Mortality and Morbidity Effects of Long-Term Exposure to Low-Level PM2.5, BC, NO2, and O3: An Analysis of European Cohorts in the ELAPSE Project.

INTRODUCTION: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM2.5, but increasingly associations with nitrogen dioxide (NO2) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO2. Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O3). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM2.5. Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM2.5, NO2, BC, and O3) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM2,5. METHODS: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM2.5, NO2, and O3. We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM2.5, NO2, and O3, and ESCAPE monitoring data for BC and PM2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM2.5 and NO2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM2.5 25 µg/m3 (EU limit value), 20, 15, 12 µg/m3 (U.S. EPA National Ambient Air Quality Standard), and 10 µg/m3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM2.5, we evaluated 10, 7.5, and 5 µg/m3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC). RESULTS: In the pooled cohort, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values (25 µg/m3 and 40 µg/m3, respectively). More than 50,000 had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3). More than 25,000 subjects had a residential PM2.5 exposure below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 µg/m3 PM2.5, 1.09 (CI = 1.07, 1.10) for an increase of 10 µg/m3 NO2, and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10-5/m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM2.5, NO2, and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM2.5 and NO2, the U.S. NAAQS values for PM2.5, and the WHO guidelines for PM2.5 and NO2. The mortality associations were robust to alternative specifications of exposure, including different time periods, PM2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant forPM2.5 and NO2. In two-pollutant models of PM2.5 and NO2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM2.5 and 1.05 (CI = 1.03, 1.07) for NO2. Associations with O3 were attenuated but remained negative in two-pollutant models with NO2, BC, and PM2.5. We found significant positive associations between PM2.5, NO2, and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO2 was significantly related to acute coronary heart disease and PM2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM2.5 below 20 µg/m3 and possibly 12 µg/m3. Associations remained even when NO2 was below 30 µg/m3 and in some cases 20 µg/m3. In two-pollutant models, NO2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM2.5 was not associated with these outcomes in two-pollutant models with NO2. PM2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3) and more than 1.9 million had residential PM2.5 exposures below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 µg/m3 PM2.5, 1.04 (CI = 1.02, 1.07) for an increase of 10 µg/m3 NO2, and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10-5/m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 µg/m3 O3. The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. BC and NO2 remained significantly associated with mortality in two-pollutant models with PM2.5 and O3. The PM2.5 HR attenuated to unity in a two-pollutant model with NO2. The negative O3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM2.5 model did not differ from the MAPLE PM2.5 model on average, but in individual cohorts, substantial differences were found. CONCLUSIONS: Long-term exposure to PM2.5, NO2, and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM2.5 and NO2. Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO2 and PM2.5. We mostly found negative associations with O3. In two-pollutant models with NO2, the negative associations with O3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O3 remained in two-pollutant models. Long-term exposure to PM2.5, NO2, and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM2.5, NO2, and BC. For acute coronary heart disease, an increased HR was observed for NO2. For lung cancer, an increased HR was found only for PM2.5. Associations mostly showed steeper slopes at low exposures with no indication of a threshold.

Possible early prediction of preterm birth by determination of novel proinflammatory factors in midtrimester amniotic fluid.

Interferon-gamma-inducible T cell-alpha chemoattractant (ITAC) is a chemokine, directing activated T lymphocytes toward sites of inflammation. ADAM-8 (A disintegrin and metalloprotease-8) is a glycoprotein expressed in cells promoting inflammation. Elastase, a protease targeting at the degradation of intra- or extracellular proteins, is inhibited by secretory leukocyte proteinase inhibitor (SLPI), which protects against microbial invasion. Adhesion molecules (soluble intercellular adhesion molecule--sICAM-1 and soluble vascular cell adhesion molecule-sVCAM--1) serve as markers of inflammation or tissue damage. We hypothesized that elevated midtrimester amniotic fluid concentrations of above substances, and decreased levels of SLPI could possibly be useful predictors of asymptomatic intra-amniotic inflammation and/or infection, eventually resulting in preterm labor and delivery. The study involved 312 women undergoing midtrimester amniocentesis. Thirteen cases, progressing to preterm delivery (<37 weeks), were matched with 21 controls (delivering >37 weeks) for age, parity, and gestational age at amniocentesis. Amniotic fluid levels of the above substances were measured by enzyme-linked immunosorbent assay (ELISA). Only amniotic fluid ITAC and ADAM-8 levels were significantly higher (P=0.005 and P < 0.02, respectively) in women delivering at <37 weeks than at >37 weeks. SLPI concentrations significantly increased in women going into labor without ruptured membranes irrespective of pre- or term delivery (P < 0.007, P < 0.001, respectively) and correlated with elastase (r=0.508, P < 0.002). In conclusion, elevated midtrimester amniotic fluid levels of ITAC and ADAM-8 could predict occult infections/inflammations, possibly resulting in preterm birth.

Diet during pregnancy and levels of maternal pregnancy hormones in relation to the risk of breast cancer in the offspring.

Birth weight is positively associated with the risk of breast cancer in the offspring and the underlying process is likely to involve the pregnancy endocrine milieu. We have examined the association of diet and related factors during pregnancy with the levels (at the 16th and 27th gestational week) of maternal pregnancy oestradiol, oestriol, sex hormone-binding globulin (SHBG), progesterone and prolactin, in a cohort of 270 Caucasian women who delivered in a major hospital in Boston, USA. Oestradiol and oestriol were not strongly associated with any of the diet-related variables, but SHBG was significantly and consistently related inversely to pre-pregnancy body mass index and weight gain during pregnancy, and positively to vegetable and pulses intake. Pregnancy progesterone was associated positively with alcohol and inversely with polyunsaturated lipid and vitamin B12 intake, whereas pregnancy prolactin was inversely associated with cereal consumption. If the pregnancy hormones studied are indeed involved in the intra-uterine origin of breast cancer, these findings, if confirmed, would focus dietary advice to pregnant women, with a view to reducing the risk of breast cancer in the offspring, towards avoidance of excess energy intake and an emphasis on plant foods. This advice does not contradict current dietary advice on prudent diet during pregnancy and throughout life.

The temporal pattern of respiratory and heart disease mortality in response to air pollution.

Short-term changes in ambient particulate matter with aerodynamic diameters < 10 micro m (PM10) have been associated with short-term fluctuations in mortality or morbidity in many studies. In this study, we tested whether those deaths are just advanced by a few days or weeks using a multicity hierarchical modeling approach for all-cause, respiratory, and cardiovascular deaths, for all ages and stratifying by age groups, within the APHEA-2 (Air Pollution and Health: A European Approach) project. We fit a Poisson regression and used an unconstrained distributed lag to model the effect of PM10 exposure on deaths up to 40 days after the exposure. In baseline models using PM10 the day of and day before the death, we found that the overall PM10 effect (per 10 micro g/m3) was 0.74% [95% confidence interval (95% CI), -0.17 to 1.66] for respiratory deaths and 0.69% (95% CI, 0.31-1.08) for cardiovascular deaths. In unrestricted distributed lag models, the effect estimates increased to 4.2% (95% CI, 1.08-7.42) for respiratory deaths and to 1.97% (95% CI, 1.38-2.55) for cardiovascular deaths. Our study confirms that most of the effect of air pollution is not simply advanced by a few weeks and that effects persist for more than a month after exposure. The effect size estimate for PM10 doubles when we considered longer-term effects for all deaths and for cardiovascular deaths and becomes five times higher for respiratory deaths. We found similar effects when stratifying by age groups. These larger effects are important for risk assessment.

Maternal mortality in Greece, 1996-2006.

OBJECTIVE: To present retrospective data for maternal deaths in Greece from 1996 to 2006. METHODS: Demographic information and information on the causes of death was provided by the Hellenic Statistical Authority. Maternal deaths were assessed by cause of death, maternal age, and place of residence. The maternal mortality ratio (MMR) was estimated and expressed as the number of deaths per 100,000 live births. RESULTS: From 1996 to 2006, 29 deaths were attributed to pregnancy and childbirth, yielding a total MMR of 2.63. The leading cause of direct deaths was hemorrhage and that of indirect deaths was cardiac disease. There was a borderline significant decline in the MMR during the study period. The MMR was significantly higher at the extremes of the reproductive age range. CONCLUSION: Maternal mortality in Greece is low; however, no formal data have been published since 1996. Knowledge of the causes of maternal death can lead to the prevention of maternal deaths and safer motherhood.

Occupational physical activity in relation with prostate cancer and benign prostatic hyperplasia.

Using data from two case-control studies undertaken in Athens, Greece from 1994 to 1997, we have examined the association of occupational physical activity with the risk of prostate cancer and benign prostatic hyperplasia (BPH). Cases consisted of 320 patients with histologically confirmed incident prostate cancer and 184 patients with surgically treated BPH. Controls were 246 patients hospitalized for minor conditions. Occupations before retirement were classified, independently and blindly as to case-control status, into high, medium, and low physical activity levels. After fine controlling for years of schooling, there was a suggestive inverse association of physical activity with prostate cancer (P for trend 0.12) and a significant one with BPH (P for trend 0.04). The odds ratio (95% confidence interval) for high versus low activity was 0.69 (0.40-1.22) for prostate cancer and 0.59 (0.31-1.11) for BPH. The association of physical activity with both conditions tended to be more pronounced among men 65 years old or younger. Given the high frequency of occurrence of the examined conditions in the male population and our limited knowledge about other modifiable risk factors, preventive measures may have to focus on increasing physical activity.

Elevated second trimester amniotic fluid interferon gamma-inducible T-cell alpha chemoattractant concentrations as a possible predictor of preterm birth.

OBJECTIVE: To determine and correlate midtrimester amniotic fluid concentrations of interferon gamma-inducible T-cell alpha chemoattractant (ITAC, a chemokine directing the migration of activated T lymphocytes toward inflammation sites) and C-reactive protein (CRP) in women undergoing amniocentesis and subsequently delivering pre-or full-term infants. METHODS: Among 312 women undergoing midtrimester transabdominal amniocentesis, 13 progressed to spontaneous delivery at less than 37 gestational weeks (GW). Subjects were matched for maternal age, parity, and GW at amniocentesis with 21 controls who delivered at greater than 37 GW. Amniotic fluid ITAC and CRP levels were determined by enzyme-linked immunosorbent assay (ELISA) and by nephelometry, respectively. RESULTS: Both ITAC and CRP values were significantly higher (P = .005 and P = .04, respectively) in the amniotic fluid of women delivering at less than 37 GW. A statistically significant correlation between amniotic fluid ITAC and CRP concentrations was also found (r = .366, P < .05). The receiver operator curve (ROC) analysis of delivery at less than 37 GW gave the best cutoff point for ITAC at a concentration of 44 pg/mL and for CRP at a concentration of 0.16 mg/dL. Positive and negative predictive values for ITAC were 82% and 85%, respectively, and for CRP, 55% and 76%, respectively. CONCLUSIONS: Present data indicate that from the second trimester of pregnancy elevated amniotic fluid concentrations of ITAC are found in women delivering at less than 37 GW, as compared to women delivering at term. Therefore, ITAC in combination with other cytokines or CRP could possibly serve as predictor of preterm delivery.

Investigation of midtrimester amniotic fluid factors as potential predictors of term and preterm deliveries.

AIMS: Our aim is to investigate, in 13 cases (delivering preterm) and 21 matched (for age, parity, and gestational age) controls (delivering at term), whether midtrimester amniotic fluid concentrations of elastase, secretory leukocyte proteinase inhibitor (SLPI), soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule predict asymptomatic intra-amniotic inflammation/infection and preterm labor. RESULTS: Concentrations of all substances were not statistically different among mothers, delivering preterm or at term. SLPI concentrations significantly increased in women, going into labor without ruptured membranes, irrespective of pre- or term delivery (P < .007, P < .001, resp) and correlated with elastase (r = 0.508, P < .002). CONCLUSIONS: Midtrimester amniotic fluid SLPI concentrations significantly decrease when membrane rupture precedes pre- or full-term labor. However, none of the investigated substances predict preterm delivery.

Elevated mid-trimester amniotic fluid ADAM-8 concentrations as a potential risk factor for preterm delivery.

OBJECTIVE: To determine during mid-trimester amniocentesis if elevated concentrations of ADAM-8 (A Disintegrin And Metalloprotease 8) and/or cortisol can recognize women at risk for spontaneous preterm delivery. METHODS: The study involved 312 women who underwent mid-trimester amniocentesis. Thirteen patients, who progressed to preterm delivery, were matched with 21 controls for age, parity, gestational age at amniocentesis, and year of amniocentesis. ADAM-8 and cortisol levels were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. RESULTS: ADAM-8 mean amniotic fluid concentrations were significantly higher in women with preterm delivery than in women delivering at term (mean 1213.9 [SE 96.7] pg/mL [range, 780 to 1854 pg/mL] vs mean 937.2 [SE 50.3] pg/mL [range, 486 to 1508 pg/mL], P < .02). Amniotic fluid ADAM-8 concentrations higher than 1149 pg/mL had the highest specificity and odds ratio (OR) in the identification of the women with increased risk for preterm delivery (sensitivity 61.5%; specificity 81.7%; OR, 9.6 [95% confidence interval (CI), 1.8 to 50.3]). Women with preterm delivery had suggestively higher amniotic fluid concentrations of cortisol (mean 1.3 [SE 0.2] microg/dL [range, 0.4 to 2.2 microg/dL]) than women delivering at term (mean 1.0 [SE 0.09] microg/dL [range, 0.6 to 1.7 microg/dL], P < .07). Furthermore, cortisol levels were positively correlated with ADAM-8 levels (Spearman's r = .418, P < .014). CONCLUSIONS: Elevated mid-trimester amniotic fluid ADAM-8 concentrations possibly are a risk factor for preterm delivery, particularly if ADAM-8 levels are greater than 1149 pg/mL. Potential intrauterine inflammation is also associated with suggestively increased amniotic fluid cortisol levels.

Maternal height, pregnancy estriol and birth weight in reference to breast cancer risk in Boston and Shanghai.

Birth weight has been positively associated with breast cancer risk in adult life and is positively associated with the principal pregnancy estrogen estriol. Birth weight is lower among Chinese women than among Caucasian women, but paradoxically, pregnancy estriol levels are higher among the former than the latter. We studied a cohort of 317 Caucasian pregnant women in Boston, MA, and 339 Chinese pregnant women in Shanghai, China. We investigated whether maternal height, which is inversely associated with pregnancy estriol levels, interacts with this hormone in relation to birth weight, thus accommodating the apparently contradictory ecologic and analytic evidence concerning the role of pregnancy estrogens on breast cancer risk in the offspring. In both Boston and Shanghai, there was a positive association of pregnancy estriol with birth weight among taller women, whereas among shorter women the association was essentially null. The relevant interaction terms were highly significant in Boston (p approximately 0.006), whereas in Shanghai, where pregnant women were generally shorter, the interaction term was suggestive (p approximately 0.14). We conclude that maternal height should be considered an important risk factor for breast cancer in the offspring since it is a crucial determinant of birth weight, both directly and through positive interaction with the principal pregnancy estrogen estriol.

Flavonoid intake in relation to lung cancer risk: case-control study among women in Greece.

We have examined the role of three classes of flavonoids that are relatively common in the Greek diet (flavanones, flavan-3-ols, and flavonols) in the etiology of lung cancer using data from a case-control study among women, which was undertaken in Athens, Greece, in the late 1980s. Study subjects were 154 women with lung cancer and 145 control women with orthopedic conditions. Women reported their life-long smoking histories and average frequency of consumption, before onset of present disease, of 47 food items or beverages that collectively covered >80% of the intake of each of the energy-providing nutrients. Intakes of flavonoids were calculated using the recently published U.S. Department of Agriculture database. The data were modeled through logistic regression, controlling for energy intake and smoking. There was no indication that intake of any of the studied flavonoid categories reduces the risk of lung cancer; indeed, for flavonols there was an unexpected positive association. Thus, our study does not indicate a protective effect of flavanones, flavan-3-ols, or flavonols on lung cancer risk and indicates that the factors responsible for the protective effect of vegetables and fruits against the risk of this cancer are unlikely to belong to these flavonoid categories.

The temporal pattern of mortality responses to air pollution: a multicity assessment of mortality displacement.

Although the association between particulate matter and mortality or morbidity is generally accepted, controversy remains about the importance of the association. If it is due solely to the deaths of frail individuals, which are brought forward by only a brief period of time, the public health implications of the association are fewer than if there is an increase in the number of deaths. Recently, other research has addressed the mortality displacement issue in single-city analysis. We analyzed this issue with a distributed lag model in a multicity hierarchic modeling approach, within the Air Pollution and Health: A European Approach (APHEA-2) study. We fit a Poisson regression model and a polynomial distributed lag model with up to 40 days of delay in each city. In the second stage we combined the city-specific results. We found that the overall effect of particulate matter less than 10 microM in aerodynamic diameter (PM10) per 10 microg/m3 for the fourth-degree distributed lag model is a 1.61% increase in daily deaths (95% CI = 1.02-2.20), whereas the mean of PM10 on the same day and the previous day is associated with only a 0.70% increase in deaths (95% CI = 0.43-0.97). This result is unchanged using an unconstrained distributed lag model. Our study confirms that the effects observed in daily time-series studies are not due primarily to short-term mortality displacement. The effect size estimate for airborne particles more than doubles when we consider longer-term effects, which has important implications for risk assessment.