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

By Brender, Jean D.; Weyer, Peter J. et al. | Environmental Health Perspectives, September 2013 | Go to article overview

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


Brender, Jean D., Weyer, Peter J., Romitti, Paul A., Mohanty, Binayak P., Shinde, Mayura U., Vuong, Ann M., Sharkey, Joseph R., Dwivedi, Dipankar, Horel, Scott A., Kantamneni, Jiji, Huber, John C., Jr., Zheng, Qi, Werler, Martha M., Kelley, Katherine E., Griesenbeck, John S., Zhan, F. Benjamin, Langlois, Peter H., Suarez, Lucina, Canfield, Mark A., Environmental Health Perspectives


Introduction

Nitrate is one of the most widespread chemical contaminants in aquifers around the world (Spalding and Exner 1993). Results from several epidemiologic studies have suggested an association between prenatal exposure to nitrates in drinking water and birth defects in offspring, including neural tube defects (NTDs) (Brender et al. 2004; Croen et al. 2001; Dorsch et al. 1984), central nervous system defects overall (Arbuckle et al. 1988), oral cleft defects (Dorsch et al. 1984), musculoskeletal defects (Dorsch et al. 1984), and congenital heart defects (Cedergren et al. 2002). In these studies, exposure was assigned on the basis of nitrate levels detected in drinking-water sources without further estimating individual consumption of nitrate from such sources. It is noteworthy that previous associations observed between birth defects and nitrates in drinking water were often observed at levels below the current allowable maximum contaminant level for nitrate (10 mg/L as nitrate-nitrogen or 45 mg/L as total nitrate) set by the U.S. Environmental Protection Agency (National Primary Drinking Water Regulations 2010).

Once ingested and absorbed, approximately 25% of nitrate is secreted in saliva (Mensinga et al. 2003), where about 20% is converted to nitrite by bacteria in the mouth (Spiegelhalder et al. 1976). This endogenously formed nitrite, along with nitrite from dietary and drinking-water sources, can react with nitrosatable compounds such as amine- and amide-containing drugs to form N-nitroso compounds in the stomach (Gillatt et al. 1985). N-Nitroso compounds have been found to be teratogens in animal models (Nagao et al. 1991; Platzek et al. 1983). These compounds are formed to a greater extent in the presence of a nitrosatable compound if nitrite concentration is high (Choi 1985); and when combined with higher nitrite, nitrosatable compounds have been reported to be more strongly associated with exencephaly and skeletal malformations in mice (Teramoto et al. 1980) and with NTDs (Brender et al. 2004, 2011b) and other types of birth defects in humans (Brender et al. 2012). In a small case-control study of Mexican-American women, nitrosatable drug exposure was more strongly associated with NTDs in offspring of women whose drinking-water nitrate measured [greater than or equal to] 3.5 mg/L than among births to women with lower measured nitrate in their drinking water (Brender et al. 2004).

The objectives of our study were to

a) examine the relation between prenatal exposure to drinking-water nitrate and birth defects in offspring (selected from defect groups previously associated with higher nitrate in drinking water), accounting for maternal water consumption patterns; and

b) investigate whether higher daily exposure to drinking-water nitrate or total nitrite that included contributions from diet and drinking water strengthened associations between prenatal exposure to nitrosatable drugs and selected birth defects in offspring.

Methods

Study population and design. To address the study objectives, we used data from the Iowa and Texas sites of the National Birth Defects Prevention Study (NBDPS), an ongoing population-based case-control study of birth defects in the United States (includes sites in 10 states) that began in 1997 (Yoon et al. 2001). The Iowa and Texas sites identify deliveries with major birth defects from live births, stillbirths, and elective terminations as part of their population-based birth defect surveillance. In the NBDPS, case classification is standardized, and clinical information on potentially eligible births is evaluated by a clinical geneticist at each study site and also independently reviewed by one or more other clinical geneticists. For the present study, women with estimated dates of delivery from 1 October 1997 through 31 December 2005 who had deliveries with an NTD, oral cleft, limb deficiency, or congenital heart defect were included. …

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