Jean D. Brender

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.

Dietary nitrites and nitrates, nitrosatable drugs, and neural tube defects.

Background: Amine-containing (nitrosatable) drugs can react with nitrite to form N-nitroso compounds, some of which are teratogenic. Data are lacking on whether dietary intake of nitrates and nitrites modifies the association between maternal nitrosatable drug exposure and neural tube defects (NTDs) in offspring. Methods: We examined nitrosatable drug exposure and NTD-affected pregnancies in relation to dietary nitrite and total nitrite intake in a case-control study of Mexican American women. We interviewed 184 women with NTD-affected pregnancies and 225 women with normal live births, including questions on periconceptional drug exposures and dietary intake. For 110 study participants, nitrate was also measured in the usual source of drinking water. Results: Women who reported taking drugs classified as nitrosatable were 2.7 times more likely to have an NTD-affected pregnancy than women without this exposure (95% confidence interval [CI] = 1.4–5.3). The effect of nitrosatable drugs was observed only in women with higher intakes of dietary nitrite and total nitrite (dietary nitrite + 5% dietary nitrate). Women within the highest tertile (greater than 10.5 mg/day) of total nitrite were 7.5 times more likely to have an NTD-affected pregnancy if they took nitrosatable drugs (95% CI = 1.8–45.4). The association between nitrosatable drug exposure and NTDs was also stronger in women whose water nitrate levels were higher. Conclusions: Findings suggest that effects of nitrosatable drug exposure on risk for neural tube defects in offspring could depend on the amounts of dietary nitrite and total nitrite intake.

Development of estimates of dietary nitrates, nitrites, and nitrosamines for use with the short willet food frequency questionnaire

BackgroundStudies have suggested that nitrates, nitrites, and nitrosamines have an etiologic role in adverse pregnancy outcomes and chronic diseases such as cancer. Although an extensive body of literature exists on estimates of these compounds in foods, the extant data varies in quality, quantified estimates, and relevance.MethodsWe developed estimates of nitrates, nitrites, and nitrosamines for food items listed in the Short Willet Food Frequency Questionnaire (WFFQ) as adapted for use in the National Birth Defects Prevention Study. Multiple reference databases were searched for published literature reflecting nitrate, nitrite, and nitrosamine values in foods. Relevant published literature was reviewed; only publications reporting results for items listed on the WFFQ were selected for inclusion. The references selected were prioritized according to relevance to the U.S. population.ResultsBased on our estimates, vegetable products contain the highest levels of nitrate, contributing as much as 189 mg/serving. Meat and bean products contain the highest levels of nitrites with values up to 1.84 mg/serving. Alcohol, meat and dairy products contain the highest values of nitrosamines with a maximum value of 0.531 μg/serving. The estimates of dietary nitrates, nitrites, and nitrosamines generated in this study are based on the published values currently available.ConclusionTo our knowledge, these are the only estimates specifically designed for use with the adapted WFFQ and generated to represent food items available to the U.S. population. The estimates provided may be useful in other research studies, specifically in those exploring the relation between exposure to these compounds in foods and adverse health outcomes.

Parental occupation and neural tube defect-affected pregnancies among Mexican Americans.

In a case–control study, we examined whether parental occupational exposures were related to neural tube defect (NTD)–affected pregnancies among Mexican Americans living along the Texas–Mexico border. Case women were 184 Mexican-American women with NTD-affected pregnancies; control women were 225 study-area residents who delivered normal babies during the same period as the case women. The women were interviewed in person about maternal and paternal occupations and work exposures during the periconceptional period. Compared with control women, case women were more likely to have had occupational exposures to solvents (odds ratio [OR], ∞; 95% confidence interval [CI], 2.4−∞) and also were more likely to have worked in cleaning (OR 9.5; 95% CI, 1.1 to 82.2) or health care occupations (OR 3.0; 95% CI, 1.0 to 9.0) than control women. No compelling associations were found between paternal work exposures or occupations and NTDs in offspring in this population.

Maternal pesticide exposure and neural tube defects in Mexican Americans.

PURPOSE The relation between maternal pesticide exposures and neural tube defects (NTDs) in offspring was evaluated in 184 Mexican American case-women and 225 comparison women. METHODS In-person interviews solicited information about environmental and occupational exposures to pesticides during the periconceptional period. RESULTS With adjustment for maternal education, smoking, and folate intake, women who reported using pesticides in their homes or yards were two times more likely (95% confidence interval [CI], 1.2-3.1) to have NTD-affected pregnancies than women without these reported exposures. Case-women were also more likely to report living within 0.25 mile of cultivated fields than control-women (odds ratio [OR] 3.6; 95% CI, 1.7-7.6). As sources of pesticide exposure opportunities increased, risk of NTDs also increased. The adjusted ORs and 95% CIs for one, two, and three or more exposure sources were 1.2 (0.69-1.9), 2.3 (1.3-4.1) and 2.8 (1.2-6.3) respectively, and this positive trend was stronger for risk of anencephaly than for spina bifida. CONCLUSIONS Self-reported pesticide exposures were associated with NTD risk in this study population, especially use of pesticides within the home and a periconceptional residence within 0.25 mile of cultivated fields.

Prenatal Nitrate Intake from Drinking Water and Selected Birth Defects in Offspring of Participants in the National Birth Defects Prevention Study

Background: Previous studies of prenatal exposure to drinking-water nitrate and birth defects in offspring have not accounted for water consumption patterns or potential interaction with nitrosatable drugs. Objectives: We examined the relation between prenatal exposure to drinking-water nitrate and selected birth defects, accounting for maternal water consumption patterns and nitrosatable drug exposure. Methods: With data from the National Birth Defects Prevention Study, we linked addresses of 3,300 case mothers and 1,121 control mothers from the Iowa and Texas sites to public water supplies and respective nitrate measurements. We assigned nitrate levels for bottled water from collection of representative samples and standard laboratory testing. Daily nitrate consumption was estimated from self-reported water consumption at home and work. Results: With the lowest tertile of nitrate intake around conception as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ingest ≥ 5 mg nitrate daily from drinking water (vs. < 0.91 mg) than control mothers. During 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily (vs. < 1.0 mg). Higher water nitrate intake did not increase associations between prenatal nitrosatable drug use and birth defects. Conclusions: Higher water nitrate intake was associated with several birth defects in offspring, but did not strengthen associations between nitrosatable drugs and birth defects. Citation: Brender JD, Weyer PJ, Romitti PA, Mohanty BP, Shinde MU, Vuong AM, Sharkey JR, Dwivedi D, Horel SA, Kantamneni J, Huber JC Jr., Zheng Q, Werler MM, Kelley KE, Griesenbeck JS, Zhan FB, Langlois PH, Suarez L, Canfield MA, and the National Birth Defects Prevention Study. 2013. Prenatal nitrate intake from drinking water and selected birth defects in offspring of participants in the National Birth Defects Prevention Study. Environ Health Perspect 121:1083–1089; http://dx.doi.org/10.1289/ehp.1206249

Maternal serum homocysteine and risk for neural tube defects in a Texas‐Mexico border population

BACKGROUND To better understand the neural tube defect (NTD) causal pathway, the authors measured homocysteine, an indicator of tissue micronutrient deficiencies. The authors examined independent and joint associations of serum homocysteine, B12, and folate and red blood cell (RBC) folate with NTD-affected pregnancies. METHODS Case women in this population-based study had NTD-affected pregnancies and resided and delivered in one of the 14 Texas-Mexico border counties from 1995 through 2000. Control women were study area residents delivering normal live births during the same period. The authors measured homocysteine levels using tandem mass spectroscopy; competitive binding was used for other biomarkers. RESULTS Homocysteine testing was done on 103 cases and 139 controls. Odds ratios (ORs) were increased in all upper homocysteine quintiles compared to the lowest quintile (1.7, 1.3, 2.8, 2.4). Women with high homocysteine values had increased ORs regardless of high versus low levels for B12 (OR = 3.5, 4.8, respectively) or RBC folate (OR = 2.9, 3.5, respectively). CONCLUSIONS High serum homocysteine levels are associated with NTD-affected pregnancies. Moreover, high homocysteine levels have a detrimental effect on NTD-risk even when serum B12 or RBC folate levels are high. Excess homocysteine might play an independent role in the development of NTDs.

The prevalence and predictors of anencephaly and spina bifida in Texas

Texas shares a 1255-mile border with Mexico and encompasses a variety of ecosystems, industries and other potential environmental exposures. The Texas Birth Defects Registry is an active surveillance system which covers all pregnancy outcomes (livebirths, fetal deaths and elective pregnancy terminations). This study describes the occurrence and the predictors of neural tube defects (anencephaly and spina bifida) in Texas between 1999 and 2003. Birth prevalence, crude and adjusted prevalence ratios and 95% confidence intervals were calculated using Poisson regression, for each defect, by fetal/infant sex, delivery year and maternal sociodemographic characteristics. Among approximately 1.8 million livebirths, a total of 1157 neural tube defects cases were ascertained by the Registry, resulting in an overall prevalence of 6.33 cases per 10 000 livebirths. The prevalences of anencephaly and spina bifida were 2.81 and 3.52 per 10 000 livebirths respectively. Prevalences of both defects were highest in Hispanics, among mothers living along the border with Mexico, among women of higher parity and among mothers who were 40+ years of age. In addition, the prevalence of each defect was higher among women with no record of prenatal care and among women with less than 7 years of education. Hispanic ethnicity was an important predictor for anencephaly, along with sex, maternal age, parity and border residence. However, only border residence and delivery year were significant predictors for spina bifida.

Maternal residential proximity to waste sites and industrial facilities and conotruncal heart defects in offspring

Most studies of the relationship between maternal residential proximity to sources of environmental pollution and congenital cardiovascular malformations have combined heart defects into one group or broad subgroups. The current case-control study examined whether risk of conotruncal heart defects, including subsets of specific defects, was associated with maternal residential proximity to hazardous waste sites and industrial facilities with recorded air emissions. Texas Birth Defects Registry cases were linked to their birth or fetal death certificate. Controls without birth defects were randomly selected from birth certificates. Distances from maternal addresses at delivery to National Priority List (NPL) waste sites, state superfund waste sites, and Toxic Release Inventory (TRI) facilities were determined for 1244 cases (89.5% of those eligible) and 4368 controls (88.0%). Living within 1 mile of a hazardous waste site was not associated with risk of conotruncal heart defects [adjusted odds ratio (aOR) = 0.83, 95% confidence interval (CI) = 0.54, 1.27]. This was true whether looking at most types of defects or waste sites. Only truncus arteriosus showed statistically elevated ORs with any waste site (crude OR: 2.80, 95% CI 1.19, 6.54) and with NPL sites (crude OR: 4.63, 95% CI 1.18, 13.15; aOR 4.99, 95% CI 1.26, 14.51), but the latter was based on only four exposed cases. There was minimal association between conotruncal heart defects and proximity to TRI facilities (aOR = 1.10, 95% CI = 0.91, 1.33). Stratification by maternal age or race/ethnic group made little difference in effect estimates for waste sites or industrial facilities. In this study population, maternal residential proximity to waste sites or industries with reported air emissions was not associated with conotruncal heart defects or its subtypes in offspring, with the exception of truncus arteriosus.

Maternal Residential Proximity to Waste Sites and Industrial Facilities and Oral Clefts in Offspring

Objective: This study examined the association between oral clefts and maternal residential proximity to waste sites or industries. Methods: In a case–control study, maternal residences at birth of 1781 births with oral clefts and 4368 comparison births were related to locations of waste sites and industrial facilities in Texas through geographic information systems. Results: Compared with women who lived farther, women who lived within a mile of these sites or facilities were not more likely to have offspring with oral clefts. Among women ≥35 years, oral clefts in offspring were associated with living within a mile of industrial facilities (odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.3–4.2), especially smelters (OR = 15.0, 95% CI = 2.8–151). Conclusion: These findings suggest that maternal residential proximity to industries might be associated with oral clefts in births to older mothers.