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1.  Thyroid cancer risk and dietary nitrate and nitrite intake in the Shanghai Women’s Health Study 
Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds and nitrate can disrupt thyroid homeostasis by inhibiting iodide uptake. We evaluated nitrate and nitrite intake and risk of thyroid cancer in the Shanghai Women’s Health Study that included 73,317 women, aged 40–70 years enrolled in 1996–2000. Dietary intake was assessed at baseline using a food frequency questionnaire. During approximately 11 years of follow-up, 164 incident thyroid cancer cases with complete dietary information were identified. We used Cox proportional hazards regression to estimate relatives risks (RRs). We determined the nitrate and nitrite contents of foods using values from the published literature and focusing on regional values for Chinese foods. Nitrate intake was not associated with thyroid cancer risk (RRQ4 = 0.93; 95%CI: 0.42–2.07; p for trend = 0.40). Compared with the lowest quartile, women with the highest dietary nitrite intake had about a two-fold risk of thyroid cancer (RRQ4 = 2.05; 95%CI: 1.20–3.51;) but there was not a monotonic trend with increasing intake (p for trend= 0.36). The trend with increasing nitrite intake from animal sources was significant (p for trend = 0.02) and was stronger for nitrite from processed meats (RRQ4 = 1.96; 95%CI: 1.28–2.99; p for trend <0.01). Although we did not observe an association for nitrate as hypothesized, our results suggest that women consuming higher levels of nitrite from animal sources, particularly from processed meat, may have an increased risk of thyroid cancer.
PMCID: PMC3443521  PMID: 22674227
2.  Farm residence and lymphohematopoietic cancers in the Iowa Women’s Health Study 
Environmental research  2014;133:353-361.
Cancer incidence in male farmers has been studied extensively; however, less is known about risk among women residing on farms or in agricultural areas, who may be exposed to pesticides by their proximity to crop fields. We extended a previous follow-up of the Iowa Women’s Health Study cohort to examine farm residence and the incidence of lymphohematopoietic cancers. Further, we investigated crop acreage within 750 m of residences, which has been associated with higher herbicide levels in Iowa homes.
We analyzed data for a cohort of 37,099 Iowa women aged 55–69 years who reported their residence location (farm, rural (not a farm), town size based on population) at enrollment in 1986. We identified incident lymphohematopoietic cancers (1986–2009) by linkage with the Iowa Cancer Registry. Using a geographic information system, we geocoded addresses and calculated acreage of pasture and row crops within 750 m of homes using the 1992 National Land Cover Database. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariate analyses of cancer risk in relation to both residence location and crop acreage.
As found in an earlier analysis of residence location, risk of acute myeloid leukemia (AML) was higher among women living on farms (HR= 2.23, 95%CI: 1.25–3.99) or rural areas (but not on a farm) (HR= 1.95, 95%CI: 0.89–4.29) compared with women living in towns of > 10,000 population. We observed no association between farm or rural residence and non-Hodgkin lymphoma (NHL; overall or for major subtypes) or multiple myeloma. In analyses of crop acreage, we observed no association between pasture or row crop acreage within 750 m of homes and risk of leukemia overall or for the AML subtype. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) risk was nonsignificantly elevated among women with pasture acreage within 750 m of their home (HRs for increasing tertiles= 1.8, 1.8 and 1.5) and with row crop acreage within 750 m (HRs for increasing tertiles of acreage= 1.4, 1.5 and 1.6) compared to women with no pasture or row crop acreage, respectively.
Iowa women living on a farm or in a rural area were at increased risk of developing AML, which was not related to crop acreage near the home. Living near pasture or row crops may confer an increased risk of CLL/SLL regardless of residence location. Further investigation of specific farm-related exposures and these cancers among women living on farms and in agricultural areas is warranted.
PMCID: PMC4324553  PMID: 25038451
Farm residence; Pesticides; Iowa Women’s Health Study; GIS; Land use
3.  Heme iron from meat and risk of adenocarcinoma of the esophagus and stomach 
Iron can cause oxidative stress and DNA damage, and heme iron can catalyze endogenous formation of N-nitroso compounds, which are potent carcinogens. Dietary iron promotes esophageal cancer incidence in animal studies and has been identified as a growth factor for Helicobacter pylori, an established risk factor for stomach cancer.
We conducted a population-based case-control study of adenocarcinoma of the esophagus (n=124) and stomach (n=154) and 449 controls in Nebraska. Heme iron and total iron intake were estimated from a food-frequency questionnaire and databases of heme and total iron. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for known risk factors.
Esophageal cancer was positively associated with higher intakes of heme iron (ORQ4 vs. Q1 =3.04, 95% CI 1.20–7.72; p-trend=0.009) and total iron from meat sources (ORQ4 vs. Q1 =2.67, 95% CI 0.99–7.16; p-trend=0.050). Risk of stomach cancer was elevated among those with higher intakes of heme iron (ORQ4vs.Q1=1.99, 95% CI 1.00–3.95, p-trend=0.17) and total iron from meat (OR=2.26, 95% CI 1.14–4.46; p-trend=0.11). Iron intake from all dietary sources was not significantly associated with risk of either cancer.
Our results suggest that high intakes of heme and iron from meat may be important dietary risk factors for esophageal and stomach cancer and may partly explain associations with red meat.
PMCID: PMC3261306  PMID: 22044848
Iron; heme iron; nutrition; esophageal cancer; stomach cancer
4.  Accuracy of residential geocoding in the Agricultural Health Study 
Environmental exposure assessments often require a study participant’s residential location, but the positional accuracy of geocoding varies by method and the rural status of an address. We evaluated geocoding error in the Agricultural Health Study (AHS), a cohort of pesticide applicators and their spouses in Iowa and North Carolina, U.S.A.
For 5,064 AHS addresses in Iowa, we compared rooftop coordinates as a gold standard to two alternate locations: 1) E911 locations (intersection of the private and public road), and 2) geocodes generated by matching addresses to a commercial street database (NAVTEQ) or placed manually. Positional error (distance in meters (m) from the rooftop) was assessed overall and separately for addresses inside (non-rural) or outside town boundaries (rural). We estimated the sensitivity and specificity of proximity-based exposures (crops, animal feeding operations (AFOs)) and the attenuation in odds ratios (ORs) for a hypothetical nested case–control study. We also evaluated geocoding errors within two AHS subcohorts in Iowa and North Carolina by comparing them to GPS points taken at residences.
Nearly two-thirds of the addresses represented rural locations. Compared to the rooftop gold standard, E911 locations were more accurate overall than address-matched geocodes (median error 39 and 90 m, respectively). Rural addresses generally had greater error than non-rural addresses, although errors were smaller for E911 locations. For highly prevalent crops within 500 m (>97% of homes), sensitivity was >95% using both data sources; however, lower specificities with address-matched geocodes (more common for rural addresses) led to substantial attenuation of ORs (e.g., corn <500 m ORobs = 1.47 vs. ORtrue = 2.0). Error in the address-matched geocodes resulted in even greater ORobs attenuation for AFO exposures. Errors for North Carolina addresses were generally smaller than those in Iowa.
Geocoding error can be minimized when known coordinates are available to test alternative data and methods. Our assessment suggests that where E911 locations are available, they offer an improvement upon address-matched geocodes for rural addresses. Exposure misclassification resulting from positional error is dependent on the geographic database, geocoding method, and the prevalence of exposure.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-072X-13-37) contains supplementary material, which is available to authorized users.
PMCID: PMC4203975  PMID: 25292160
Geocoding; Positional error; Rural location; Environmental exposure assessment; Accuracy
5.  Residential Levels of Polybrominated Diphenyl Ethers and Risk of Childhood Acute Lymphoblastic Leukemia in California 
Environmental Health Perspectives  2014;122(10):1110-1116.
Background: House dust is a major source of exposure to polybrominated diphenyl ethers (PBDEs), which are found at high levels in U.S. homes.
Methods: We studied 167 acute lymphoblastic leukemia (ALL) cases 0–7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity from the Northern California Childhood Leukemia Study. In 2001–2007, we sampled carpets in the room where the child spent the most time while awake; we used a high-volume small-surface sampler or we took dust from the home vacuum. We measured concentrations of 14 PBDE congeners including penta (28, 47, 99, 100, 153, 154), octa (183, 196, 197, 203), and decaBDEs (206–209). Odds ratios (ORs) were calculated using logistic regression, adjusting for demographics, income, year of dust collection, and sampling method.
Results: BDE-47, BDE-99, and BDE-209 were found at the highest concentrations (medians, 1,173, 1,579, and 938 ng/g, respectively). Comparing the highest to lowest quartile, we found no association with ALL for summed pentaBDEs (OR = 0.7; 95% CI: 0.4, 1.3), octaBDEs (OR = 1.3; 95% CI: 0.7, 2.3), or decaBDEs (OR = 1.0; 95% CI: 0.6, 1.8). Comparing homes in the highest concentration (nanograms per gram) tertile to those with no detections, we observed significantly increased ALL risk for BDE-196 (OR = 2.1; 95% CI: 1.1, 3.8), BDE-203 (OR = 2.0; 95% CI: 1.1, 3.6), BDE-206 (OR = 2.1; 95% CI: 1.1, 3.9), and BDE-207 (OR = 2.0; 95% CI: 1.03, 3.8).
Conclusion: We found no association with ALL for common PBDEs, but we observed positive associations for specific octa and nonaBDEs. Additional studies with repeated sampling and biological measures would be informative.
Citation: Ward MH, Colt JS, Deziel NC, Whitehead TP, Reynolds P, Gunier RB, Nishioka M, Dahl GV, Rappaport SM, Buffler PA, Metayer C. 2014. Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California. Environ Health Perspect 122:1110–1116;
PMCID: PMC4181922  PMID: 24911217
6.  Environmental determinants of polychlorinated biphenyl concentrations in residential carpet dust 
Environmental science & technology  2013;47(18):10405-10414.
Polychlorinated biphenyls (PCBs), banned in the United Sates in the late 1970s, are still found in indoor and outdoor environments. Little is known about the determinants of PCB levels in homes. We measured concentrations of 5 PCB congeners (105, 138, 153, 170, 180) in carpet dust collected between 1998–2000 from 1,187 homes in four sites: Detroit, Iowa, Los Angeles, and Seattle. Home characteristics, occupational history, and demographic information were obtained by interview. We used a geographic information system to geocode addresses and determine distances to the nearest major road, freight route, and railroad, percentage of developed land, number of industrial facilities within 2 km of residences, and population density. Ordinal logistic regression was used to estimate the associations between the covariates of interest and the odds of PCB detection in each site separately. Total PCBs levels (all congeners < maximum practical quantitation limit [MPQL] vs. at least one congener ≥ MPQL to < median concentration vs. at least one congener >median concentration) were positively associated with either percentage of developed land (ORrange: 1.01-1.04 for each percentage increase) or population density (OR: 1.08 for every 1,000/mi2) in each site. The number of industrial facilities within 2 km of a home was associated with PCB concentrations; however, facility type and the direction of the association varied by site. Our findings suggest that outdoor sources of PCBs may be significant determinants of indoor concentrations.
PMCID: PMC4076890  PMID: 23952055
7.  Reliability of Maternal-Reports Regarding the Use of Household Pesticides: Experience from a Case-Control Study of Childhood Leukemia 
Cancer epidemiology  2012;36(4):375-380.
Self-reported household pesticide use has been associated with higher risk of childhood leukemia in a number of case-control studies. The aim of this study is to assess the reliability of self-reported household use of pesticides and potential differences in reliability by case-control status, and by socio-demographic characteristics.
Analyses are based on a subset of the Northern California Childhood Leukemia Study population. Eligible households included those with children less than 8 years old who lived in the same residence since diagnosis (reference date for controls). The reliability was based on two repeated in-person interviews. Kappa, percent positive and negative agreements were used to assess reliability of responses to ever/never use of six pesticides categories.
Kappa statistics ranged from 0.31 to 0.61 (fair to substantial agreement), with 9 out of the 12 tests indicating moderate agreement. The percent positive agreement ranged from 46–80% and the percent negative agreement from 54–95%. Reliability for all pesticide types as assessed by the three reliability measures did not differ significantly for cases and controls as confirmed by bootstrap analysis. For most pesticide types, Kappa and percent positive agreement were higher for non-Hispanics than Hispanics and for households with higher income versus lower income.
Reproducibility of maternal-reported pesticide use was moderate to high and was similar among cases and controls suggesting that differential recall is not likely to be a major source of bias.
PMCID: PMC4140525  PMID: 22277328
reliability; case-control study; leukemia; recall bias
8.  Follicular Thyroid Cancer Incidence Patterns in the United States, 1980–2009 
Thyroid  2013;23(8):1015-1021.
The increases in thyroid cancer overall and in the predominant papillary type have been well documented, but trends for follicular thyroid cancer, a less common but more aggressive variant, have not been as well characterized. In this study, we determined the incidence patterns for follicular thyroid cancer and compared trends between the follicular and papillary thyroid cancers in the United States.
We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program to examine incidence in the United States during 1980–2009, stratified by demographic and tumor characteristics. Incidence rates (IR) were calculated, relative risks were expressed as incidence rate ratios (IRR), and temporal trends were expressed as percentage changes and plotted.
Overall we observed a modest increase in age-adjusted follicular thyroid cancer rates among women (31.89%) and men (35.88%). Rates increased most dramatically for regional stage tumors compared to localized tumors in women, whereas the rates for all tumor sizes rose. These findings reveal increases in more aggressive tumors in women in addition to small and localized tumors. The trends for males were different from those among females. Among males, the largest increase was observed for regional and smaller size tumors. The papillary-to-follicular IRR overall was 7.07 [95% confidence interval 6.91–7.24], which varied from 7.37 among Whites to 3.86 among Blacks (SEER race/ethnicity categories), and increased significantly from 3.98 during 1980–1984 to 9.88 during 2005–2009.
The different trends for follicular and papillary types of thyroid cancer illustrate that thyroid cancer is a heterogeneous disease. Our results do not support the hypothesis that increasing thyroid cancer rates are largely due to improvements in detection, and suggest the importance of evaluating thyroid cancer types separately in future studies.
PMCID: PMC3752506  PMID: 23360496
9.  A Case-Control Study of Occupational Exposure to Metalworking Fluids and Bladder Cancer Risk Among Men 
Metalworking has been associated with an excess risk of bladder cancer in over 20 studies. Metalworking fluids (MWFs) are suspected as the responsible exposure, but epidemiologic data are limited. We investigated this association among men in the New England Bladder Cancer Study using state-of-the-art, quantitative exposure assessment methods.
Cases (n=895) and population controls (n=1,031) provided occupational histories during personal interviews. For selected jobs, exposure-oriented modules were administered to collect information on use of three MWF types: (1) straight (mineral oil, additives), (2) soluble (mineral oil, water, additives), and (3) synthetic (water, organics, additives) or semi-synthetic (hybrid of soluble and synthetic). We computed odds ratios (ORs) and 95% confidence intervals (CIs) relating bladder cancer risk to a variety of exposure metrics, adjusting for smoking and other factors. Non-metalworkers who had held jobs with possible exposure to mineral oil were analyzed separately.
Bladder cancer risk was elevated among men who reported using straight MWFs (OR=1.7, 95% CI=1.1–2.8); risk increased monotonically with increasing cumulative exposure (p=0.041). Use of soluble MWFs was associated with a 50% increased risk (95% CI=0.96–2.5). ORs were nonsignificantly elevated for synthetic/semi-synthetic MWFs based on a small number of exposed men. Non-metalworkers holding jobs with possible exposure to mineral oil had a 40% increased risk (95% CI=1.1–1.8).
Exposure to straight MWFs was associated with a significantly increased bladder cancer risk, as was employment in non-metalworking jobs with possible exposure to mineral oil. These findings strengthen prior evidence for mineral oil as a bladder carcinogen.
PMCID: PMC4116153  PMID: 25018457
10.  Long-Term Exposure to Fine Particulate Matter: Association with Nonaccidental and Cardiovascular Mortality in the Agricultural Health Study Cohort 
Environmental Health Perspectives  2014;122(6):609-615.
Background: Few studies have examined the relationship between long-term exposure to ambient fine particulate matter (PM2.5) and nonaccidental mortality in rural populations.
Objective: We examined the relationship between PM2.5 and nonaccidental and cardiovascular mortality in the U.S. Agricultural Health Study cohort.
Methods: The cohort (n = 83,378) included farmers, their spouses, and commercial pesticide applicators residing primarily in Iowa and North Carolina. Deaths occurring between enrollment (1993–1997) and 30 December 2009 were identified by record linkage. Six-year average (2001–2006) remote-sensing derived estimates of PM2.5 were assigned to participants’ residences at enrollment, and Cox proportional hazards models were used to estimate hazard ratios (HR) in relation to a 10-μg/m3 increase in PM2.5 adjusted for individual-level covariates.
Results: In total, 5,931 nonaccidental and 1,967 cardiovascular deaths occurred over a median follow-up time of 13.9 years. PM2.5 was not associated with nonaccidental mortality in the cohort as a whole (HR = 0.95; 95% CI: 0.76, 1.20), but consistent inverse relationships were observed among women. Positive associations were observed between ambient PM2.5 and cardiovascular mortality among men, and these associations were strongest among men who did not move from their enrollment address (HR = 1.63; 95% 0.94, 2.84). In particular, cardiovascular mortality risk in men was significantly increased when analyses were limited to nonmoving participants with the most precise exposure geocoding (HR = 1.87; 95% CI: 1.04, 3.36).
Conclusions: Rural PM2.5 may be associated with cardiovascular mortality in men; however, similar associations were not observed among women. Further evaluation is required to explore these sex differences.
Citation: Weichenthal S, Villeneuve PJ, Burnett RT, van Donkelaar A, Martin RV, Jones RR, DellaValle CT, Sandler DP, Ward MH, Hoppin JA. 2014. Long-term exposure to fine particulate matter: association with nonaccidental and cardiovascular mortality in the Agricultural Health Study Cohort. Environ Health Perspect 122:609–615;
PMCID: PMC4050514  PMID: 24633320
11.  Dietary flavonoid intake and non-Hodgkin lymphoma risk 
The role of dietary factors in non-Hodgkin lymphoma (NHL) risk is not yet well understood. Dietary flavonoids are polyphenolic compounds proposed to be anticarcinogenic. Flavonoids are well-characterized antioxidants and metal chelators, and certain flavonoids exhibit antiproliferative and antiestrogenic effects.
We aimed to evaluate the hypothesis that higher flavonoid intake is associated with lower NHL risk.
During 1998–2000, we identified incident NHL cases aged 20–74 y from 4 US Surveillance, Epidemiology, and End Results cancer registries. Controls without history of NHL were selected by random-digit dialing or from Medicare files and frequency-matched to cases by age, center, race, and sex. Using 3 recently developed US Department of Agriculture nutrient-specific databases, flavonoid intake was estimated from participant responses to a 117-item food-frequency questionnaire (n = 466 cases and 390 controls). NHL risk in relation to flavonoid intake in quartiles was evaluated after adjustment for age, sex, registry, education, NHL family history, and energy intake.
Higher total flavonoid intake was significantly associated with lower risk of NHL (P for trend < 0.01): a 47% lower risk in the highest quartile of intake than in the lowest (95% CI: 31%, 73%). Higher intakes of flavonols, epicatechins, anthocyanidins, and proanthocyanidins were each significantly associated with decreased NHL risk. Similar patterns of risk were observed for the major NHL subtypes—diffuse large B-cell lymphoma (n = 167) and follicular lymphoma (n = 146).
A higher intake of flavonoids, dietary components with several putative anticarcinogenic activities, may be associated with lower NHL risk.
PMCID: PMC3971470  PMID: 18469269
12.  Household endotoxin levels and the risk of non-Hodgkin lymphoma 
Cancer causes & control : CCC  2013;24(2):357-364.
Endotoxin, a component of the outer membrane of gram-negative bacteria, elicits a strong innate and inflammatory immune response associated with secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α). Because TNF-α polymorphisms that increase TNF-α production are associated with an increased risk of non-Hodgkin lymphoma (NHL), we hypothesized that increased levels of household endotoxin would be associated with an increased NHL risk.
We evaluated this association in the National Cancer Institute/Surveillance, Epidemiology and End Result (NCI/SEER) NHL multi-center population-based case-control study. Used vacuum cleaner bags were collected from participants during a home interview. Dust samples from the bags of 594 cases and 442 controls were analyzed for endotoxin (Endotoxin Unit [EU]/mg of dust) using the kinetic chromogenic Limulus amebocyte lysate assay. Multivariable logistic regression was used to estimate the effect of endotoxin on NHL risk adjusted for age, sex, race, education, study center, and farm exposure.
Endotoxin was not associated with NHL overall (odds ratio [OR] for highest quartile of endotoxin levels = 0.81, 95% confidence interval [CI]= 0.55,1.20; P for trend=0.35), or with diffuse large B-cell lymphoma (OR= 0.63, 95% CI= 0.34, 1.16; P= 0.31) or follicular lymphoma (OR= 0.1.07, 95% CI=0.61, 1.89; P=0.73) subtypes. Both working and living on a farm were associated with higher household endotoxin levels compared to never working (P=0.009) or living (P=0.01) on a farm. Excluding farmers from the analysis did not change the results.
We found no evidence of a role for household endotoxin in NHL etiology.
PMCID: PMC3800025  PMID: 23277417
Endotoxin; Non-Hodgkin lymphoma; Epidemiology; Farming; Risk; Case-control
13.  Nitrate Intake and the Risk of Thyroid Cancer and Thyroid Disease 
Epidemiology (Cambridge, Mass.)  2010;21(3):389-395.
Nitrate is a contaminant of drinking water in agricultural areas and is found at high levels in some vegetables. Nitrate competes with uptake of iodide by the thyroid, thus potentially affecting thyroid function.
We investigated the association of nitrate intake from public water supplies and diet with the risk of thyroid cancer and self-reported hypothyroidism and hyperthyroidism in a cohort of 21,977 older women in Iowa who were enrolled in 1986 and who had used the same water supply for >10 years. We estimated nitrate ingestion from drinking water using a public database of nitrate measurements (1955–1988). Dietary nitrate intake was estimated using a food frequency questionnaire and levels from the published literature. Cancer incidence was determined through 2004.
We found an increased risk of thyroid cancer with higher average nitrate levels in public water supplies and with longer consumption of water exceeding 5 mg/L nitrate-N (for ≤5 years at >5 mg/L, relative risk [RR] = 2.6 [95% confidence interval (CI) = 1.1–6.2]). We observed no association with prevalence of hypothyroidism or hyperthyroidism. Increasing intake of dietary nitrate was associated with an increased risk of thyroid cancer (highest vs. lowest quartile, RR = 2.9 [1.0–8.1]; P for trend = 0.046) and with the prevalence of hypothyroidism (odds ratio = 1.2 [95% CI = 1.1–1.4]), but not hyperthyroidism.
Nitrate may play a role in the etiology of thyroid cancer and warrants further study.
PMCID: PMC2879161  PMID: 20335813
14.  Performance of cancer cluster Q-statistics for case-control residential histories 
Few investigations of health event clustering have evaluated residential mobility, though causative exposures for chronic diseases such as cancer often occur long before diagnosis. Recently developed Q-statistics incorporate human mobility into disease cluster investigations by quantifying space- and time-dependent nearest neighbor relationships. Using residential histories from two cancer case-control studies, we created simulated clusters to examine Q-statistic performance. Results suggest the intersection of cases with significant clustering over their life course, Qi, with cases who are constituents of significant local clusters at given times, Qit, yielded the best performance, which improved with increasing cluster size. Upon comparison, a larger proportion of true positives were detected with Kulldorf’s spatial scan method if the time of clustering was provided. We recommend using Q-statistics to identify when and where clustering may have occurred, followed by the scan method to localize the candidate clusters. Future work should investigate the generalizability of these findings.
PMCID: PMC3582034  PMID: 23149326
Geographic information systems; Residential mobility; Space–time clustering
15.  Impaired lung function and lung cancer incidence in a cohort of Swedish construction workers 
Thorax  2006;62(1):51-56.
Although impaired lung function in general has been associated with an increased risk of lung cancer, past studies typically have not attempted to investigate separately the obstructive and restrictive components of respiratory impairment. To deal with this question further, data from a large (n = 176 997) cohort of male Swedish construction workers, for whom spirometry measurements before follow‐up were available, were analysed.
Cancer incidence for 1971–2001 was obtained through linkage with the national cancer registry. Using a modification of the Global Initiative for Chronic Obstructive Lung Disease criteria for chronic obstructive pulmonary disease (COPD), subjects were classified into five categories of lung function: normal, mild COPD, moderate COPD, severe COPD and restrictive lung disease (RLD). Rate ratios (RR) and 95% confidence intervals (CI) for lung cancer across lung function categories were calculated using Poisson regression, adjusted for age and smoking. Other end points (histological types of lung cancer, non‐lung tobacco‐related cancers, other cancers, total mortality) were also investigated.
834 incident cases of lung cancer were identified. Increased rates of lung cancer were observed for both COPD (mild: RR 1.5, 95% CI 1.2 to 1.9; moderate/severe: RR 2.2, 95% CI 1.8 to 2.7) and RLD (RR 2.0, 95% CI 1.6 to 2.5) relative to normal lung function. These associations did not meaningfully change on applying follow‐up lag times of 5, 10 and 15 years after spirometry. When analysed by histological type, associations with both COPD and RLD were stronger for squamous cell carcinoma and small cell carcinoma, and weaker for adenocarcinoma. Both COPD and RLD were associated with increased rates of total mortality.
Obstructive and restrictive impairments in lung function are associated with increased lung cancer risk.
PMCID: PMC2111275  PMID: 16928722
16.  Adenocarcinoma of the Stomach and Esophagus and Drinking Water and Dietary Sources of Nitrate and Nitrite 
We conducted a population-based case-control study of adenocarcinoma of the stomach and esophagus in Nebraska, U.S.A. Nitrate concentrations in public drinking water supplies were linked to residential water source histories. Among those using private wells at the time of the interview, we measured nitrate levels in water samples from wells. Dietary nitrate and nitrite were estimated from a food-frequency questionnaire. Among those who primarily used public water supplies (79 distal stomach, 84 esophagus, 321 controls), average nitrate levels were not associated with risk (highest versus lowest quartile: stomach OR=1.2, 95% CI [0.5–2.7]; esophagus OR=1.3, 95% CI [0.6–3.1]). We observed the highest ORs for distal stomach cancer among those with higher water nitrate ingestion and higher intake of processed meat compared with low intakes of both; however, the test for positive interaction was not significant (p=0.213). We did not observe this pattern for esophagus cancer. Increasing intake of nitrate and nitrite from animal sources was associated with elevated ORs for stomach cancer and with a significant positive trend in risk of esophagus cancer (P-trend=0.325 and 0.015, respectively). Larger studies with higher exposures to drinking water sources of nitrate are warranted to further evaluate N-nitroso compound precursors as risk factors for these cancers.
PMCID: PMC2797489  PMID: 18686719
Nitrate; nitrite; stomach cancer; esophagus cancer; diet; drinking water
17.  Spatial-temporal analysis of non-Hodgkin lymphoma risk using multiple residential locations 
Exploring spatial-temporal patterns of disease incidence and mortality can identify areas of significantly elevated or decreased risk, providing potential etiologic clues. Several methodological issues arise in spatial-temporal analysis of cancer, including population mobility, disease latency, and confounding, but applying modern statistical methods to case-control studies with residential histories can address these issues. As an example, we present a spatial-temporal analysis of non-Hodgkin lymphoma (NHL) risk using data from Los Angeles County, one of four centers in a population-based case-control study. Using residential histories, we fitted generalized additive models (GAMs) adjusted for known risk factors to model spatially the probability that an individual had NHL and identify areas of significantly elevated NHL risk. In previous analyses using models with single lag times, the lag time of 20 years yielded the most significant decrease in model deviance. To better assess cumulative effects of unmeasured environmental exposures over space and time, we considered models that allowed for multiple residences per subject through spatial smoothing functions of residential location at different times. We found that the model with the best goodness-of-fit included components for residential change and residential duration, although the model that included residential duration was not meaningfully better than the model that included only residential change. The estimated cumulative spatial risk surface from the model with residential change amplified the risk surface in some areas compared with the surface based on the model with a single component for the most significant time lag.
PMCID: PMC3372929  PMID: 22682442
cancer; generalized additive model; spatial risk; latency; exposure
18.  Poultry and Livestock Exposure and Cancer Risk among Farmers in the Agricultural Health Study 
Cancer causes & control : CCC  2012;23(5):663-670.
The purpose of this study is to evaluate cancer risk associated with raising animals as commodities, which is associated with a variety of exposures, such as infectious agents and endotoxins.
Information was available for 49,884 male farmers in the Agricultural Health Study, who reported livestock and poultry production at enrollment (1993–1997). Cancer incidence data were obtained through annual linkage to state registries. Using Poisson regression analyses, we evaluated whether the number and type of animals raised on the farm impacted cancer risk.
Overall, 31,848 (63.8%) male farmers reported raising any animals. Lung cancer risk decreased with increasing number of livestock on the farm (p-trend=0.04) and with raising poultry (Relative Risk (RR)= 0.6; 95% Confidence Interval (CI): 0.4–0.97). Raising poultry was associated with an increased risk of colon cancer (RR=1.4; 95% CI: 0.99–2.0) with further increased with larger flocks (p-trend=0.02). Risk of non-Hodgkin lymphoma was also elevated in those who raised poultry (RR=1.6; 95% CI: 1.0–2.4), but there was no evidence of increased risk with larger flocks (p-trend=0.5). Raising sheep was associated with a significantly increased risk of multiple myeloma (RR=4.9; 95% CI: 2.4–12.0). Performing veterinary services increased the risk of Hodgkin lymphoma (RR=12.2; 95% CI: 1.6–96.3).
We observed an inverse association between raising poultry and livestock and lung cancer risk and some evidence of increased risk of specific lymphohematopoietic malignancies with specific types of animals and performing veterinary services. Further research into associations between raising animals and cancer risk should focus on identification of etiologic agents.
PMCID: PMC3337970  PMID: 22407136
livestock; poultry; cancer; cohort study; agriculture
19.  Temporal Variability of Pesticide Concentrations in Homes and Implications for Attenuation Bias in Epidemiologic Studies 
Environmental Health Perspectives  2013;121(5):565-571.
Background: Residential pesticide exposure has been linked to adverse health outcomes in adults and children. High-quality exposure estimates are critical for confirming these associations. Past epidemiologic studies have used one measurement of pesticide concentrations in carpet dust to characterize an individual’s average long-term exposure. If concentrations vary over time, this approach could substantially misclassify exposure and attenuate risk estimates.
Objectives: We assessed the repeatability of pesticide concentrations in carpet dust samples and the potential attenuation bias in epidemiologic studies relying on one sample.
Methods: We collected repeated carpet dust samples (median = 3; range, 1–7) from 21 homes in Fresno County, California, during 2003–2005. Dust was analyzed for 13 pesticides using gas chromatography–mass spectrometry. We used mixed-effects models to estimate between- and within-home variance. For each pesticide, we computed intraclass correlation coefficients (ICCs) and the estimated attenuation of regression coefficients in a hypothetical case–control study collecting a single dust sample.
Results: The median ICC was 0.73 (range, 0.37–0.95), demonstrating higher between-home than within-home variability for most pesticides. The expected magnitude of attenuation bias associated with using a single dust sample was estimated to be ≤ 30% for 7 of the 13 compounds evaluated.
Conclusions: For several pesticides studied, use of one dust sample to represent an exposure period of approximately 2 years would not be expected to substantially attenuate odds ratios. Further study is needed to determine if our findings hold for longer exposure periods and for other pesticides.
PMCID: PMC3672902  PMID: 23462689
dust; environmental exposure; pesticides; reliability
20.  Dietary Nitrate and Nitrite Intake and Non-Hodgkin Lymphoma Survival 
Nutrition and Cancer  2012;64(3):488-492.
Nitrate and nitrite are precursors in the formation of N-nitroso compounds. We recently found a 40% increased risk of NHL with higher dietary nitrite intake and significant increases in risk for follicular and T-cell lymphoma. It is possible that these compounds also affect NHL prognosis by enhancing cancer progression in addition to development by further impairing immune system function. To test the hypothesis that nitrate and nitrite intake affects NHL survival, we evaluated the association in study participants that have been followed post-disease diagnosis in a population-based case-control study among women in Connecticut. We did not observe a significant increasing trend of mortality for NHL overall or by subtype for nitrate or nitrite intake for deaths from NHL or death from any cause, although a borderline significant protective trend was observed for follicular lymphoma with increasing nitrate intake. We did not identify a difference in overall survival for nitrate (P = 0.39) or for nitrite (P = 0.66) or for NHL specific survival for nitrate (P = 0.96) or nitrite (P = 0.17). Thus, our null findings do not confer support for the possibility that dietary nitrate and nitrite intake impacts NHL survival by promoting immune unresponsiveness.
PMCID: PMC3380447  PMID: 22420290
21.  Residential proximity to industrial combustion facilities and risk of non-Hodgkin lymphoma: a case–control study 
Environmental Health  2013;12:20.
Residence near municipal solid waste incinerators, a major historical source of dioxin emissions, has been associated with increased risk of non-Hodgkin lymphoma (NHL) in European studies. The aim of our study was to evaluate residence near industrial combustion facilities and estimates of dioxin emissions in relation to NHL risk in the United States.
We conducted a population-based case–control study of NHL (1998–2000) in four National Cancer Institute-Surveillance Epidemiology and End Results centers (Detroit, Iowa, Los Angeles, Seattle). Residential histories 15 years before diagnosis (similar date for controls) were linked to an Environmental Protection Agency database of dioxin-emitting facilities for 969 cases and 749 controls. We evaluated proximity (3 and 5 km) to 10 facility types that accounted for >85% of U.S. emissions and a distance-weighted average emission index (AEI [ng toxic equivalency quotient (TEQ)/year]).
Proximity to any dioxin-emitting facility was not associated with NHL risk (3 km OR = 1.0, 95% CI 0.8-1.3). Risk was elevated for residence near cement kilns (5 km OR = 1.7, 95% CI 0.8-3.3; 3 km OR = 3.8, 95% CI 1.1-14.0) and reduced for residence near municipal solid waste incinerators (5 km OR = 0.5, 95% CI 0.3-0.9; 3 km OR = 0.3, 95% CI 0.1-1.4). The AEI was not associated with risk of NHL overall. Risk for marginal zone lymphoma was increased for the highest versus lowest quartile (5 km OR = 2.6, 95% CI 1.0-6.8; 3 km OR = 3.0, 95% CI 1.1-8.3).
Overall, we found no association with residential exposure to dioxins and NHL risk. However, findings for high emissions and marginal zone lymphoma and for specific facility types and all NHL provide some evidence of an association and deserve future study.
PMCID: PMC3599890  PMID: 23433489
Non-Hodgkin lymphoma; Lymphomas; Dioxins; Air pollution; Geographic information systems; Case–control study
22.  Characterization of Residential Pesticide Use and Chemical Formulations through Self-Report and Household Inventory: The Northern California Childhood Leukemia Study 
Environmental Health Perspectives  2012;121(2):276-282.
Background: Home and garden pesticide use has been linked to cancer and other health outcomes in numerous epidemiological studies. Exposure has generally been self-reported, so the assessment is potentially limited by recall bias and lack of information on specific chemicals.
Objectives: As part of an integrated assessment of residential pesticide exposure, we identified active ingredients and described patterns of storage and use.
Methods: During a home interview of 500 residentially stable households enrolled in the Northern California Childhood Leukemia Study during 2001–2006, trained interviewers inventoried residential pesticide products and queried participants about their storage and use. U.S. Environmental Protection Agency registration numbers, recorded from pesticide product labels, and pesticide chemical codes were matched to public databases to obtain information on active ingredients and chemical class. Poisson regression was used to identify independent predictors of pesticide storage. Analyses were restricted to 259 participating control households.
Results: Ninety-five percent (246 of 259) of the control households stored at least one pesticide product (median, 4). Indicators of higher sociodemographic status predicted more products in storage. We identified the most common characteristics: storage areas (garage, 40%; kitchen, 20%), pests treated (ants, 33%; weeds, 20%), pesticide types (insecticides, 46%; herbicides, 24%), chemical classes (pyrethroids, 77%; botanicals, 50%), active ingredients (pyrethrins, 43%) and synergists (piperonyl butoxide, 42%). Products could contain multiple active ingredients.
Conclusions: Our data on specific active ingredients and patterns of storage and use will inform future etiologic analyses of residential pesticide exposures from self-reported data, particularly among households with young children.
PMCID: PMC3569677  PMID: 23110983
exposure assessment; pesticides; population-based study; residential pesticide use; U.S. EPA
23.  Epithelial ovarian cancer and exposure to dietary nitrate and nitrite in the NIH-AARP Diet and Health Study 
Ovarian cancer is a leading cause of cancer death among women in the United States and it has the highest mortality rate of all gynecologic cancers. Internationally, there is a five-fold variation in incidence and mortality of ovarian cancer, which suggests a role for environmental factors, including diet. Nitrate and nitrite are found in various food items and they are precursors of N-nitroso compounds, which are known carcinogens in animal models. We evaluated dietary nitrate and nitrite intake and epithelial ovarian cancer in the National Institutes of Health (NIH)-AARP Diet and Health Study, including 151 316 women aged 50–71 years at the time of the baseline questionnaire in 1995–1996. The nitrate and nitrite intake was assessed using a 124-item validated food frequency questionnaire. Through 31 December 2006, 709 incident epithelial ovarian cancer cases with complete dietary information were identified. Using Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs), women in the highest intake quintile of dietary nitrate had a 31% increased risk (95% CI: 1.01–1.68) of epithelial ovarian cancer, compared with those in the lowest intake quintile. Although there was no association for total dietary nitrite, those in the highest intake category of animal sources of nitrite had a 34% increased risk (95% CI: 1.05–1.69) of ovarian cancer. There were no clear differences in risk by histologic subtype of ovarian cancer. Our findings suggest that a role of dietary nitrate and nitrite in ovarian cancer risk should be followed in other large cohort studies.
PMCID: PMC3394850  PMID: 21934624
epithelial; nitrate and nitrite; ovarian cancer
24.  Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium 
Background Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms.
Methods Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m2) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender.
Results The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI ≥40 was associated with both OA (OR 4.76, 95% CI 2.96–7.66) and OGJA (OR 3.07, 95% CI 1.89–4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk.
Conclusions These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.
PMCID: PMC3535758  PMID: 23148106
Oesophageal neoplasms; aetiology; risk factors; gastro-oesophageal reflux; obesity; oesophagogastric junction
25.  The importance of delivery rate on odds ratios by cigarette smoking and alcohol consumption for esophageal adenocarcinoma and squamous cell carcinoma in the Barrett’s and Esophageal Adenocarcinoma Consortium 
Cancer epidemiology  2012;36(3):306-316.
Cigarette smoking is associated with esophageal adenocarcinoma (EAC), esophagogastric junctional adenocarcinoma (EGJA) and esophageal squamous cell carcinoma (ESCC), and alcohol consumption with ESCC. However, no analyses have examined how delivery rate modifies the strength of odds ratio (OR) trends with total exposure, i.e., the impact on the OR for a fixed total exposure of high exposure rate for short duration compared with low exposure rate for long duration.
The authors pooled data from 12 case-control studies from the Barrett’s Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), including 1,242 (EAC), 1,263 (EGJA) and 954 (ESCC) cases and 7,053 controls, modeled joint ORs for cumulative exposure and exposure rate for cigarette smoking and alcohol consumption, and evaluated effect modification by sex, body mass index (BMI), age and self-reported acid reflux.
For smoking, all sites exhibited inverse delivery rate effects, whereby ORs with pack-years increased, but trends weakened with increasing cigarettes/day. None of the examined factors modified associations, except for ESCC where younger ages at diagnosis enhanced smoking effects (P<0.01). For EAC and EGJA, ORs with drink-years exhibited inverse associations in <5 drinks/day consumers and no association in heavier consumers. For ESCC, ORs with drink-years increased, with trends strengthening with greater drinks/day. There was no significant effect modification, except for EAC and EGJA where acid reflux mitigated the inverse associations (P=0.02). For ESCC, younger ages at diagnosis enhanced drinking-related ORs (P<0.01).
Patterns of ORs by pack-years and drink-years, delivery rate effects and effect modifiers revealed common as well as distinct etiologic elements for these diseases.
PMCID: PMC3489030  PMID: 22504051
alcohol drinking; risk model; smoking

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