Executive Summary

The Safe Drinking Water Act directs the U.S. Environmental Protection Agency (EPA) to establish national drinking-water standards for chemical and biological contaminants in public water supplies. The standards are to be set at concentrations at which no adverse effects on human health occur or are expected to occur from lifetime consumption, allowing a margin of safety; enforceable standards are standards that are feasible to achieve with the use of the best technology available. The standards are to be reviewed periodically to ensure continued protection of public health.

Consistent with the requirement for periodic review, EPA asked the National Research Council to evaluate the current drinking-water maximum-contaminant-level goals (MCLGs) and maximum contaminant levels (MCLs) for nitrate and nitrite in public water supplies. The Subcommittee on Nitrate and Nitrite in Drinking Water, convened under National Research Council procedures, reviewed information on the occurrence and toxicity of nitrate and



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Nitrate and Nitrite in Drinking Water Executive Summary The Safe Drinking Water Act directs the U.S. Environmental Protection Agency (EPA) to establish national drinking-water standards for chemical and biological contaminants in public water supplies. The standards are to be set at concentrations at which no adverse effects on human health occur or are expected to occur from lifetime consumption, allowing a margin of safety; enforceable standards are standards that are feasible to achieve with the use of the best technology available. The standards are to be reviewed periodically to ensure continued protection of public health. Consistent with the requirement for periodic review, EPA asked the National Research Council to evaluate the current drinking-water maximum-contaminant-level goals (MCLGs) and maximum contaminant levels (MCLs) for nitrate and nitrite in public water supplies. The Subcommittee on Nitrate and Nitrite in Drinking Water, convened under National Research Council procedures, reviewed information on the occurrence and toxicity of nitrate and

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Nitrate and Nitrite in Drinking Water nitrite. The subcommittee evaluated this information in the context of the drinking-water standards for those substances and drew conclusions about the adequacy of the current standards to protect human health. HAZARD IDENTIFICATION Methemoglobinemia is the primary adverse health effect associated with human exposure to nitrate or nitrite. To cause methemoglobinemia, nitrate must be converted to nitrite. Methemoglobinemia occurs when nitrite oxidizes the Fe2+in hemoglobin to Fe3+, a form that does not allow oxygen transport. Methemoglobinemia can lead to cyanosis (insufficient oxygenation of the blood characterized by bluish skin and lips) and, ultimately, death. Methemoglobinemia in adults is rare; most methemoglobinemia victims are infants who have been fed formula mixed with nitrate-containing well water or food with a high nitrate content or who have diarrhea. Results of epidemiologic studies are inadequate to support an association between high nitrate or nitrite exposure from drinking water in the United States and increased cancer rates in humans. In laboratory animals, nitrate and nitrite are not carcinogenic unless they are administered concurrently with nitrosatable amines. Studies in humans are also inadequate to support an association between nitrite or nitrate exposure and reproductive or developmental effects. Results of studies in laboratory animals suggest that reproductive and developmental toxicity might occur, primarily at high doses, which also can produce maternal methemoglobinemia. At high doses, inorganic nitrite, but not nitrate, can produce hypotension in humans as a result of its action as a smooth muscle relaxer.

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Nitrate and Nitrite in Drinking Water DOSE-RESPONSE ASSESSMENT The toxic effects of nitrate are closely related to its conversion to nitrite by bacteria in the alimentary tract. These effects depend not only on dose, but also on the concentration and type of bacteria present. Dose-response relationships are highly variable among species. Studies that include dose information have reported nitrate-induced methemoglobinemia in infants occurring very rarely at nitrate concentrations below 50 mg/L; most of the cases occurred when bacterial contamination of water supplies was present as well. Infection resulting from bacterial contamination can increase endogenous nitrate production. In adults, methemoglobinemia has been reported only in cases of accidental ingestion of large amounts of nitrite. However, the concentration of methemoglobin that constitutes an adverse health effect has not been established definitively. Other factors, such as infantile diarrhea, can influence methemoglobin concentrations as a result of endogenous nitrate synthesis in the absence of increased concentrations of nitrate in food or water. A discussion of dose-response relationships between human carcinogenesis and nitrate or nitrite exposure is not appropriate without supporting epidemiologic data and a physiologically based pharmacokinetic model that would permit analysis of the complex relationships between exogenous and endogenously formed nitrate, nitrite, and N-nitrosamines. In addition, because there is no evidence that either nitrate or nitrite alone is carcinogenic in animals, a discussion of dose-response relationships between carcinogenesis in animals and nitrate or nitrite exposure is not possible. The only evidence of a role of nitrite in carcinogenesis comes from studies in which nitrite was administered to laboratory animals simultaneously with a nitrosatable amine; in these cases, carcinogenesis can be

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Nitrate and Nitrite in Drinking Water attributed to the endogenous formation of carcinogenic nitrosamines. No studies in humans have demonstrated reproductive or developmental effects that can be attributed to nitrate or nitrite toxicity, so developing dose-response relationships based on human data is not possible. One study reported that nitrate produced alterations in rat neurobehavioral development, although the study has several drawbacks. Developmental effects of nitrite that have been reported in rodents appear to result from exposure after birth and not in utero. Further research on the possible reproductive or developmental effects of nitrate and nitrite would be helpful. Human dosages equivalent to those that elicited developmental effects in rodents were calculated. The vasodilator effects of sodium nitrite in humans overlap the dosage ranges that cause methemoglobinemia. EXPOSURE ASSESSMENT Most nitrate and nitrite to which humans are exposed is in their diet, as either natural components or intentional additives. A previous Natinal Research Council report on the health effects of nitrate, nitrite, and N-nitroso compounds concluded that for more than 99% of the U.S. population, about 97% of nitrate intake comes from the diet (99% in the case of vegetarians) and about 99% of nitrite intake comes from the diet. Vegetables are the primary source of nitrate and nitrite in food. Inorganic fertilizers and human and animal wastes (from livestock operations and septic tanks) are the primary sources of nitrate and nitrite contamination of drinking water. Nitrate released to soil as a result of human or animal activities can enter groundwater or surface water as a result of leaching or runoff. Some nitrate and nitrite exposure also originates in endogenous production of nitric oxide by many

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Nitrate and Nitrite in Drinking Water types of cells. Endogenous nitrate formation occurs at a rate that constitutes about 50% of total nitrate exposure for most of the U.S. population. Infections and inflammatory reactions can increase endogenous nitrate synthesis in both infants and adults. Estimates of daily intake indicate that drinking water is not an important contributor to nitrite exposure and that it contributes substantially to nitrate exposure only in areas of notable contamination. RISK CHARACTERIZATION When EPA evaluated the toxicity of nitrate and nitrite for the purpose of establishing drinking-water criteria, it did not assign a weight-of-evidence classification for their carcinogenic potential (EPA 1990a). EPA concluded that there are no convincing data to suggest that nitrate or nitrite is associated with any adverse effect other than methemoglobinemia, and it identified a no-observed-adverse-effect level (NOAEL) for nitrate of 10 mg of nitrate nitrogen per liter (1.6 mg/kg-day) on the basis of epidemiologic studies (Walton 1951). That value is equivalent to nitrate at 44 mg/L. To obtain a reference dose (RfD) from the NOAEL, an uncertainty factor of 1 was used because the NOAEL was derived from studies in humans of the most sensitive subpopulation. For nitrite, EPA assumed that the conversion rate of nitrate to nitrite by gastrointestinal tract bacteria in infants is about 10%, from which an RfD of 1 mg of nitrite nitrogen per liter (0.16 mg/kg-day) was calculated. That value is equivalent to nitrite at 3.3 mg/L. The MCLGs for nitrate and nitrite are based on these RfDs: nitrate nitrogen at 10 mg/L and nitrite nitrogen at 1 mg/L (EPA 1991). The subcommittee concluded that exposure to the nitrate concentrations found in drinking water in the United States is unlikely to contribute to human cancer risk. Attempting to limit

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Nitrate and Nitrite in Drinking Water nitrate or nitrite exposure on the basis of carcinogenicity would implicate the diet, and vegetables in particular, as the primary source of risk for most of the U.S. population. But diets rich in vegetables have consistently been shown to reduce cancer risk. Any theoretical cancer risk should be weighed against the benefits of eating vegetables. Regulating exogenous nitrate exposure on the basis of carcinogenicity would also be inconsistent with endogenous nitrate formation. Available data are inadequate to support an association between nitrate and nitrite exposure from drinking water and any noncancer effects except for methemoglobinemia in infants, which might occur as a result of exposure to nitrate-contaminated water or to vegetables with high concentrations of nitrate or as a result of increased endogenous nitrate synthesis in cases of infection. Limiting infant exposure to nitrate would be a sensible public-health measure. It could be accomplished by minimizing exposure to both foods and water that are high in nitrate and by protecting infants from infection. Infection is the major contributor to methemoglobinemia from nitrate exposure; the incremental contribution of drinking water is negligible. There are very few published reports of methemoglobinemia occurring at concentrations of drinking-water nitrate less than 50 mg/L, and these are of uncertain quality. In addition, no cases of methemoglobinemia occurring at exposure concentrations less than 50 mg/L have been reported in the United States. The absence of reported cases might in part be due to the lack of requirements for reporting cases of methemoglobinemia. The subcommittee concludes that EPA's current MCLGs and MCLs of nitrate at 44 mg/L (nitrate nitrogen at 10 mg/L) and nitrite at 3.3 mg/L (nitrite nitrogen at 1 mg/L) are adequate to protect human health. The MCLGs for nitrate and nitrite are identical with their MCLs because the technology needed to implement the MCLGs is considered available and inexpensive.

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Nitrate and Nitrite in Drinking Water Nitrate and Nitrite in Drinking Water

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