Mary H. Ward

Workgroup Report: Drinking-Water Nitrate and Health-Recent Findings and Research Needs

Human alteration of the nitrogen cycle has resulted in steadily accumulating nitrate in our water resources. The U.S. maximum contaminant level and World Health Organization guidelines for nitrate in drinking water were promulgated to protect infants from developing methemoglobinemia, an acute condition. Some scientists have recently suggested that the regulatory limit for nitrate is overly conservative; however, they have not thoroughly considered chronic health outcomes. In August 2004, a symposium on drinking-water nitrate and health was held at the International Society for Environmental Epidemiology meeting to evaluate nitrate exposures and associated health effects in relation to the current regulatory limit. The contribution of drinking-water nitrate toward endogenous formation of N-nitroso compounds was evaluated with a focus toward identifying subpopulations with increased rates of nitrosation. Adverse health effects may be the result of a complex interaction of the amount of nitrate ingested, the concomitant ingestion of nitrosation cofactors and precursors, and specific medical conditions that increase nitrosation. Workshop participants concluded that more experimental studies are needed and that a particularly fruitful approach may be to conduct epidemiologic studies among susceptible subgroups with increased endogenous nitrosation. The few epidemiologic studies that have evaluated intake of nitrosation precursors and/or nitrosation inhibitors have observed elevated risks for colon cancer and neural tube defects associated with drinking-water nitrate concentrations below the regulatory limit. The role of drinking-water nitrate exposure as a risk factor for specific cancers, reproductive outcomes, and other chronic health effects must be studied more thoroughly before changes to the regulatory level for nitrate in drinking water can be considered.

International patterns and trends in thyroid cancer incidence, 1973–2002

During the past several decades, an increasing incidence of thyroid cancer has been reported in many parts of the world. To date, no study has compared the trends in thyroid cancer incidence across continents. We examined incidence data from cancer incidence in five continents (CI5) over the 30-year period 1973–2002 from 19 populations in the Americas, Asia, Europe, and Oceania. Thyroid cancer rates have increased from 1973–1977 to 1998–2002 for most of the populations except Sweden, in which the incidence rates decreased about 18% for both males and females. The average increase was 48.0% among males and 66.7% among females. More recently, the age-adjusted international thyroid cancer incidence rates from 1998 to 2002 varied 5-fold for males and nearly 10-fold for females by geographic region. Considerable variation in thyroid cancer incidence was present for every continent but Africa, in which the incidence rates were generally low. Our analysis of published CI5 data suggests that thyroid cancer rates increased between 1973 and 2002 in most populations worldwide, and that the increase does not appear to be restricted to a particular region of the world or by the underlying rates of thyroid cancer.

Thyroid Cancer Incidence Patterns in the United States by Histologic Type, 1992–2006

BACKGROUND The increasing incidence of thyroid cancer in the United States is well documented. In this study, we assessed the incidence patterns by histologic type according to demographic and tumor characteristics to further our understanding of these cancers. METHODS We used the National Cancer Institutes Surveillance, Epidemiology, and End Results (SEER) program for cases diagnosed during 1992-2006 to investigate patterns for the four major histologic types of thyroid cancer by gender, race/ethnicity, and age as well as registry, tumor stage, and size. RESULTS Among women, papillary thyroid cancer rates were highest among Asians (10.96 per 100,000 woman-years) and lowest among blacks (4.90 per 100,000 woman-years); follicular cancer rates did not vary substantially by race/ethnicity (p-values >0.05), medullary cancer rates were highest among Hispanics (0.21 per 100,000 woman-years) and whites (0.22 per 100,000 woman-years), and anaplastic rates were highest among Hispanics (0.17 per 100,000 woman-years). Among men, both papillary and follicular thyroid cancer rates were highest among whites (3.58 and 0.58 per 100,000 man-years, respectively), medullary cancer rates were highest among Hispanics (0.18 per 100,000 man-years), and anaplastic rates were highest among Asians (0.11 per 100,000 man-years). Racial/ethnic-specific rates did not vary notably across registries. In contrast to age-specific rates of papillary thyroid cancer that peaked in midlife (age 50), especially pronounced among women, rates for follicular, medullary, and anaplastic types continued to rise across virtually the entire age range, especially for anaplastic carcinomas. Female-to-male incidence rate ratios among whites decreased with age most steeply for the follicular type and least steeply for the medullary type; it was <1 until the very oldest ages for the anaplastic type. CONCLUSION We conclude that the similar age-specific patterns and lack of geographical variation across the SEER racial/ethnic groups indicate that detection effects cannot completely explain the observed thyroid cancer incidence patterns as variation in the amount or quality of healthcare provided has been shown to vary by SEER racial/ethnic groups, gender, and age. We find that the variations in age-specific patterns by gender and across histologic types are intriguing and recommend that future etiologic investigation focus on exogenous and endogenous exposures that are experienced similarly by racial/ethnic groups, more strongly among women, and distinctively by age.

A Large Prospective Study of Meat Consumption and Colorectal Cancer Risk: An Investigation of Potential Mechanisms Underlying this Association

Although the relation between red and processed meat intake and colorectal cancer has been reported in several epidemiologic studies, very few investigated the potential mechanisms. This study examined multiple potential mechanisms in a large U.S. prospective cohort with a detailed questionnaire on meat type and meat cooking methods linked to databases for estimating intake of mutagens formed in meats cooked at high temperatures (heterocyclic amines, polycyclic aromatic hydrocarbons), heme iron, nitrate, and nitrite. During 7 years of follow-up, 2,719 colorectal cancer cases were ascertained from a cohort of 300,948 men and women. The hazard ratios (HR) and 95% confidence intervals (95% CI) comparing the fifth to the first quintile for both red (HR, 1.24; 95% CI, 1.09-1.42; P(trend) < 0.001) and processed meat (HR, 1.16; 95% CI, 1.01-1.32; P(trend) = 0.017) intakes indicated an elevated risk for colorectal cancer. The potential mechanisms for this relation include heme iron (HR, 1.13; 95% CI, 0.99-1.29; P(trend) = 0.022), nitrate from processed meats (HR, 1.16; 95% CI, 1.02-1.32; P(trend) = 0.001), and heterocyclic amine intake [HR, 1.19; 95% CI, 1.05-1.34; P(trend) < 0.001 for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and HR, 1.17; 95% CI, 1.05-1.29; P(trend) <0.001 for 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)]. In general, the elevated risks were higher for rectal cancer than for colon cancer, with the exception of MeIQx and DiMeIQx, which were only associated with colon cancer. In conclusion, we found a positive association for red and processed meat intake and colorectal cancer; heme iron, nitrate/nitrite, and heterocyclic amines from meat may explain these associations.

Drinking water nitrate and the risk of non-Hodgkin's lymphoma.

&NA; The increasing incidence of non‐Hodgkins lymphoma (NHL) in the United States is only partially explained by known risk factors. Nitrate is a contaminant of drinking water in many rural areas. We evaluated its association with NHL after accounting for dietary nitrate intake. For 156 cases and 527 controls who used Nebraska community supplies, average nitrate exposure was estimated from 1947 through 1979. Longterm consumption of community water with average nitrate levels in the highest quartile (≥4 mg per liter nitrate‐nitrogen) was positively associated with risk [odds ratio (OR) = 2.0; 95% confidence interval (CI) = 1.1‐3.6]. Dietary nitrate, which came mainly from vegetables, was not associated with NHL risk, after adjusting for vitamin C and carotene intakes. Persons with a lower intake of vitamin C were at slightly higher risk of developing NHL than persons whose daily intake was ≥130 mg, for all levels of intake of drinking water nitrate; our findings were similar for the combined effect of water nitrate and carotene intake. Nitrate levels in private wells were measured at the time of the interview for 51 cases and 150 controls but were not associated with the risk of NHL after adjusting for pesticide use on the farm. These findings indicate that longterm exposure to elevated nitrate levels in drinking water may contribute to the risk of NHL.

Cigarette Smoking and Adenocarcinomas of the Esophagus and Esophagogastric Junction: A Pooled Analysis From the International BEACON Consortium

BACKGROUND Previous studies that showed an association between smoking and adenocarcinomas of the esophagus and esophagogastric junction were limited in their ability to assess differences by tumor site, sex, dose-response, and duration of cigarette smoking cessation. METHODS We used primary data from 10 population-based case-control studies and two cohort studies from the Barretts Esophagus and Esophageal Adenocarcinoma Consortium. Analyses were restricted to white non-Hispanic men and women. Patients were classified as having esophageal adenocarcinoma (n = 1540), esophagogastric junctional adenocarcinoma (n = 1450), or a combination of both (all adenocarcinoma; n = 2990). Control subjects (n = 9453) were population based. Associations between pack-years of cigarette smoking and risks of adenocarcinomas were assessed, as well as their potential modification by sex and duration of smoking cessation. Study-specific odds ratios (ORs) estimated using multivariable logistic regression models, adjusted for age, sex, body mass index, education, and gastroesophageal reflux, were pooled using a meta-analytic methodology to generate summary odds ratios. All statistical tests were two-sided. RESULTS The summary odds ratios demonstrated strong associations between cigarette smoking and esophageal adenocarcinoma (OR = 1.96, 95% confidence interval [CI] = 1.64 to 2.34), esophagogastric junctional adenocarcinoma (OR = 2.18, 95% CI = 1.84 to 2.58), and all adenocarcinoma (OR = 2.08, 95% CI = 1.83 to 2.37). In addition, there was a strong dose-response association between pack-years of cigarette smoking and each outcome (P < .001). Compared with current smokers, longer smoking cessation was associated with a decreased risk of all adenocarcinoma after adjusting for pack-years (<10 years of smoking cessation: OR = 0.82, 95% CI = 0.60 to 1.13; and > or =10 years of smoking cessation: OR = 0.71, 95% CI = 0.56 to 0.89). Sex-specific summary odds ratios were similar. CONCLUSIONS Cigarette smoking is associated with increased risks of adenocarcinomas of the esophagus and esophagogastric junction in white men and women; compared with current smoking, smoking cessation was associated with reduced risks.

Linking environmental nutrient enrichment and disease emergence in humans and wildlife

Worldwide increases in human and wildlife diseases have challenged ecologists to understand how large-scale environmental changes affect host-parasite interactions. One of the most profound changes to Earths ecosystems is the alteration of global nutrient cycles, including those of phosphorus (P) and especially nitrogen (N). Along with the obvious direct benefits of nutrient application for food production, anthropogenic inputs of N and P can indirectly affect the abundance of infectious and noninfectious pathogens. The mechanisms underpinning observed correlations, however, and how such patterns vary with disease type, have long remained conjectural. Here, we highlight recent experimental advances to critically evaluate the relationship between environmental nutrient enrichment and disease. Given the interrelated nature of human and wildlife disease emergence, we include a broad range of human and wildlife examples from terrestrial, marine, and freshwater ecosystems. We examine the consequences of nutrient pollution on directly transmitted, vector-borne, complex life cycle, and noninfectious pathogens, including West Nile virus, malaria, harmful algal blooms, coral reef diseases, and amphibian malformations. Our synthetic examination suggests that the effects of environmental nutrient enrichment on disease are complex and multifaceted, varying with the type of pathogen, host species and condition, attributes of the ecosystem, and the degree of enrichment; some pathogens increase in abundance whereas others decline or disappear. Nevertheless, available evidence indicates that ecological changes associated with nutrient enrichment often exacerbate infection and disease caused by generalist parasites with direct or simple life cycles. Observed mechanisms include changes in host/vector density, host distribution, infection resistance, pathogen virulence or toxicity, and the direct supplementation of pathogens. Collectively, these pathogens may be particularly dangerous because they can continue to cause mortality even as their hosts decline, potentially leading to sustained epidemics or chronic pathology. We suggest that interactions between nutrient enrichment and disease will become increasingly important in tropical and subtropical regions, where forecasted increases in nutrient application will occur in an environment rich with infectious pathogens. We emphasize the importance of careful disease management in conjunction with continued intensification of global nutrient cycles.

Risk of adenocarcinoma of the stomach and esophagus with meat cooking method and doneness preference

Meats cooked at high temperatures (frying, grilling) and for a long duration contain heterocyclic amines (HCAs), which are both mutagens and animal carcinogens. Additionally, barbecuing/grilling of meats produces polycyclic aromatic hydrocarbons (PAHs). Consumption of well‐done meat has been associated with an increased risk of colon cancer but has not been evaluated as a risk factor for stomach or esophageal cancers. We conducted a population‐based case‐control study in 66 counties of eastern Nebraska. Telephone interviews were conducted with white men and women diagnosed with adenocarcinoma of the stomach (n = 176) and esophagus (n = 143) between July 1988 and June 1993 and 502 controls. The dietary assessment included several questions about usual cooking methods for meats and doneness preference for beef. High intake of red meat was associated with increased risks for both stomach and esophageal cancers. Overall, broiling or frying of beef, chicken or pork was not associated with the risk of these tumors. Barbecuing/grilling, reported as the usual cooking method for a small number of study participants, was associated with an elevated risk of stomach and esophageal cancers. after excluding those who reported usually barbecuing/grilling, a source of both PAHc and HCAs, we evaluated doneness level as a surrogate for HCA exposure. Compared to a preference for rare/medium rare beef, odds ratios were 2.4 for medium, 2.4 for medium well and 3.2 for well done, a significant positive trend. Doneness level was not associated with a significant trend in risk of esophageal cancer. Int. J. Cancer, 71:14–19, 1997.

Nutrient Intakes and Adenocarcinoma of the Esophagus and Distal Stomach

We studied the relationship between nutrient intakes and adenocarcinoma of the esophagus and distal stomach among 124 esophageal adenocarcinoma cases, 124 distal stomach cancer cases, and 449 controls in a population-based case-control study in eastern Nebraska. The residual method was used to adjust nutrient intake quartiles or tertiles for energy intake. We observed significant inverse associations with risk of esophageal adenocarcinoma for dietary intakes of total vitamin A [highest vs. lowest quartile, multivariate odds ratio (OR) = 0.5, P for trend = 0.05], β-cryptoxanthin (OR = 0.5, P = 0.05), riboflavin (OR = 0.5, P = 0.01), folate (OR = 0.5, P = 0.03), zinc (OR = 0.5, P = 0.05), dietary fiber (OR = 0.5, P = 0.05), protein (OR = 0.5, P = 0.02), and carbohydrate (OR = 0.4, P = 0.02). For distal stomach cancer, only vitamin C (OR = 0.6, P = 0.04), dietary fiber (OR = 0.4, P = 0.007), and carbohydrate (OR = 0.4, P = 0.004) were inversely associated with risk. Our analyses showed significant interaction between dietary fat intake, but not intakes of other nutrients, and respondent type for both cancer sites. Subgroup analyses among self-respondents revealed positive associations between saturated fat intake and risk of esophageal adenocarcinoma (OR = 1.0, 4.1, and 4.6 for intake tertiles, P for trend = 0.02) and risk of distal stomach cancer (OR = 1.0, 1.2, and 3.6, P = 0.03). However, no such associations were found among proxy respondents. Our data suggest that greater intake of dietary fiber, certain carotenoids, and vitamins may decrease the risk of esophageal adenocarcinoma, whereas greater intake of saturated fat may increase the risk of esophageal adenocarcinoma and distal stomach cancer.

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (>/= 35) kg/m(2)) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.