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Background: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation)., Objective: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California., Methods: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000-2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman's residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20-31 and 32-36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies., Results: Spontaneous preterm birth at 20-31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to < 10 mg / L [odds ratio ( OR ) = 1.47 ; 95% confidence interval (CI): 1.29, 1.67] and ≥ 10 mg / L ( OR = 2.52 ; 95% CI: 1.49, 4.26) compared with < 5 mg / L (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32-36 wk were positive but close to the null for 5 to < 10 mg / L nitrate ( OR = 1.08 ; 95% CI: 1.02, 1.15) and for ≥ 10 mg / L nitrate ( OR = 1.05 ; 95% CI: 0.85, 1.31) vs. < 5 mg / L nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design., Discussion: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to < 10 mg / L (below the federal drinking water standard of 10 mg / L ) relative to < 5 mg / L . https://doi.org/10.1289/EHP8205.

Contamination of freshwater ecosystems with nitrate is a growing global concern. Although nitrate pollution is recognized as a cause of aquatic eutrophication, few studies have examined the possible physiological impacts of nitrate exposure. In this study, we surveyed several reproductive variables of viviparous female Gambusia holbrooki (Poeciliidae) captured from eight springs in Florida. The eight springs represent a gradient of nitrate contamination (1-5 mg/L nitrate-nitrogen). We had two objectives in this study: to describe reproductive biology of female mosquitofish in the springs and to understand reproductive variation in the context of water quality, particularly the nitrate concentration. Our data show a significant negative association between nitrate and both dry weight of developing embryos and rate of reproductive activity among mature females. In addition, variation in Gambusia condition index and embryo number and dry weight was related to temperature variation, and hepatic weight was negatively related to dissolved oxygen concentration. Finally, we observed that many of the measured reproductive variables were interrelated and changeable, depending on gestational stage. Specifically, we provide evidence that maternal support of the embryo occurs at least during the first two thirds of gestation and that female fecundity is affected by an apparent tradeoff between embryo size and embryo number.

In this nested case-control study, we investigated the risk factors for methemoglobinemia (MHG) in 71 children in the Transylvania region of Romania. This study was unique in that the exposures for cases and controls were calculated as continuous values and were reported in milligrams per kilogram per day of nitrate/nitrite based on careful dietary reconstruction and environmental sampling. This procedure allowed us to compare point estimates of nitrate/nitrite exposure with other continuous, categoric, and ranked risk factors such as the presence or absence of diarrheal disease, reported severity of diarrheal disease, the use of vitamin supplements, the presence, absence, and/or duration of breast-feeding, and whether or not first-generation relatives experienced MHG. Analysis of these factors and exposure levels using both univariate and multivariate whole-model tests was performed to understand the relative significance of risk factors at varying levels of exposure to the development of MHG. Univariate and multifactorial analysis of risk factors for MHG underscored that, for this population, MHG is most strongly associated with nitrate/nitrite exposure through the dietary route (p = 0.0318), via feeding of formula and tea made with water containing high levels of nitrates, and that breast-feeding protects infants younger than 6 months of age (p = 0.0244). Our findings also raise questions about the role of diarrheal disease in the development of MHG, as likelihood ratios (likelihood 4.323, p = 0.0376) and multifactorial analysis indicated a significant role for diarrheal disease for some individuals.

The use of nitrate-contaminated drinking water to prepare infant formula is a well-known risk factor for infant methemoglobinemia. Affected infants develop a peculiar blue-gray skin color and may become irritable or lethargic, depending on the severity of their condition. The condition can progress rapidly to cause coma and death if it is not recognized and treated appropriately. Two cases of blue baby syndrome were recently investigated. Both cases involved infants who became ill after being fed formula that was reconstituted with water from private wells. Water samples collected from these wells during the infants' illnesses contained nitrate-nitrogen concentrations of 22.9 and 27.4 mg/L.

In recent years, several studies have addressed a possible relationship between nitrate exposure and childhood type 1 insulin-dependent diabetes mellitus. The present ecologic study describes a possible relation between the incidence of type 1 diabetes and nitrate levels in drinking water in The Netherlands, and evaluates whether the World Health Organization and the European Commission standard for nitrate in drinking water (50 mg/L) is adequate to prevent risk of this disease. During 1993-1995 in The Netherlands, 1,104 cases of type 1 diabetes were diagnosed in children 0-14 years of age. We were able to use 1,064 of these cases in a total of 2,829,020 children in this analysis. We classified mean nitrate levels in drinking water in 3,932 postal code areas in The Netherlands in 1991-1995 into two exposure categories. One category was based on equal numbers of children exposed to different nitrate levels (0.25-2.08, 2.10-6.42, and 6.44-41.19 mg/L nitrate); the other was based on cut-off values of 10 and 25 mg/L nitrate. We determined standardized incidence ratios (SIRs) for type 1 diabetes in subgroups of the 2,829,020 children with respect to both nitrate exposure categories, sex, and age and as compared in univariate analysis using the chi-square test for trend. We compared the incidence rate ratios (IRRs) by multivariate analysis in a Poisson regression model. We found an effect of increasing age of the children on incidence of type 1 diabetes, but we did not find an effect of sex or of nitrate concentration in drinking water using the two exposure categories. For nitrate levels > 25 mg/L, an increased SIR and an increased IRR of 1.46 were observed; however, this increase was not statistically significant, probably because of the small number of cases (15 of 1,064). We concluded that there is no convincing evidence that nitrate in drinking water at current exposure levels is a risk factor for childhood type 1 diabetes mellitus in The Netherlands, although a threshold value > 25 mg/L for the occurrence of this disease can not be excluded.

A review of the literature indicated an association among high nitrate ingestion, methemoglobinemia, and pathologic changes in bronchi and lung parenchyma. The present study examined a possible correlation among drinking water nitrate concentration, methemoglobin levels, cytochrome b(5) reductase activity, and acute respiratory tract infection with a history of recurrence (RRTI). Our study was conducted in five village units in the state of Rajasthan, India, with nitrate concentrations of 26, 45, 95, 222, and 459 mg NO(3) ion/L. We randomly selected 88 children. The children were up to 8 years of age, age matched, and represented 10% of the total population of these areas. We obtained detailed RRTI histories and conducted medical examinations. Methemoglobin levels and cytochrome b(5) reductase activity were estimated biochemically. The data collected were statistically analyzed using spreadsheet software on a personal computer. We observed strong interdependence between methemoglobin levels and RRTI in children up to 8 years of age. Methemoglobin levels alone explained 80% of the variation in the RRTI cases. This study indicates that methemoglobinemia, secondary to high nitrate ingestion in drinking water, causes RRTI. Increased production of methemoglobin and free radicals of nitric oxide and oxygen due to nitrate metabolism in the body lead to alveolar damage and mismatching of ventilation and perfusion, which may be the reason for high mortality in children due to RRTI.

Ingestion of nitrates in drinking water has long been thought to be a primary cause of acquired infantile methemoglobinemia, often called blue baby syndrome. However, recent research and a review of historical cases offer a more complex picture of the causes of infantile methemoglobinemia. Gastrointestinal infection and inflammation and the ensuing overproduction of nitric oxide may be the cause of many cases of infantile methemoglobinemia previously attributed to drinking water nitrates. If so, current limits on allowable levels of nitrates in drinking water, which are based solely on the health threat of infantile methemoglobinemia, may be unnecessarily strict.

Formation of nitrite from ingested nitrate can result in several adverse health effects and implies a genotoxic risk as a consequence of endogenous formation of carcinogenic N-nitroso compounds. We studied the formation of volatile N-nitrosamines after intake of nitrate at the acceptable daily intake (ADI) level in combination with a fish meal rich in amines as nitrosatable precursors. Twenty-five volunteers consumed this meal during 7 consecutive days; a diet low in nitrate was consumed during 1 week before and 1 week after the test week. Nitrate intake at the ADI level resulted in a significant rise in mean salivary nitrate and nitrite concentrations. Mean urinary nitrate excretion increased from 76 mg/24 hr in the first control week to 194 and 165 mg/24 hr in the test week, followed by a decline to 77 mg/24 hr in the second control week. The urine samples were analyzed for volatile N-nitrosamines, and both N-nitrosodimethylamine (NDMA) and N-nitrosopiperidine (NPIP) were detected in the samples. Mean urinary NDMA excretion significantly increased from 287 ng/24 hr in the control week to 871 and 640 ng/24 hr in the test week and declined to 383 ng/24 hr in the second control week. Excretion of NPIP was not directly related to the nitrate intake and composition of the diet. Nitrate excretion and NDMA excretion were significantly correlated, as well as salivary nitrate and nitrite concentration and NDMA excretion. We conclude that nitrate intake at the ADI level in combination with a fish meal containing nitrosatable precursors increases NDMA excretion in urine and thus demonstrates increased formation of carcinogenic N-nitrosamines.

We studied peripheral lymphocyte HPRT variant frequency and endogenous nitrosation in human populations exposed to various nitrate levels in their drinking water. Four test populations of women volunteers were compared. Low and medium tap water nitrate exposure groups (14 and 21 subjects) were using public water supplies with nitrate levels of 0.02 and 17.5 mg/l, respectively. Medium and high well water nitrate exposure groups (6 and 9 subjects) were using private water wells with mean nitrate levels of 25 and 135 mg/l, respectively. Higher nitrate intake by drinking water consumption resulted in a dose-dependent increase in 24-hr urinary nitrate excretion and in increased salivary nitrate and nitrite levels. The mean log variant frequency of peripheral lymphocytes was significantly higher in the medium well water exposure group than in the low and medium tap water exposure groups. An inverse correlation between peripheral lymphocyte labeling index and nitrate concentration of drinking water was observed. Analysis of N-nitrosamine in the urine of 22 subjects by gas chromatography-mass spectrometry revealed the presence of N-nitrosopyrrolidine in 18 subjects. Analysis of the mutagenicity of well water samples showed that a small number of the well water samples were mutagenic in the Ames Salmonella typhimurium test after concentration over XAD-2 resin. In conclusion, consumption of drinking water, especially well water, with high nitrate levels can imply a genotoxic risk for humans as indicated by increased HPRT variant frequencies and by endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite.

Nitrate contamination of drinking water implies a genotoxic risk to man due to the endogenous formation of carcinogenic N-nitroso compounds from nitrate-derived nitrite. Thus far, epidemiological studies have presented conflicting results on the relation of drinking water nitrate levels with gastric cancer incidence. This uncertainty becomes of relevance in view of the steadily increasing nitrate levels in regular drinking water supplies. In an attempt to apply genetic biomarker analysis to improve the basis for risk assessment with respect to drinking water nitrate contamination, this study evaluates peripheral lymphocyte chromosomal damage in human populations exposed to low, medium, and high drinking water nitrate levels, the latter being present in private water wells. It is shown that nitrate contamination of drinking water causes dose-dependent increases in nitrate body load as monitored by 24-hr urinary nitrate excretion in female volunteers, but this appears not to be associated with peripheral lymphocyte sister chromatid exchange frequencies.

Research on human exposure to acidic aerosols and the health effects of such exposures has substantially strengthened the hypothesis that such aerosols are a causal factor for excesses in human mortality and morbidity that have been previously associated with crude exposure indices such as British Smoke, total suspended particulate matter, and sulfur dioxide. Research reported at this symposium also showed that combined exposures to acid aerosols and other ubiquitous air pollutants such as O3, NO2, HNO3, and SO2 produce greater effects in both humans and animals than exposures to each agent separately. The responses reported ranged from physiological functions to lung structure. Furthermore, some of the effects were cumulative with increasing duration of daily exposure and number of repetitive exposures. Critical areas for further research include better definition of the critical temporal parameters affecting exposure and response, effects of mixed pollutant exposures, and pathogenetic mechanisms for acid aerosol-induced chronic lung damage.

In several regions of Czechoslovakia with intensive agricultural production, the correlation between the amount of nitrogen fertilizer applied and the nitrate content in groundwater has been recognized. Nitrate pollution of groundwater is considered to be the most serious source of nonpoint pollution in Czechoslovakia. A program of research into the effects of farming activities on groundwater quality in Czechoslovakia is under way on experimental fields (20 to 30 hectares) and, simultaneously, in regions in which shallow, vulnerable aquifers occur. The importance of the soil organic matter's stability for maintaining the groundwater quality is emphasized. Research based on nitrogen and organic carbon balance has shown that the restoration of a soil-groundwater system is a complicated process that usually requires changes in the extent and intensity of agricultural activities and consistent attention to the effects produced by natural conditions. Regional investigation of the impact of farming on shallow aquifers in the fluvial deposits of the Elbe River in Bohemia has proved the hydrochemical instability and vertical hydrochemical heterogeneity of these aquifers. The WASTEN deterministic model was used for modeling the transport and transformation of various types of inorganic fertilizers. The input data is based on laboratory and field measurements. Special topics are the verification of model calculations and the time and spatial variability of input data with respect to the unsaturated zone. The research results are being used for making regional and national agro-groundwater managerial schemes more precise, as well as for decision-making.

Acid fog is complex and contains multiple stimuli that may be capable of inducing bronchoconstriction. These stimuli include sulfuric and niric acids, the principal inorganic acids present; sulfites, formed in the atmosphere as a reaction product of sulfur dioxide and water droplets; fog water itself, a hypoosmolar aerosol; the organic acid hydroxymethanesulfonate, the bisulfite adduct of formaldehyde; and gaseous pollutants, e.g., sulfur dioxide, oxides of nitrogen, ozone. Given this complexity, evaluation of the respiratory health effects of naturally occurring acid fog requires assessment of the bronchoconstrictor potency of each component stimulus and possible interactions among these stimuli. We summarize the results of three studies that involve characterization of the bronchoconstrictor potency of acid fog stimuli and/or their interaction in subjects with asthma. The results of the first study indicate that titratable acidity appears to be a more important stimulus to bronchoconstriction than is pH. The results of the second study demonstrate that sulfite species are capable of inducing bronchoconstriction, especially when inhaled at acid pH. The results of the third study suggest that acidity can potentiate hypoosmolar fog-induced bronchoconstriction.

Utilization of wastes from livestock complexes for irrigation involves the danger of groundwater pollution by nitrates. In order to prevent and minimize pollution, it is necessary to apply geological-hydrogeological evidence and concepts to the situation of wastewater irrigation for the purposes of studying natural groundwater protectiveness and predicting changes in groundwater quality as a result of infiltrating wastes. The procedure of protectiveness evaluation and quality prediction is described. With groundwater pollution by nitrate nitrogen, the concentration of ammonium nitrogen noticeably increases. One of the reasons for this change is the process of denitrification due to changes in the hydrogeochemical conditions in a layer. At representative field sites, it is necessary to collect systematic stationary observations of the concentrations of nitrogenous compounds in groundwater and changes in redox conditions and temperature.

There is concern about the human health effects of inhalation of acid compounds found in urban air pollution. It was the purpose of this study to investigate three of these acid compounds, sulfur dioxide (SO2), sulfuric acid (H2SO4), and nitric acid (HNO3) in a group of allergic adolescent subjects. Subjects were exposed during rest and moderate exercise to 0.7 mumole/m3 (68 micrograms/m3) H2SO4, 4.0 mumole/m3 (0.1 ppm) SO2, or 2.0 mumole/m3 (0.05 ppm) HNO3. Pulmonary functions (FEV1, total respiratory resistance, and maximal flow) were measured before and after exposure. Preliminary analysis based on nine subjects indicates that exposure to 0.7 mumole/m3 H2SO4 alone and in combination with SO2 caused significant changes in pulmonary function, whereas exposure to air or SO2 alone did not. FEV1 decreased an average of 6% after exposure to H2SO4 alone and 4% when the aerosol was combined with SO2. The FEV1 decrease was 2% after both air and SO2 exposures. Total respiratory resistance (RT) increased 15% after the combined H2SO4 exposures, 12% after H2SO4 alone, and 7% after exposure to air. After exposures to HNO3 alone, FEV1 decreased by 4%, and RT increased by 23%. These results are preliminary; final conclusions must wait for completion of the study.

The effects of ambient relative humidity and particle size on acid deposition within the airways have been examined with a computer model. For H2SO4 particles initially at 90% relative humidity in ambient air that are inhaled via the nose or mouth, there is significant deposition of acid in the airways even in the presence of typical values of respiratory NH3. When these same particles are found in a fog at 100.015% relative humidity, there is significant deposition of acid in the nasal region during nose breathing but insignificant deposition to the deep lung for either nose or mouth breathing. The factors governing the partitioning of labile acid gases in the gas and liquid phases prior to inhalation are also discussed.