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Background: From 1958 to 1970, >100,000 people in northern Chile were exposed to a well-documented, distinct period of high drinking water arsenic concentrations. We previously reported ecological evidence suggesting that early-life exposure in this population resulted in increased mortality in adults from several outcomes, including lung and bladder cancer., Methods: We have now completed the first study ever assessing incident cancer cases after early-life arsenic exposure, and the first study on this topic with individual participant exposure and confounding factor data. Subjects included 221 lung and 160 bladder cancer cases diagnosed in northern Chile from 2007 to 2010, and 508 age and gender-matched controls., Results: ORs adjusted for age, sex, and smoking in those only exposed in early life to arsenic water concentrations of ≤110, 110 to 800, and >800 μg/L were 1.00, 1.88 [95% confidence interval (CI), 0.96-3.71], and 5.24 (3.05-9.00; P(trend) < 0.001) for lung cancer, and 1.00, 2.94 (1.29-6.70), and 8.11 (4.31-15.25; P(trend) < 0.001) for bladder cancer. ORs were lower in those not exposed until adulthood. The highest category (>800 μg/L) involved exposures that started 49 to 52 years before, and ended 37 to 40 years before the cancer cases were diagnosed., Conclusion: Lung and bladder cancer incidence in adults was markedly increased following exposure to arsenic in early life, even up to 40 years after high exposures ceased. Such findings have not been identified before for any environmental exposure, and suggest that humans are extraordinarily susceptible to early-life arsenic exposure., Impact: Policies aimed at reducing early-life exposure may help reduce the long-term risks of arsenic-related disease., (©2014 American Association for Cancer Research.)

Background: Cell-cycle proteins are important predictive markers in urothelial carcinoma but may also exhibit exposure-specific heterogeneity., Methods: Tumor tissue from 491 bladder cancer cases enrolled in the Maine and Vermont component of the New England Bladder Cancer Study was assembled as tissue microarrays and examined for aberrant expression of p53, p63, p16, cyclin D1, Rb, and Ki-67. The association between expression and histopathology, demographics, and cigarette smoking was examined using χ(2) tests, multivariable Poisson, and multinomial regression models., Results: We found that overexpression of p53 and Ki-67 was associated with high-stage/grade tumors [relative risk (RR), 1.26; P(trend) = 0.003; and RR, 3.21; P(trend) < 0.0001, respectively], whereas expression of p63 and p16 was decreased in high-stage/grade tumors (RR, 0.52; P(trend) < 0.0001; and RR, 0.88; P(trend) = 0.04, respectively). No significant aberrations of cell-cycle proteins were identified using various smoking variables and multiple statistical models., Conclusion: The results of this population-based study of histologically confirmed urothelial carcinomas show significant aberration of cell-cycle proteins p53, p63, p16, and Ki-67, but not Rb or cyclin D1. p53 showed the most significant heterogeneity with respect to tumor stage and grade, especially when stratified for different staining intensities using novel digital image analysis techniques. Our findings do not support that smoking modifies expression of cell-cycle proteins., Impact: Our study shows significant heterogeneity in the expression of key cell-cycle proteins that are associated with disease progression in bladder cancer. Further studies may lead to the identification of biomarkers and their multiplexed interactions as useful prognostic and therapeutic targets., (©2012 AACR)

Background: Selenium is considered to be an antioxidant, and its high levels have been inversely associated with cancer risk of several sites. This meta-analysis examined the relationship between levels of selenium measured in serum and toenails, and the risk of bladder cancer., Methods: A meta-analysis using data from seven published epidemiologic studies (three case-control, three nested case-control, one case-cohort) published before March 2010 was done to examine the association between levels of selenium and bladder cancer. Fixed and random effects analyses were done to calculate meta-odds ratio (mOR) and 95% confidence intervals (CI). Heterogeneity among studies was measured by the I(2) statistic., Results: Overall, the risk of bladder cancer was inversely associated with elevated levels of selenium according to a random-effects model (mOR = 0.61; 95% CI, 0.42-0.87). The mORs were 0.95 (95% CI, 0.69-1.27) and 0.55 (95% CI, 0.32-0.95) among men and women, respectively. Sex, type of sample specimen, smoking status, and study design were found to be potential sources of heterogeneity., Conclusions: A significant protective effect of selenium, observed mainly among women, may result from gender-specific differences in its accumulation and excretion. The heterogeneity found among studies was mainly linked to the different biological sample specimens used to measure the selenium concentrations and the small size of the studies. Although these results suggest a protective effect of selenium for bladder cancer risk, additional large studies are warranted to support these preliminary evidence., Impact: The present results suggest a beneficial effect of high selenium intake for bladder cancer risk., ((c)2010 AACR.)

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder cancer and with increased bulky DNA adduct levels in several studies, mainly in smokers. We investigated the relation between bulky PAH-DNA adducts in peripheral blood mononuclear cells and bladder cancer in nonsmoking subjects from a large hospital-based case-control study in Spain. Additionally, we examined the association between DNA adduct formation and several air pollution proxies. The study comprised 76 nonsmoking cases and 76 individually matched controls by sex, region of residence, age, and smoking status (never, former). To maximize the relevance of the DNA adduct measurement as a proxy of PAH exposure, subjects selected had not changed residence, occupation, and major lifestyle factors during the last 10 years. Bulky DNA adducts were measured using the (32)P-postlabeling technique, nuclease P1 treatment. The percentage of detectable adducts was higher in controls (41%) than in cases (32%) with an odds ratio of 0.75 (95% confidence interval, 0.36-1.58). In an analysis limited to controls, a higher percentage of DNA adducts was found among those whose last residence was in a big city (50%) compared with those living in villages (19%; P = 0.04). No consistent associations were found for other markers of air pollution. In this study, among nonsmokers with stable environmental and lifestyle factors, bulky DNA adducts were not associated with bladder cancer risk. Results do not support an association of bladder cancer risk with low-level exposure to PAHs as measured through the formation of bulky DNA adducts in peripheral mononuclear cells.

The incidence of non-Hodgkin's lymphoma (NHL) unrelated to HIV infection has steadily increased over the past several decades and remains substantially unexplained. Limited evidence suggests that increased concentrations of polychlorinated biphenyls (PCB) measured in blood or fat tissue are associated with increased risk of NHL. Although PCB congeners vary in their biological activity, the relation between individual congeners and NHL risk has not been examined previously using prospectively collected biospecimens. We examined congener-specific associations in three prospective cohorts. Prediagnostic serum or plasma concentrations of selected PCB congeners were measured among NHL cases and controls from these cohorts: Janus (190 cases and 190 controls) in Norway and CLUE I (74 cases and 147 controls) and the Nurses' Health Study (30 cases and 78 controls) in the United States. All blood samples were collected in the 1970s or 1980s. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the relations between risk of NHL and lipid-corrected plasma or serum concentrations. Several congeners (i.e., 118, 138, and 153) that were present at higher levels and were moderately to highly correlated with each other showed exposure-response trends with risk of NHL in all three cohorts. These associations were observed primarily among subjects diagnosed closer to the date of blood collection in the two cohorts with sufficient cases to permit stratification by time. Among cases diagnosed within the median years of follow-up (16 years in Janus and 12 years in CLUE I), ORs and 95% CIs for increasing fourths of concentration of congener 118 relative to the lowest fourth were as follows: 2.4 (0.9-6.5), 4.9 (1.6-15.3), and 5.3 (1.5-18.8; P(trend) < 0.005) in Janus and 8.1 (1.0-68.9), 6.6 (0.7-59.0), and 13.0 (1.6-106.8; P(trend) < 0.05) in CLUE I. Similar patterns were seen for congeners 138 and 153 and for total PCBs. Limited evidence of exposure-response trends was also observed for several other congeners. The primary 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane metabolite, p,p'-DDE, was not significantly associated with NHL in most analyses but slightly to moderately confounded the PCB associations. The results from these three cohorts suggest that concentrations of certain PCBs in blood are associated with increased risk of NHL.

To investigate whether the association between agricultural pesticide use and the risk of non-Hodgkin's lymphoma (NHL) is modified by a family history of hematopoietic cancer, including leukemia, myeloma, and lymphoma, we analyzed pooled data on white men from three population-based, case-control studies of NHL conducted in Iowa/Minnesota, Kansas, and Nebraska. Information on the agricultural use of insecticides, fungicides, and herbicides; a family history of cancer; and other risk factors was obtained by interviewing 973 cases and 2,853 controls or, if deceased, their next-of-kin (37% of cases, 43% of controls). The NHL risk was estimated by odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, state of residence, type of respondent, and use of hair dye. Compared to men with no family history of cancer, the ORs (95% CIs) of NHL was 1.5 (1.3-1.8) for men with a family history of nonhematopoietic cancer, and 2.7 (1.9-3.7) for those with a history of hematopoietic cancer among first-degree relatives. This positive association was noted for each group of NHL defined according to the Working Formulation, and was most pronounced for small lymphocytic NHL. Among direct respondents, farmers who used pesticides and had a positive family history of cancer or hematopoietic cancer were not at elevated risk of NHL, compared to nonfarmers who had no family cancer history. However, among proxy respondents, ORs were elevated for farmers who had a positive family history of hematopoietic cancer and used animal insecticides (OR = 4.6; 1.9-11.2), crop insecticides (OR = 4.7; 1.6-13.4), or herbicides (OR = 4.9; 1.7-14.2), although the interaction of family history of cancer and agricultural pesticide use was not statistically significant. In summary, the joint effects of the family cancer history and pesticide use were limited to proxy respondents with wide CIs and, thus, provide little evidence that a family history of cancer modifies the association of agricultural exposures with NHL.

A family history of prostate cancer has been associated with prostate cancer risk in most prior studies, and more limited data suggest that a family history of breast cancer may also be important; however, there are no data from a population-based cohort study of prostate cancer incidence that adjusts for major confounders. We conducted follow-up through 1995 on 1557 men, ages 40-86 years, who were randomly selected (81% response rate) as cancer-free controls for a population-based case-control study conducted in Iowa from 1987-1989. Family history of cancer in parents and siblings was obtained using a mailed questionnaire. Incident cancers and deaths were ascertained through linkages to state and national databases; 101 incident cases of prostate cancer were identified. At baseline, 4.6% of the cohort reported a family history of prostate cancer in a brother or father, and this was positively associated with prostate cancer risk after adjustment for age [relative risk (RR) = 3.2; 95% confidence interval (CI), 1.8-5.7] or after multivariate adjustment for age, alcohol, and dietary factors (RR = 3.7; 95% CI, 1.9-7.2). Risk was greater if a brother had prostate cancer (RR = 4.5; 95% CI, 2.1-9.7) than if a father had prostate cancer (RR = 2.3; 95% CI, 1.0-5.3). Also at baseline, 9.6% of the cohort had a family history of breast and/or ovarian cancer in a mother or sister, and this was positively associated with prostate cancer risk (age-adjusted RR = 1.7; 95% CI, 1.0-3.0; multivariate RR = 1.7; 95% CI, 0.9-3.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR = 5.8; 95% CI, 2.4-14). There was no association with a family history of colon cancer. Exclusion of well-differentiated, localized tumors did not alter these findings. These data from an incidence study confirm that a family history of prostate cancer is a strong prostate cancer risk factor after adjustment for dietary and other risk factors, and suggest that selection and recall bias have not had an important influence on most case-control study results. These data also support the idea that a family history of breast cancer may also be a prostate cancer risk factor.

The review of the literature regarding non-Hodgkin's lymphoma and occupational and environmental factors presented at this workshop suggested associations with viruses, solvents, and hair dyes. A population-based case-control study among men from Iowa and Minnesota notes similar associations. Workers engaged in metal working, hair care, painting, and dry cleaning experienced nonsignificant excesses. Risks from specific exposures showed some variation by histological type. Both follicular and diffuse non-Hodgkin's lymphoma were associated with benzene. The diffuse type was linked to solvents other than benzene and formaldehyde, while the follicular was excessive among workers exposed to oils and greases.

Data from an in-person interview study of 622 white men with newly diagnosed non-Hodgkin's lymphoma and 1245 population-based controls in Iowa and Minnesota were used to measure the risk associated with farming occupation and specific agricultural exposures. Men who ever farmed were at slightly elevated risk of non-Hodgkin's lymphoma (odds ratio = 1.2, 95% confidence interval = 1.0-1.5) that was not linked to specific crops or particular animals. Elevated risks were found, with odds ratio generally 1.5-fold or greater, for personal handling, mixing, or application of several pesticide groups and for individual insecticides, including carbaryl, chlordane, dichlorodiphenyltrichloroethane, diazinon, dichlorvos, lindane, malathion, nicotine, and toxaphene. Associations were generally stronger for first use prior to 1965 than more recently, and when protective clothing or equipment was not used. Small risks were associated with the use of the phenoxyacetic acid herbicide 2,4-dichlorophenoxyacetic acid, but the risks did not increase with latency or failure to use protective equipment. Exposure to numerous pesticides poses problems of interpreting risk associated with a particular chemical, and multiple comparisons increase the chances of false-positive findings. In contrast, nondifferential exposure misclassification due to inaccurate recall can bias risk estimates toward the null and mask positive associations. In the face of these methodological and statistical issues, the consistency of several findings, both within this study and with observations of others, suggests an important role for several insecticides in the etiology of non-Hodgkin's lymphoma among farmers.

Mortality surveys and death certificate studies have suggested an association between leukemia and farming. To investigate whether exposure to carcinogens in an agricultural setting is related to risk of leukemia, the authors conducted a population-based case-control interview study of 578 white men with leukemia and 1245 controls living in Iowa and Minnesota. Consistent with recent mortality studies, there were slight, but significant, elevations in risk for all leukemia [odds ratio (OR) 1.2] and chronic lymphocytic leukemia (OR 1.4) for farmers compared to nonfarmers. There were no significant associations with leukemia for exposure to specific fungicides, herbicides (including 2,4-D and 2,4,5-T), or crop insecticides. However, significantly elevated risks for leukemia of greater than or equal to 2.0 were seen for exposure to specific animal insecticides including the organophosphates crotoxyphos (OR 11.1), dichlorvos (OR 2.0), and famphur (OR 2.2) and the natural product pyrethrins (OR 3.7) and the chlorinated hydrocarbon methoxychlor (OR 2.2). There were also smaller, but significant, risks associated with exposure to nicotine (OR 1.6) and DDT (OR 1.3). This finding of elevated risks for insecticides used on animals deserves further evaluation.

The relation between use of hair dyes and risk of bladder cancer was assessed using data from a case-control study of bladder cancer. Incident cases (2982) and general population controls (5782) were interviewed. The overall estimate of relative risk of bladder cancer for users of hair dyes was 1.0 (95%) confidence interval, 0.9 to 1.2) compared to nonusers. No consistent pattern of association was detected between bladder cancer risk and various indices of timing or intensity of exposure to hair dyes. Various explanations of the lack of association are discussed.

Age-adjusted mortality rates for non-Hodgkin's lymphoma in counties of the contiguous United States were examined by sex and race during 1950 to 1975 and were correlated through 1969 with demographic and industrial data. Mortality was consistently elevated in counties with large populations, especially in those with higher income and education levels. Among males, but not females, elevated rates appeared in counties with high percentages of residents of Russian or Greek descent. A series of contiguous counties with high rates was seen along the coast of California. Lower rates in the South were explained in a multivariate analysis by the generally lower socioeconomic levels in this region. Counties with industrial concentration in food packing showed higher mortality rates among males than did comparable counties without these industries. All regions and all sex-race groups showed an increase over time in mortality from non-Hodgkin's lymphoma, especially reticulum cell sarcoma.