Except for exposure to air pollution, the two groups were comparable, i.e., they had similar terms of employment and working conditions. The exposure ranges during an 8-h work day, averaged from readings taken at five monitored street positions, were: 41-257 ppb nitric oxide (1-h max: 865 ppb); 23-43 ppb nitrogen dioxide (1-h max: 208 ppb); 1.0-4.3 ppm carbon monoxide (8-h max: 7.1 ppm); 14-28 ppb sulfur dioxide (1-h max: 112 ppb); and 10-38 ppb ozone (1-h max: 72 ppb).