Nitrate and Nitrite in Drinking Water [1 ed.] 9780309573153
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Copyright © 1995. National Academies Press. All rights reserved.
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i
Nitrate and Nitrite in Drinking Water
Subcommittee on Nitrate and Nitrite in Drinking Water Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council
NATIONAL ACADEMY PRESS WASHINGTON D.C. 1995
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ii NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce M. Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Harold Liebowitz is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce Alberts and Dr. Harold Liebowitz are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the U.S. Environmental Protection Agency under contract No. DAMD17-89-C-9086. Additional copies of this report are available from the Board on Environmental Studies and Toxicology, 210l Constitution Ave., N.W., Washington, D.C. 20418 Copyright 1995 by the National Academy of Sciences. Printed in the United States of America
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SUBCOMMITTEE ON NITRATE AND NITRITE IN DRINKING WATER GERALD N. WOGAN (Chairman), Massachusetts Institute of Technology, Cambridge, Mass. WALDERICO GENEROSO, Oak Ridge National Laboratory, Oak Ridge, Tenn. LOREN D. KOLLER, Oregon State University, Corvallis, Oreg. ROGER P. SMITH, Dartmouth Medical School, Hanover, N.H. STEVEN R. TANNENBAUM, Massachusetts Institute of Technology, Cambridge, Mass. Staff GAIL CHARNLEY, Project Director NORMAN GROSSBLATT, Editor LUCY V. FUSCO, Project Assistant CATHERINE M. KUBIK, Senior Project Assistant Sponsor: U.S. Environmental Protection Agency
Nitrate and Nitrite in Drinking Water, National Academies Press, 1995. ProQuest Ebook Central,
Nitrate and Nitrite in Drinking Water, National Academies Press, 1995. ProQuest Ebook Central,
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Copyright © 1995. National Academies Press. All rights reserved.
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COMMITTEE ON TOXICOLOGY ROGENE F. HENDERSON (Chair), Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. DONALD E. GARDNER (Vice Chair), Raleigh, N.C. DEBORAH A. CORY-SLECHTA, University of Rochester School of Medicine, Rochester, N.Y. ELAINE FAUSTMAN, School of Public Health and Community Medicine, University of Washington, Seattle, Wash. CHARLES E. FEIGLEY, University of South Carolina, Columbia, S.C. DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Ark. WALDERICO M. GENEROSO, Oak Ridge National Laboratory, Oak Ridge, Tenn. IAN A. GREAVES, University of Minnesota, Minneapolis, Minn. SIDNEY GREEN, U.S. Food and Drug Administration, Laurel, Md. LOREN D. KOLLER, Oregon State University, Corvallis, Oreg. MICHELE A. MEDINSKY, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, N.Y. ROBERT SNYDER, Rutgers University, Piscataway, N.J. ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tenn. HANSPETER R. WITSCHI, University of California, Davis, Calif. GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge, Mass. GAROLD S. YOST, University of Utah, Salt Lake City, Utah
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Staff
KULBIR S. BAIKSHI, Program Director for the Committee on Toxicology MARVIN A. SCHNEIDERMAN, Senior Staff Scientist RUTH E. CROSSGROVE, Editor CATHERINE M. KUBIK, Senior Program Assistant SHARON HOLZMANN, Administrative Associate LUCY V. FUSCO, Project Assistant
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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY PAUL G. RISSER (Chair), Miami University, Oxford, Ohio MICHAEL J. BEAN, Environmental Defense Fund, Washington, D.C. EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio EDWIN H. CLARK II, Clean Sites, Inc., Alexandria, Va. ALLAN H. CONNEY, Rutgers University, Piscataway, N.J. ELLIS COWLING, North Carolina State University, Raleigh, N.C. JOHN L. EMMERSON, Eli Lilly & Company, Greenfield, Ind. ROBERT C. FORNEY, Unionville, Pa. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. KAI LEE, Williams College, Williamstown, Mass. JANE LUBCHENCO, Oregon State University, Corvallis, Ore. GORDON ORIANS, University of Washington, Seattle, Wash. FRANK L. PARKER, Vanderbilt University, Nashville, Tenn. GEOFFREY PLACE, Hilton Head, S.C. DAVID P. RALL, Washington, D.C. LESLIE A. REAL, Indiana University, Bloomington, Ind. KRISTIN SHRADER-FRECHETTE, University of South Florida, Tampa, Fla. BURTON H. SINGER, Princeton University, Princeton, N.J. MARGARET STRAND, Bayh, Connaughton and Malone, Washington, D.C. GERALD VAN BELLE, University of Washington, Seattle, Wash. BAILUS WALKER, JR., Howard University, Washington, D.C.
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Staff
JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology CAROL A. MACZKA, Program Director for Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering
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COMMISSION ON LIFE SCIENCES THOMAS D. POLLARD (Chair), Johns Hopkins Medical School, Baltimore, Md. BRUCE N. AMES, University of California, Berkeley, Calif. JOHN C. BAILAR III, McGill University, Montreal, Quebec MICHAEL BISHOP, Hooper Research Foundation, University of California Medical Center, San Francisco, Calif. JOHN E. BURRIS, Marine Biological Laboratory, Woods Hole, Mass. MICHAEL T. CLEGG, University of California, Riverside, Calif. GLENN A. CROSBY, Washington State University, Pullman, Wash. MARIAN E. KOSHLAND, University of California, Berkeley, Calif. RICHARD E. LENSKI, Michigan State University, East Lansing, Mich. EMIL A. PFITZER, Hoffmann-La Roche Inc., Nutley, N.J. MALCOLM C. PIKE, University of Southern California School of Medicine, Los Angeles, Calif. HENRY C. PITOT III, University of Wisconsin, Madison, Wisc. JONATHAN M. SAMET, The Johns Hopkins University School of Medicine, Baltimore, Md. HAROLD M. SCHMECK JR., Armonk, N.Y. CARLA J. SHATZ, University of California, Berkeley, Calif. SUSAN S. TAYLOR, University of California at San Diego, La Jolla, Calif. P. ROYVAGELOS, Merck & Company, Whitehouse Station, N.J. JOHN L. VANDEBERG, Southwestern Foundation for Biomedical Research, San Antonio, Tex. PAUL GILMAN, Executive Director
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OTHER RECENT REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
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Other Recent Reports of the Board on Environmental Studies and Toxicology
Science and the Endangered Species Act (1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Sites for Remedial Action (1994) Review of EPA's Environmental Monitoring and Assessment Program: Forests and Estuaries (1994) Review of EPA's Environmental Monitoring and Assessment Program: Surface Waters (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Biologic Markers in Immunotoxicology (1992) Dolphins and the Tuna Industry (1992) Environmental Neurotoxicology (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV ( 1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Tracking Toxic Substances at Industrial Facilities (1990) Biologic Markers in Pulmonary Toxicology (1989) Biologic Markers in Reproductive Toxicology (1989) Copies of these reports may be ordered from the National Academy Press: (800) 624-6242; (202) 334-3313
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CONTENTS
EXECUTIVE SUMMARY 1
1 INTRODUCTION AND BACKGROUND 9
2 HAZARD IDENTIFICATION Methemoglobinemia Cancer Reproductive and Developmental Toxicity Other Effects 13 13 15 23 27
3 DOSE-RESPONSE ASSESSMENT Methemoglobinemia Cancer Reproductive and Developmental Toxicity Other Effects 29 29 31 32 33
4 EXPOSURE ASSESSMENT Exposure from Food and Water Endogenous Synthesis Estimated Daily Intake Biologic Fate 35 35 37 37 42
5
RISK CHARACTERIZATION Cancer Risks Noncancer Risks
45 46 48
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xii
APPENDIX A Physiologically Based Pharmacokinetic Model for Assessing the Risk of Cancer Associated with Nitrate Exposure 51
REFERENCES 53
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xiii
Nitrate and Nitrite in Drinking Water
Nitrate and Nitrite in Drinking Water, National Academies Press, 1995. ProQuest Ebook Central,
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xiv
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EXECUTIVE SUMMARY
1
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 maximumcontaminant-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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EXECUTIVE SUMMARY
2
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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EXECUTIVE SUMMARY
3
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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EXECUTIVE SUMMARY
4
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 doseresponse 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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EXECUTIVE SUMMARY
5
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 noobserved-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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EXECUTIVE SUMMARY
6
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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INTRODUCTION AND BACKGROUND
9
1 Introduction and Background
Under the Safe Drinking Water Act, the U.S. Environmental Protection Agency (EPA) establishes the concentrations of contaminants that are permitted in public drinking-water supplies. Specifically, Section 1412 of the act, as amended in 1986, requires EPA to publish maximum-contaminant-level goals (MCLGs) and promulgate national primary drinking-water regulations for contaminants in drinking water that might cause any adverse effect on health and that are known or expected to occur in public water systems. The act defines public water systems as systems that provide piped water for human consumption and that have at least 15 connections or regularly serve at least 25 people. MCLGs are to be concentrations at which no known or expected adverse health effects occur and are to allow an adequate margin of safety. The Safe Drinking Water Act also requires EPA to review its existing standards periodically and incorporate new data if they are available. To that end, the EPA Office of Water has asked the
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INTRODUCTION AND BACKGROUND
10
National Research Council to review the current basis of its MCLGs for nitrate and nitrite in drinking water and to determine whether they are protective of public health. The Research Council, through the Board on Environmental Studies and Toxicology in the Commission on Life Sciences, convened a subcommittee of the Committee on Toxicology and asked it to: • Review the current toxicologic and exposure data on nitrate and nitrite. • Characterize the risk associated with nitrate and nitrite exposure through drinking water. • Determine whether the current MCLGs for nitrate and nitrite are adequate to protect public health. • Identify data needs and make recommendations for future research. Throughout this report, by the Subcommittee on Nitrate and Nitrite in Drinking Water, concentrations of nitrate and nitrite are expressed in terms of milligrams per liter (mg/L). Another common unit of measurement is milligrams of nitrate nitrogen or nitrite nitrogen per liter. The nitrogen oxides have multiple interconvertible forms, although the deleterious effects of concern arise through a common intermediate. Each of the precursors of that intermediate has a different molecular weight; using a weight measure, such as milligrams, to evaluate usefully the relative contribution of nitrite versus nitrate, for example, requires a conversion factor. The conversion factors are 1 mg of NO3- per liter = 0.226 mg of NO3- nitrogen per liter, 1 mg of NO3- nitrogen per liter = 4.429 mg of NO3-per liter, 1 mg of NO2- per liter = 0.304 mg of NO2- nitrogen per liter,
and 1 mg of NO2 - nitrogen per liter = 3.290 mg of NO2- per liter.
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INTRODUCTION AND BACKGROUND
11
Use of either unit does not permit easy comparisons between nitrate and nitrite or from one medium to another, however, because such concentrations are not comparable on a molar basis. The appropriate unit for comparisons is the mole (or millimole): 1 mmol per liter = 62 mg of NO3- per liter = 46 mg of NO2- per liter, and 1 mmol per liter = 14 mg of NO3- nitrogen per liter = 14 mg of NO2nitrogen per liter. Nitrate is a normal component of the human diet. The National Research Council report The Health Effects of Nitrate, Nitrite, and N- Nitroso Compounds (NRC 1981) estimated that a typical daily intake of nitrate by an adult in the United States is about 75 mg. Over 85% of that comes from the natural nitrate content of vegetables, such as beets, celery, lettuce, and spinach. Daily intakes of nitrate by vegetarians can exceed 250 mg/day (NRC 1981). The contribution of drinking water to daily nitrate intake is usually only about 2-3% of the total (NRC 1981). The toxic effects of nitrate are closely related to its conversion to nitrite by bacteria in the alimentary tract, and depends not only on dose, but also on the concentration and type of bacteria present. Therefore, dose-response relationships are highly variable among animal species. The current MCLG for nitrate in drinking water is 10 mg/L, and that for nitrite is 1 mg/L; both are measured as nitrogen (EPA 1991). The equivalent values are 44 mg of nitrate per liter and 3.3 mg of nitrite per liter. Those values are based on methemoglobinemia, the principal toxic effect observed in humans exposed to nitrate or nitrite. Methemoglobinemia occurs when nitrite oxidizes the Fe2+ in hemoglobin to Fe 3+, a form that does not allow oxygen transport. This report reviews the basis of EPA's current MCLGs and evidence of health effects that might result from nitrate or nitrite
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exposure in addition to methemoglobinemia, such as cancer and reproductive and developmental effects. It then characterizes the dose-response relationships between exposure and health effects. The human exposure to nitrate and nitrite and the relative contribution of drinking water to that exposure are assessed. Finally, the MCLGs that provide adequate margins of safety for human health are identified.
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HAZARD IDENTIFICATION
13
2 Hazard Identification
This chapter summarizes the qualitative aspects of the health effects known to be associated with nitrate and nitrite exposure. METHEMOGLOBINEMIA The primary adverse health effect associated with human exposure to nitrate or nitrite is methemoglobinemia. Nitrite converts hemoglobin to methemoglobin by oxidizing the Fe2+in heme to Fe3+, which cannot transport oxygen. Low concentrations of methemoglobin (0.5-3.0%) occur in normal people, although concentrations up to 10% can occur without clinical signs (EPA 1990a; Walton 1951). Concentrations above 10% can cause cyanosis, characterized by bluish skin and lips, and concentrations above 25% are associated with hypotension, rapid pulse, and rapid breathing, as a result of the vasodilator effects of nitrite. Concentrations above 50% can be fatal (EPA 1990a).
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HAZARD IDENTIFICATION
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To cause methemoglobinemia, nitrate must be converted to nitrite. The conversion is performed by bacteria in the mouth and stomach. The extent of toxicity of nitrate depends on the extent to which it is converted to nitrite, which depends on the concentration and type of bacteria in the mouth and stomach. In adults, the acidity of the stomach is usually great enough that bacterial growth and the consequent conversion of nitrate to nitrite are negligible; probably about 5% of a dose of nitrate is reduced to nitrite, on average (ECETOC 1988), and methemoglobinemia is rare. In infants, however, the low gastric acidity is thought to favor the growth of nitrate-reducing bacteria, and infants are the group most susceptible to methemoglobinemia. Most infant victims of methemoglobinemia have reportedly been fed infant formula mixed with well water that contained high concentrations of nitrate, but cases have also been associated with the consumption of spinach and carrots, which are high in nitrate and nitrite (Bruning-Fann and Kaneene 1993). However, several authors have reported that achlorhydria and gastric nonsterility are rare in infants, even infants with methemoglobinemia (Bodo 1955; Simon et al. 1962; Agunod et al. 1969); that observation suggests a role of pathways other than gastrointestinal nitrite synthesis. Other investigators have reported that infant gastric acidity is low enough to support bacterial growth (EPA 1990a). Hegesh and Shiloah (1982) studied newborns hospitalized for acute diarrhea and found no correlation between ingestion of food or water containing high concentrations of nitrate or nitrite and methemoglobinemia; they concluded that endogenous synthesis of nitrite resulting from diarrhea was the principal cause of infantile methemoglobinemia. Thus, diarrhea apparently can be a major cause of infant methemoglobinemia unrelated to the nitrate content of food and water (endogenous synthesis is discussed in Chapter 4). A 1990 EPA publication (EPA 1990a) provides a thorough review of the literature available on the occurrence of methemoglo
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HAZARD IDENTIFICATION
15
binemia in infants, children, and adults, including case reports, reports of surveys, clinical studies, and epidemiologic studies. The subcommittee could find no studies of nitrate-induced methemoglobinemia reported since the 1990 EPA publication. The absence of reports might in part be due to the lack of requirements for reporting cases of methemoglobinemia. In addition, the studies reviewed by EPA are of uncertain quality largely because of the lack of controls for the presence of confounding factors. CANCER Nitrate and nitrite have been tested for carcinogenicity in laboratory animals, and epidemiologic studies of human cancer rates among populations with high nitrate or nitrite exposure concentrations have been performed. In general, nitrate and nitrite are not carcinogenic in laboratory animals when administered in the absence of nitrosatable amines. When nitrite and nitrosatable amines are administered together, however, carcinogenic nitrosamines can be formed in the stomach and lead to various tumors. Similar results have not been reported for simultaneous administration of nitrate and nitrosatable amines. Nitrosamine formation is inhibited by antioxidants, such as vitamin C and vitamin E. Results of epidemiologic studies have not supported an association between high nitrate or nitrite exposure from drinking water in the United States and increased cancer rates in humans. Both the animal and human studies are reviewed in detail in publications of EPA (EPA 1990a) and the European Chemical Industry Ecology and Toxicology Centre (ECETOC 1988). Human studies reported since the EPA review are also included here. The subcommittee could find no animal-carcinogenicity studies reported since the 1990 EPA publication.
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HAZARD IDENTIFICATION
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Animal Studies Sodium nitrate and sodium nitrite have been administered in the drinking water and diet of male and female rats, mice, hamsters, and guinea pigs to assess their carcinogenicity. Several studies of nitrate and numerous studies of nitrite have shown that when administered alone at doses up to 1,755 mg/kgday and 550 mg/kg-day (as nitrate or nitrite), respectively, these substances yielded no evidence of carcinogenicity (EPA 1990a). When sodium nitrite is administered simultaneously with secondary or tertiary amines, however, tumor incidence increases at a number of sites. The increases are thought to result from the formation of nitrosamines in the stomach. Nitrosamine formation from nitrite and nitrosatable amines is of concern because nitrosamines are potent mutagens and carcinogens at various sites and in various species of laboratory animals (Peto et al. 1984; ECETOC 1988). For example, Greenblatt and Mirvish (1972) fed a diet containing piperazine at 0 or 6,250 ppm to male strain A mice for 20 weeks in addition to supplying drinking water containing NaNO2 at 0, 50, 250, 500, 1,000, or 2,000 mg/L. There was an increased rate of lung-tumor formation at all dosages except 50 mg/L, with a clear dose-response relationship. No increase in tumor rate was observed among animals receiving NaNO 2or piperazine alone or in other groups of animals receiving piperazine and NaNO 3. Taylor and Lijinsky (1975) fed drinking water containing 0.2% heptamethyleneimine (133 mg/kgday) and 0.2% NaNO 2(90 mg/kg-day) to male and female Sprague-Dawley rats. That treatment elicited oropharyngeal, tongue, esophageal, and forestomach tumors. No tumors were observed among rats receiving either component alone. Thamavit et al. (1988) administered drinking water containing aminopyrine at 0 or 1,000 mg/L and NaNO 2at 0 or 1,000 mg/L NaNO2 (nitrite at 0 or 65 mg/kg-day) to male
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HAZARD IDENTIFICATION
17
Syrian golden hamsters. An increased incidence of liver tumors was observed among animals receiving both NaNO2and aminopyrine, whereas no liver tumors were observed among untreated controls or animals receiving only one treatment. Mokhtar et al. (1988) found that the hepatotumorigenic effect of simultaneous administration of NaNO2and dibutylamine in mice was diminished by concurrent feeding with ascorbic acid. None of the investigations described above determined actual nitrosamine formation. Yamamoto et al. (1989), however, detected N-nitrosobis(2hydroxypropyl)amine in the urine of rats receiving bis(2-hydroxypropyl)amine in the diet and NaNO2in the drinking water. Treated animals exhibited increased rates of lung, esophageal, and nasal-cavity tumors. Untreated animals and those receiving NaNO 2or the amine alone neither developed tumors at those sites nor excreted the nitrosamine. Other investigators have reported detecting in vivo formation of nitrosamines in the gastro-intestinal tracts of rats and hamsters receiving oral doses of nitrite and nitrosatable amines in short-term experiments (Inui et al. 1980; Massey et al. 1988). Kamm et al. (1975) reported hepatotoxicity associated with increased plasma nitrosodiethylamine in rats administered aminopyrine and nitrite. Nitrosamine formation from nitrite and nitrosatable amines is discussed further in Chapter 4. There are several reasons why nitrosamine formation and consequent cancer risk among laboratory animals receiving nitrite and nitrosatable amines might not be relevant to similar human exposures. Nitrosamine formation in the stomach is favored by low pH. Rodents have higher gastric pHs than most humans (about 5.0 versus about 1.5), so rodents are less likely to produce nitrosamines than humans. Humans transport nitrate from blood to saliva, whereas rats do not. In addition, the dosages used in the experiments reported here are often much higher than the concentrations encountered by humans in drinking water or in the diet. For these
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reasons, pharmacokinetic characteristics must be considered if extrapolations are made. Exposure is discussed in greater detail in Chapter 4. No studies in animals have shown that cancer risk is increased by the simultaneous administration of nitrate and nitrosatable amines. Human Studies Several cohort, case-control, and geographic-correlation studies have attempted to evaluate the effects of nitrate and nitrite exposure on human cancer risk. Those studies have been reviewed in detail by EPA (1990a) and ECETOC (1988) and provide inadequate evidence of an association between nitrate or nitrite exposure and increased cancer risk. Two cohort studies—Fraser et al. (1982) and Al-Dabbagh et al. (1986)— examined cancer mortality among male fertilizer workers exposed to nitratecontaining dust in England and Wales. The latter study found that nitrate concentrations in saliva were higher in exposed workers than in controls. In both studies, however, neither overall cancer mortality nor mortality for any particular cancer site was statistically significantly higher among the exposed populations than in controls. The occupational exposures to nitrate experienced by the study populations were likely to have been much greater than the nitrate exposures expected from drinking water. One case-control study evaluated the association between nitrate exposure from drinking water and gastric-cancer risk (Rademacher et al. 1992). Persons who had died of gastric cancer in Wisconsin in 1982-1985 were matched with controls who had died from other causes, and information on their drinkingwater nitrate concentrations was compared. Nitrate concentrations rarely exceeded 50
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mg/L, and no association between nitrate exposure and gastric-cancer risk was found. Several case-control studies have evaluated dietary risk factors among patients with stomach cancer or chronic atrophic gastritis, a condition that can be a precursor of stomach cancer. For example, Risch et al. (1985) calculated intakes of specific dietary constituents on the basis of diet questionnaires and U.S. Department of Agriculture data on food composition. Associations were reported between stomach cancer and intake of nitrite, smoked meat, unsaturated fats, grains, chocolate, eggs, cream desserts, or non-refrigerated food, whereas intake of nitrate, fiber, citrus fruits, or vitamin C was associated with a reduction in stomach-cancer risk. The contributions of waterborne nitrate or nitrite were not considered in the analysis. Although the diet questionnaires evaluated current dietary practices, gastric-cancer risk was likely to be associated with dietary practices 20 or 30 years previously. A case-control study in Germany evaluated the relationship between several dietary factors and confirmed cases of glioma and meningioma (Boeing et al. 1993). The study focused on nitroso compounds because several nitrosoureas had been found to induce tumors of the nervous system in animal experiments (Preussmann and Stewart 1984). On the basis of a food-frequency questionnaire and questions on food preparation and food supply, the authors concluded that dietary intake of nitrate and nitrite was not associated with an increase in risk of glioma or meningioma in the population examined. Bunin et al. (1993, 1994) performed case-control studies to evaluate the relationship between maternal dietary exposure to nitrosamine precursors and the risk of astrocytoma and primitive neuroectodermal tumors of the brain in children in the United States and Canada. Increased nitrate intake was associated with a decrease in the risk of primitive neuroectodermal tumors, whereas there was no association between nitrate or nitrite intake and astrocytoma risk. A case-control study on diet and gastric cancer conducted in
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Spain found a positive correlation between gastric cancer and high consumption of foods containing nitrite but an inverse association with consumption of foods containing nitrate (González et al. 1994). Buiatti et al. (1990) also reported a negative trend in the association between risk of gastric cancer and nitrate intake as estimated with a food-frequency questionnaire in Italy, whereas Hansson et al. (1994) reported no association in a Swedish study. Fontham et al. (1986) actually measured nitrate and nitrite in the gastric juice of gastritis patients and found no differences from measurements of controls. Gastritis patients reportedly had consumed less fruit, vegetable, and vitamin C than controls, however. Those results were confirmed by Sobala et al. (1991), who determined concentrations of nitrate and nitrite in the gastric juice of patients with and without precancerous conditions of the stomach and found no differences related to gastric pathology. Knight et al. (1991) performed a similar study and found an inverse relationship between gastric nitrate concentration and the severity of gastric disease, but no association with gastric nitrite concentration. The case-control studies of nitrate exposure and cancer risk thus show either no association or an inverse correlation. Negative associations are likely to be a result of the fact that vegetables are the primary dietary source of nitrate; diets rich in vegetables have consistently been shown to be associated with lower cancer risk (NRC 1989). Most epidemiologic studies of nitrate, nitrite, and cancer are geographiccorrelation studies. They attempt to make associations between average cancer incidences in a geographic area and nitrate or nitrite concentrations in the food or water of that area. Such studies are useful for developing hypotheses, but they cannot demonstrate causality, because exposure to nitrate or nitrite is not established and because they seldom take other risk factors into account. In addition, correlations are generally sought between current nitrate or nitrite concentrations and current cancer inci
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dence or mortality, whereas cancer risk is a function of past exposure. Geographic studies of nitrate and nitrite concentrations in drinking water and cancer rates have not found consistent correlations. For example, Davies (1980) evaluated death rates from stomach cancer in a town in England where the water contained nitrate at 90 mg/L and found no differences from rates in towns where nitrate concentrations were not high. Juhasz et al. (1980) found that in one county in Hungary stomach-cancer incidence correlated with drinking-water nitrate concentrations in some locations but not in others. A study of esophageal-cancer rates in Iran found no correlation with drinkingwater nitrate or nitrite concentrations (Joint Iran-IARC Study Group 1977). Gilli et al. (1984) reported a positive association between gastric-cancer incidence and drinking-water nitrate concentrations in Italy, but this study did not control for other important risk factors for gastric cancer, such as age, diet, alcohol consumption, and occupation. Anquela et al. (1989) reported a positive association between drinking-water nitrate concentration and gastric-cancer mortality but also did not control for other risk factors. In a similarly uncontrolled study, Xu et al. (1992) examined a population at high risk for gastric cancer in China and reported a positive correlation between nitrate intake via drinking water and gastric disease, including cancer, but no relationship with nitrite intake. Chen et al. (1993) found no relationship between dietary nitrate and nitrite exposure and esophageal-cancer mortality when different communities in China were compared but reported a positive correlation between the urinary concentrations of N-nitrosoamino acids and nitrate that was associated with the consumption of nitrate-rich vegetables. Cuello et al. (1976) found that people in Colombia at high risk for stomach cancer lived in areas where nitrate concentrations in drinking-water wells were higher than in lower-risk areas, drank well water more frequently, and had higher urinary nitrite concentrations. In contrast, both Beresford (1985) and Forman et al.
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(1985) found that stomach-cancer mortality rates were lower in parts of the United Kingdom where nitrate intake was higher. In the context of a multistep model for gastric carcinogenesis, Correa (1992) has proposed that the overall epidemiologic and pathologic evidence suggests that ingestion of ascorbic acid and nitrate (determinants of intragastric nitrosation) is associated with effects on the intermediate stages of gastric carcinogenesis, namely, intestinal metaplasia and dysplasia. A positive correlation between urinary nitrate and nitrosamine excretion has been reported in persons with intestinal metaplasia and dysplasia in a population at high risk for gastric cancer in Colombia (Stillwell et al. 1991). A positive association between the proportion of detectable nitrite in gastric juice and the risk of gastric precancerous lesions was found in the same population (Chen et al. 1990). For various reasons, it is difficult to show a relationship between nitrate and nitrite intake from drinking water and cancer incidence or mortality in humans. First, of course, it is possible that there is no such relationship or that long latency periods or threshold effects make it difficult to establish a relationship. Second, humans are exposed to nitrate and nitrite from many sources other than drinking water and also make nitrate endogenously, so individual exposures vary widely. Third, many dietary factors inhibit nitrosamine formation from nitrite, such as antioxidants, and individual exposure to these varies widely. Fourth, intake of nitrosatable amines varies widely. Finally, the epidemiologic studies that have been conducted to date suffer from a variety of limitations, such as lack of historic exposure measurements, small sample size, and confounding by concomitant exposures. It is likely that considering nitrate or nitrite exposure without also considering exposure to nitrosatable amines is not adequate to determine cancer risk. Thus, although nitrate reduction to nitrite and later nitrosamine formation are possible in humans, many variables affect this process, and exposure to drinking water that contains
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nitrate or nitrite is unlikely to be the rate-limiting factor. However, people with a low intake of fruits and vegetables, who are at increased risk for many epithelial tumors (including stomach cancer) will receive a relatively greater proportion of nitrate from drinking water than those with high intakes of fruits and vegetables (Steinmetz and Potter, 1991). People with low fruit and vegetable intakes will also have a relatively lower intake of ascorbic acid and other vegetable-derived antioxidants, the proportion of Americans consuming the recommended five servings of fruits and vegetables per day is less than 20% (Lanza et al., 1987), so some overlap between low dietary intake and high waternitrate concentration can occur. Diets low in fruits and vegetables might or might not be high in nitrosatable amines, but this possibility contributes some uncertainty to the conclusion that exposure to nitrate or nitrite from drinking water is unlikely to be associated with increased human cancer incidence. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Numerous studies have been conducted in laboratory animals to evaluate the reproductive and developmental toxicity of nitrate and nitrite. In general, little evidence of toxicity has been found except at relatively high doses, which also can produce maternal methemoglobinemia. A single study in rats has reported developmental effects of exposures encountered by humans (Markel et al. 1989). But the few studies that have been conducted in humans have yielded no evidence of any reproductive or developmental effects of nitrate or nitrite. EPA (1990a) has reviewed the studies of the reproductive and developmental toxicity of nitrate and nitrite. Several studies reported since the EPA publication are also described here.
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Animal Studies In a large study of both reproductive and developmental effects, nitrate was administered by gavage during pregnancy to rats, mice, hamsters, and rabbits. Mice and hamsters received nitrate at up to about 300 mg/kg-day and rats and rabbits up to 180 mg/kg-day. Similar studies were performed with nitrite at up to 15 mg/kg-day in mice and rabbits, 6.5 mg/kg-day in rats, and 17 mg/kg-day in hamsters. No fetal toxicity, malformations, or effects on maternal reproductive characteristics were observed (FDA 1972a,b,c,d). Kammerer (1993) and Kammerer and Siliart (1993) studied the reproductive and developmental effects of nitrate in female rabbits and reported no effects on reproductive performance, fertility, litter size, or weight at birth or at weaning in association with nitrate at 250 or 500 mg/L of drinking water (about 9 or 18 mg/kg-day). Studies of nitrate or nitrite mutagenicity in mammalian germ cells for the purpose of determining genotoxic activity are few. Increases in sperm-head abnormalities were reported in mice that were sacrificed 5 weeks after receiving nitrate at 870 mg/kg-day or nitrite at 40 or 80 mg/kg-day by gavage for 14 days (Alavantic et al. 1988a). The pregnancy rate was reduced among females caged with males 10 days after males were treated with the highest dose of nitrite. The basis for this effect is not known. Similar effects were not seen among the mice receiving lower doses of nitrite or in the nitrate-treated groups. Sperm-head abnormalities were also increased in males sacrificed 11 or 17 days after treatment with nitrite at 80 mg/kg-day for 3 days but not in males that received nitrate at 875 mg/kg-day or nitrite at 40 mg/kg-day (Alavantic et al. 1988b). None of the 3-day treatments induced unscheduled DNA synthesis in treated spermatids. In guinea pigs receiving nitrate at 5,000 mg/kg-day in their drinking water for 143-204 days, no fetotoxicity or effects on fertility were observed (Sleight and Atallah 1968). Effects on
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HAZARD IDENTIFICATION
25
reproductive performance were observed only at the highest dosage, which was associated with a decrease in number of live births that might have been attributable to maternal methemoglobinemia. In a similar study with nitrite, reproductive performance was unaffected up to a dosage of 600 mg/kg-day but higher dosages severely reduced the numbers of live births (Sleight and Atallah 1968). Effects of nitrite on body and organ growth were reported in a threegeneration study on rats (Hugot et al. 1980). Chronic administration of nitrite at about 300 or 525 mg/kg-day in the diet of females had no effects on reproduction or fertility. The rate of weight gain by pups was lower than that in untreated controls, however, and the weights of several organs were abnormal. Similar results were obtained by Roth et al. (1987), who noted anemia and reduced weight gain among the pups of dams supplied with drinking water containing nitrite at 145 or 200 mg/kg-day during gestation and 275 or 340 mg/ kg-day during lactation. Those effects were not observed in pups exposed only during gestation, and it was concluded that postnatal exposure was more important. Markel et al. (1989) reported alterations in neurobehavioral development among the offspring of rats given nitrate at 7.5 or 15 mg/kg-day in their drinking water during gestation and lactation. The offspring were also provided with the nitrate-containing water on weaning. Nitrate-exposed offspring developed hearing-startle reaction and mature righting and cliff-avoidance reflexes earlier than untreated controls. Hyperactivity was reported soon after birth, but hypoactivity was observed at day 20. As adults, the treated male rats showed deficits in rewarded-discriminative-learning tests and in establishing active-avoidance response. No dose-response relationship was observed, however, so it is not possible to eliminate indirect behavorial effects. It is likely that the motor changes reported when the animals were young affected their learning behavior; no additional studies were performed to see
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HAZARD IDENTIFICATION
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whether the neurobehavioral effects reported were unrelated to the motor effects. Isaacson and Fahey (1987) and Viveiros and Tondat (1978) reported behavioral deficits in rats resulting from sodium nitrite exposure, but their studies were subject to the same limitations as the study of Markel et al. (1989). Additional drawbacks of the Isaacson and Fahey (1987) study include the use of a single dose administered intraperitoneally and failure to rule out a number of confounding factors. Taken together, these studies provide scant evidence that nitrate or nitrite produces neurobehavioral effects, although they provide suggestive evidence of effects that might be clarified by further research. It is not known whether the observations in rats can be extrapolated to humans. Developmental and fetal toxicity has been reported among rats and mice treated simultaneously with nitrite and nitrosatable amines (Ivankovic et al. 1973; Teramoto et al. 1980). Similar tests with nitrate have not been reported. Of the offspring of rats receiving ethylurea at 100 mg/kg and nitrite at 33 mg/ kg, 60% developed hydrocephalus and died within 8 weeks of birth; this effect was not observed when ascorbic acid at 250 mg/kg was also administered. Decreases in fetal survival and increases in fetal malformations were observed when pregnant mice were given simultaneous doses of ethylenethiourea at 400 mg/kg and nitrite at 67 or 134 mg/kg. These effects were not seen when nitrite was administered 2 hours after ethylenethiourea or when either chemical was administered alone. Results of both studies indicate that the toxic effects observed were due to nitrosamine formation. Extrapolating the results to humans must be approached with caution for the same reasons that the relevance of the carcinogenicity bioassays discussed must be questioned: the gastric acidity of humans favors nitrosamine formation but that of rodents does not, and the doses used were often much higher than those encountered in the environment. Therefore, pharmacokinetic characteristics must be considered if extrapolations are made.
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Human Studies Several case-control studies have been performed to evaluate the potential relationship between nitrate exposure from drinking water and reproductive or developmental effects in humans. One study compared people with CNS defects to controls without such effects in New Brunswick, Canada, and found no significant association between birth defects and nitrate exposure (Arbuckle et al. 1988). A study in Boston found that exposure to nitrate in water was associated with a decrease in the risk of spontaneous abortion but that exposure to nitrite had no effect (Aschengrau et al. 1989). An increase in the risk of birth defects was reported in South Australia among women consuming groundwater containing nitrate at 5-15 mg/L, compared with women consuming rainwater containing nitrate at less than 5 mg/L (Scragg et al. 1982; Dorsch et al. 1984). The authors could not attribute their results to nitrate, however, because actual exposure to nitrate was not determined and because other contaminants of groundwater were probably present as a result of the runoff of agricultural chemicals and chemicals used in the local wood-processing industries. OTHER EFFECTS Inorganic nitrite, but not inorganic nitrate, can produce hypotension in humans as a result of its action as a smooth muscle relaxer, especially in the vascular system. This effect is similar to that of some organic nitrates and is thought to result from the production of S-nitrosothiols or nitric oxide; both stimulate guanylate cyclase activity (Knowles et al. 1989). Hypotension as a result of sodium nitrite administration has been recognized for well over a century. It occurs in most, if not all, mammals, including humans,
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and at dosages that overlap with dosages that cause methemoglobinemia (Sollman 1957). .
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DOSE-RESPONSE ASSESSMENT
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3 Dose-Response Assessment
In this chapter, the dose-response relationships for the health effects of nitrates and nitrites are characterized so that the health effect of primary concern can be identified. METHEMOGLOBINEMIA Very few of the reports of studies performed on nitrate-induced methemoglobinemia in humans that include dose information involve cases occurring at nitrate concentrations below 50 mg/L, and most cases occurred when bacterial contamination of water supplies was present as well. In some cases, important dietary sources of nitrate (such as spinach) were also identified. The current MCLG for nitrate is based on the study of Walton (1951). The American Public Health Association sent questionnaires to all 48 states investigating the morbidity and mortality among infants due to methemoglobinemia induced by nitrate-contaminated water. The survey identified 278 cases and 39 deaths that could be “definitely associated with nitrate-contami
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DOSE-RESPONSE ASSESSMENT
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nated water.” Nitrate exposures were known for 214 cases, and all of them exceeded 50 mg/L; of the 214 cases, 81% occurred above 220 mg/L, 17% at 90-220 mg/L, and only 2% at 50-90 mg/L. The presence of nitrite, of bacteriologic contamination, and of gastrointestinal disease and methemoglobin concentrations were not reported. In a similar survey in Germany, 745 cases of methemoglobinemia among infants were identified (Simon et al. 1964); data on exposure were available for 249 of the cases. Nitrate concentration in water exceeded 100 mg/L in 84%, was 50-100 mg/L in 12%, and was less than 50 mg/L in only 4%. The only three cases that occurred at concentrations below 20 mg/L were associated with nitrite and substantial dietary nitrate exposure as well. Of the 306 cases for which additional information was available, 98% occurred in infants aged 3 months old or younger, and 53% of the infants had diarrhea, an indicator of bacterial contamination and a factor associated with endogenous nitrate formation. Dose-response relationships for nitrate exposure and methemoglobin concentrations have been reported in several studies of infants. For example, normal methemoglobin concentrations (less than 3%) were observed in infants fed water that contained nitrate at up to 50 mg/L, with mean methemoglobin concentrations increasing with nitrate intake up to 6.6% in those consuming over 100 mg/L (Würkert 1978; Toussaint and Würkert 1982). Similar doseresponse relationships have not been observed in children or adults, in whom increasing nitrate exposure has little or no effect on methemoglobin concentration (Craun et al. 1981). 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 in the absence of increased concentrations of nitrate in food or water.
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CANCER Epidemiologic data do not support a straightforward association between exogenous nitrate or nitrite exposure and human carcinogenesis. 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 simultaneously with a nitrosatable amine; in these cases, carcinogenesis can be attributed to the endogenous formation of carcinogenic nitrosamines. Cancer risk associated with endogenous nitrosamine formation is a function of four variables: the amount of nitrite ingested or formed from nitrate, the amount of nitrosatable substances ingested, the rate of in vivo nitrosation, and the carcinogenic potency of the resulting nitrosamine. Establishing human dose-response relationships for a phenomenon that has so many variables is not straightforward. The carcinogenic potencies of nitrosamines based on rodent bioassays vary by at least a factor of 1,000 (Shephard et al. 1987). Daily dietary intakes of nitrosatable amines, amides, guanidines, and ureas have been estimated to range from less than 1 mg to hundreds or even thousands of milligrams (Shephard et al. 1987). Dietary nitrate intake is estimated to vary from about 75 to 270 mg (NRC 1981), and the extent to which nitrate is reduced to nitrite endogenously depends on gastric acidity and the nature
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DOSE-RESPONSE ASSESSMENT
32
and number of bacteria present; dietary nitrite intakes are much lower. It is possible that the development of physiologically based pharmacokinetic models for nitrate and nitrite metabolism and nitrosamine formation would allow each of those variables to be evaluated and the bounds on the dose-response relationships to be estimated (see Appendix A). REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Studies in humans are inadequate to support an association between nitrate or nitrite exposure and reproductive or developmental effects. Therefore, developing dose-response relationships based on human data is not possible. Developmental effects and fetal toxicity have been reported among rats and mice receiving both nitrite and nitrosatable amines, but (as discussed above for cancer) developing dose-response relationships for humans on the basis of these data and estimating rates of nitrosamine formation and potency are so uncertain as to be meaningless. Nitrate has not been reported to produce reproductive effects in animal bioassays. One study reported that nitrate produced alterations in rat neurobehavioral development at 7.5 mg/kg-day (Markel et al. 1989); although the study has several drawbacks, this is the lowest dosage at which any developmental effects have been reported. This dosage can be converted to a human adult dosage as follows: (7.5 mg/kg-day)¾(70 kg) = 317 mg/day,
where the exponent ¾ is used to account for the difference in surface area between rats and humans (Federal Register 1992) and
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the average human is assumed to weigh 70 kg. Assuming that the average human infant 0-3 months old weighs about 5 kg, the adult dosage is equivalent to an infant's dosage of about 23 mg/day. Reproductive effects attributable to nitrite exposure have been reported in animal bioassays at dosages that might have been associated with maternal methemoglobinemia. Developmental effects of nitrite that have been reported at lower dosages in rodents appear to result from exposure after birth and not in utero (Roth et al. 1987). The effects included anemia and reduced weight gain. The lowest dosage at which the effects were reported was 275 mg/kg-day in rats (Roth et al. 1987). That dosage can be converted to a human infant dosage as follows: (275 mg/kg-day)¾(5 kg) = 338 mg/day,
where the same assumptions were used as for nitrate. OTHER EFFECTS In most mammals, including humans, the vasodilator effects of sodium nitrite overlap the dosage ranges that cause methemoglobinemia (Sollman 1957). The discussion of dose-response relationships for methemoglobinemia is thus applicable to the vasodilator effects as well. Although the stagnant hypoxia that results from prominent vasodilation might contribute to the anemic hypoxia resulting from methemoglobinemia, it is clear that methemoglobinemia is the primary cause of death. Methylene blue can reverse nitrite-induced methemoglobinemia and protect against death. Maintenance of normal blood pressure has never been shown to protect against nitrite lethality (Smith and Wilcox 1994).
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EXPOSURE ASSESSMENT
35
4 Exposure Assessment
This chapter identifies the primary sources of human exposure to nitrate and nitrite and assesses the extent of overall exposure. EXPOSURE FROM FOOD AND WATER Dietary Exposure Most nitrate and nitrite to which humans are exposed is in their diet, as either natural components or intentional additives. Vegetables are the primary source of nitrate and nitrite in food, and cured meat and dairy products can also contribute. The highest nitrate concentrations are found in celery, spinach, lettuce, beets, radishes, melon, turnip greens, and rhubarb (over 1000 mg/kg of vegetable) (Walker 1990). Low concentrations of nitrite (less than 10 mg/kg)
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can also be present in those vegetables. Concentrations of nitrate in vegetables depend on agricultural practices, storage conditions, the temperature and light in which they are grown, and the concentrations of nitrate in the soil, fertilizers, and water used to grow the vegetables (NRC 1981; Hwang et al. 1994). The concentrations of nitrate and nitrite in cured-meat products depend on the curing process and on the amounts added as preservatives. Concentrations of nitrite in bacon, for example, can be up to 120 ppm, which is the maximum allowed by law (9CFR 318.7B). Nitrate and nitrite are used as preservatives because of their ability to inhibit the growth of Clostridium botulinum (NRC 1981). Improved manufacturing processes have led to a steady decline in the concentrations of nitrate and nitrite in preserved meats (nitrate is now used only rarely). Dairy products contain low concentrations of nitrate and nitrite in general, rarely exceeding 5 mg/kg in milk (NRC 1981 ). Drinking-Water Exposure Nitrate and nitrite can occur in drinking water as a result of human and other activities. The microbial oxidation of ammonia to nitrate and nitrite is the primary nonhuman source. Inorganic fertilizers and human and animal wastes (from livestock operations and septic tanks) are the primary human sources. Nitrate released to soil can enter groundwater or surface water as a result of leaching or runoff. Nitrate concentrations in groundwater are typically less than 10 mg/L but can exceed that in areas of concentrated human sources. Concentrations of nitrate in surface water seldom exceed 1 mg/L except in areas of severe contamination. The nitrite in groundwater and surface water is negligible compared with the nitrate; in oxygenated waters, nitrite is rapidly converted to nitrate (EPA 1990b).
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37
Several nationwide surveys of nitrate concentrations in public drinkingwater supplies have been conducted and have been reviewed in detail (EPA 1990b). No survey data are available on nitrite concentrations. On the basis of the results of the surveys, EPA (1990b) estimated that of the roughly 219 million people using public drinking-water supplies in the United States, some 92 million (42%) either are not exposed to nitrate or are receiving drinking water with concentrations below 1.3 mg/L. An estimated 127 million (58%) are exposed to water with nitrate concentrations greater than 1.3 mg/L, of whom about 1.7 million, including about 27,000 infants, are exposed to nitrate at greater than 44 mg/L. ENDOGENOUS SYNTHESIS Some nitrate and nitrite exposure also originates in the endogenous production of nitric oxide, which can be converted to nitrate, by many types of cells, including macrophages (Iyengar et al. 1987), neutrophils (McCall et al. 1989), endothelial cells (Palmer et al. 1988), neurons (Knowles et al. 1989), and hepatocytes (Billiar et al. 1990). As a result, nitrate excretion in urine exceeds nitrate intake from food and water. In the absence of infection, endogenous nitrate synthesis approximates 62 mg/day (Tannenbaum et al. 1978; Green et al. 1981; Wagner et al. 1983; Lee et al. 1986). Infections and inflammatory reactions can increase endogenous nitrate synthesis in both infants and adults (Hegesh and Shiloah 1982; Wagner and Tannenbaum 1982). ESTIMATED DAILY INTAKE Several estimates of daily nitrate intake and its major sources are available. EPA (1990b) concluded that data were insufficient to
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EXPOSURE ASSESSMENT
38
determine the relative contributions of different sources to total intake but that food is the major source for adults. The National Research Council (1981) estimated that food provides a nitrate intake of 40-100 mg/day for males. EPA (1990b) concluded further that water could contribute comparable intake if nitrate were present at 22-44 mg/L. Nitrite intake is thought to be less than 3.3 mg/day for the majority of the United States population. An example of an intake estimate for nitrate is that of Jones (1992), which is shown in Table 4-1. Jones estimated exogenous nitrate intake at 76 mg/day. For most of the population, about 97% of daily intake comes from food and only 3% from drinking water. Endogenous nitrate production contributes about 45% of total exposure. In contrast, Van den Brandt et al. (1989) estimated exogenous nitrate intake at 113 mg/day for males and 184 mg/day for females, on the basis of an integrated approach that used a selfTABLE 4-1 Sources of Nitrate Exposure in the United Statesa Sources
Nitrate, mg/day
%
Vegetables (in omnivores) b
65
86
Fruits and juices
4
5
Cured meat
2
3
Bread and cereals
2
3
Other foods
1
1
Water (usual water supply)
2
3
Total exogenous
76
100
Endogenous
62
-
Total exogenous + endogenous
138
-
aBased
on Jones (1992). would consume considerably more nitrate (about 260 mg/day).
bVegetarians
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administered food-frequency questionnaire and measurements of urinary nitrate. Broccoli and green leafy vegetables were reported to account for 60% of total intake. ECETOC (1988) summarized daily intake estimates from several European reports. Using the duplicate-portion technique, wherein one portion is eaten and another is analyzed, several investigators reported average dietary nitrate intake of 43-131 mg/day. Their results are consistent with those of investigators who analyzed dietary components and calculated nitrate intake on the basis of data on consumption rates and reported estimates of total intake of about 31-130 mg/day for most people. Finally, investigators who measured urinary nitrate concentrations and calculated intake on the basis of observations of the proportion of nitrate excreted in urine have reported intake estimates of 64-297 mg/day for people who consume water with high nitrate concentrations. The latter estimates are unreliable because not all the nitrate that enters the body is excreted as nitrate in urine. There are losses of nitrate throughout the oral cavity and gastrointestinal tract that are characterized by stepwise reduction of nitrate to ammonia. Thus, urinary nitrate underestimates total exposure. The National Research Council report The Health Effects of Nitrate, Nitrite, and N-Nitroso Compounds (NRC 1981) reported estimates of nitrate and nitrite intake based on food-consumption tables. Those estimates are summarized in Tables 4-2 and 4-3. Estimates were made for the average U.S. population, for those whose diets contain greater than average amounts of vegetables or cured meats, and for those who consume nitrate-rich drinking water. For the average population, most nitrate exposure (86%) comes from vegetables, whereas the primary contributors to nitrite intake are cured meats (39%), baked goods and cereals (34%), and vegetables (16%). Those estimates of intake do not necessarily reflect total exposure, however, which also includes endogenous nitrate synthesis and the in vivo conversion of nitrate to nitrite.
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73
2
75
Diet
Water
Total
bAssumes
on NRC (1981). 4 times daily average consumption of cured meats. cAssumes 4 times daily average consumption of vegetables. dBased on data from central Illinois.
aBased
mg
Source
U.S. Average
Daily Nitrate (mg) and Percent Contribution from Each Source
TABLE 4-2 Estimated Daily Nitrate Intake in the United Statesa
3
97
%
78
2
76
mg
3
97
%
High-Cured-Meat Dietb
268
2
266
mg
1
99
%
Vegetarian Dietc
233
160
73
mg
69
31
%
Nitrate-Rich Waterd
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0.76
0.01
0.77
Diet
Water
Total
1
99
%
bAssumes
on NRC (1981). 4 times daily average consumption of cured meats. cAssumes 4 times daily average consumption of vegetables. dBased on data from central Illinois,
aBased
mg
Source
U.S. Average
Daily Nitrate (mg) and Percent Contribution from Each Source
TABLE 4-3 Estimated Daily Nitrite Intake in the United Statesa
1.7
0.01
1.69
mg
1
99
%
High-Cured-Meat Dietb
0.77
0.01
0.76
mg
1
99
%
Vegetarian Dietc
0.77
0.01
0.76
mg
1
99
%
Nitrate-Rich Waterd
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Both the measured and calculated estimates of nitrate and nitrite intake discussed above are averages. The primary source of nitrate, for example, is vegetables; both daily vegetable intake and the nitrate content of vegetables vary considerably. Other limitations of the estimates include those inherent in analytic techniques and inaccuracies in food-consumption tables. Nonetheless, the estimates indicate the relative importance of different sources of intake to overall exposure. In particular, they 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. Infants constitute a special case. Breast-fed infants are exposed to very little nitrate or nitrite, but formula-fed infants can be exposed to nitrate from the water used to prepare their formula. Daily fluid intake of newborn infants has been estimated at 850 mL (ICRP 1975) and 150 mL/kg (Hull and Johnstone 1987). BIOLOGIC FATE Ingested nitrate is rapidly absorbed through the small intestine and distributed throughout the body. It is excreted in saliva, sweat, feces, and urine (ECETOC 1988; EPA 1990a). Nitrate excreted in feces is used by fecal microorganisms as a source of nitrogen. Nitrate is reduced to nitrite in areas of the gastrointestinal tract where large numbers of bacteria are found—the mouth, the achlorhydric stomach, the small intestine, and the colon. The amount of nitrite formed depends on the amount of nitrate ingested, the person's nitrate reductase activity, pH, and the number and type of bacteria present and their nitrate reductase activity; but in general, about 5% of ingested nitrate is thought to be converted to nitrite (Stephany and Schuller 1980; Eisenbrand et al.
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EXPOSURE ASSESSMENT
43
1981; Walters and Smith 1981; Stuehr and Marletta 1986). Nitrite can react with dietary constituents or endogenous compounds, be absorbed by the gastrointestinal tract, or be used as a nitrogen source by bacteria, which reduce it further to ammonia and then to urea and amino acids. Absorbed nitrite reacts with hemoglobin to form methemoglobin; little is transported elsewhere. Nitrite can also react with secondary and tertiary amines to yield nitrosamines, with secondary and tertiary amides to yield nitrosamides, and with N-substituted ureas and carbamates to yield nitrosourea and nitrosocarbamates. Those reactions are pH-dependent and occur in saliva and in gastric juice at rates that vary considerably among individuals. Ascorbic acid and -tocopherol (vitamin E) can block the reactions. Human blood concentrations of nitrosamines can reflect gastric and nongastric endogenous synthesis and intake of preformed nitrosamines in food.
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5 Risk Characterization
This chapter combines information from the hazard-identification, doseresponse assessment, and exposure-assessment chapters to determine what magnitudes of human exposure to nitrate and nitrite might produce adverse health effects. 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 noobserved-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
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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 those RfDs. Assuming water consumption of 0.64 L/d by a 4-kg infant, the MCLGs for nitrate nitrogen and nitrite nitrogen are 10 mg/L and 1 mg/L, respectively. CANCER RISKS The subcommittee concludes that exposure to the nitrate and nitrite concentrations found in drinking water in the United States is unlikely to contribute to human cancer risk. That conclusion is based on the following observations: • 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. Attempting to limit 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. Any theoretical cancer risk should be weighed against the benefits of eating vegetables. • Epidemiologic studies provide inadequate evidence of an association between nitrate exposure from drinking water in the United States and cancer risk. • Studies in laboratory animals do not support an association between nitrate exposure and cancer risk or between nitrite exposure and cancer risk in the absence of concurrent exposure to nitrosatable amines.
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• Studies in laboratory animals support an association between combined exposure to nitrite and nitrosatable amines and cancer risk because of endogenous formation of nitrosamines. Cancer risk associated with endogenous nitrosamine formation is a function of four factors: the amount of nitrite ingested or formed from nitrate, the amount of nitrosatable substances ingested, the rate of in vivo nitrosation, and the carcinogenic potency of the resulting nitrosamine. Each of those factors varies over a range of a factor of 100 or more. Nitrate or nitrite intake from drinking water is unlikely to be a rate-limiting step. As a result, calculating useful estimates of potential cancer risk solely on the basis of nitrate or nitrite exposure is not possible in the absence of supporting epidemiologic data or a physiologically based pharmacokinetic model that would permit analysis of the complex relationships between exogenous and endogenously formed nitrate, nitrite, and N-nitroso compounds.1 • Endogenous nitrate formation occurs at about 1 mg/kg-day. That rate constitutes some 50% of total nitrate exposure for most of the U.S. population. Regulating exogenous nitrate exposure from water on the basis of carcinogenicity is inconsistent with such a rate of endogenous nitrate formation. The subcommittee concludes that the incremental contribution of nitrate and nitrite from drinking water in the United States to total nitrate and nitrite exposure is negligible and unlikely to contribute to human cancer risk. The current maximum-contaminant-level goals 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.
1See
Appendix A for a discussion of how a physiologically based pharmacokinetic model could be developed to assess the risk of cancer associated withexposure to nitrate.
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NONCANCER RISKS Available data are inadequate to support an association between nitrate and nitrite exposure from drinking water and any non-cancer effects other than methemoglobinemia in infants. That conclusion is based on the following observations: • No studies in humans have demonstrated adverse health effects that can be attributed to nitrate or nitrite toxicity other than methemoglobinemia in infants. • There is scant evidence from laboratory animals of developmental effects attributable to nitrate. One study reported deficits in neurobehavioral development when pregnant rats and their offspring received a low dosage of nitrate, 7.5 mg/kg-day. That is the lowest dosage at which adverse health effects of nitrate or nitrite have been reported in laboratory animals. The study had several limitations, and it is not known whether the neurobehavioral effects reported in rats can be extrapolated to humans; however, if so, converting the dosage to an adult human dosage yields 317 mg of nitrate per day, which is equivalent to the total dietary intake of a typical pregnant woman. That dosage is therefore unlikely to pose a threat to the fetus. The adverse effects reported in rats might have resulted from exposure after birth; the equivalent human infant nitrate dosage is about 23 mg/day. If an infant drinks 850 mL of formula prepared with water that contains nitrate at 44 mg/L each day, more than 23 mg of nitrate would be received each day. It would be inappropriate to classify nitrate as a developmental toxicant on the basis of this limited experimental evidence, although the results suggest that further studies of such effects should be conducted. • Methemoglobinemia in infants is the only adverse effect that has been associated with nitrate exposure. It can occur as a result
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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. There are very few published reports of methemoglobinemia occurring in infants whose drinking water contains nitrate at less than 50 mg/L, and none of the reported cases occurred in the United States. The subcommittee concludes that 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. However, in view of the uncertain quality of historical data and the absence of current data—the absence of which might be due in part to the lack of requirements for reporting cases of methemoglobinemia—it is prudent to maintain EPA's current MCLGs 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). These MCLGs are adequate to protect human health from the potential consequences of exposure to nitrate and nitrite in public water supplies because they are based on human data derived from the most sensitive subpopulation and because no cases of methemoglobinemia have been reported in the United States at dosages below the MCLGs. 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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APPENDIX A
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Appendix A Physiologically Based Pharmakinetic Model for Assessing the Risk of Cancer Associated with Nitrate Exposure T he risk of cancer associated with exogenous nitrate exposure is related to its potential for conversion to nitrite by bacteria in the oral cavity and the gastrointestinal tract. Some proportion of the nitrite formed is assumed to participate in reactions that lead to the formation of potentially carcinogenic Nnitroso compounds. To estimate the relative contribution of nitratecontaminated drinking water to this process, a physiologically based pharmacokinetic model is needed that can reflect several sources of nitrate exposure. A model could be constructed that is consistent with the following physiologic processes.1 Nitrate exposure originates from exogenous sources (food and water) and from the endogenous synthesis of nitric oxide. Exogenous nitrite exposure may be ignored because
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APPENDIX A
52
it makes a negligible incremental contribution to total exposure. Nitrate from all sources is mixed in extracellular body water. Losses and removal occur as a result of urinary excretion of nitrate and by conversion to reduced or reactive forms that are ultimately lost in feces. The half-life for clearance of nitrate from blood is about 5 hours, and the fraction lost by urinary excretion is 30-50%. An important component of human physiology is the ability of salivary glands to transport nitrate from blood into saliva. The process is either absent or diminished in all nonhuman species studied; only humans have the capacity to introduce substantial amounts of nitrite into an acidic stomach. (The optimal pH for nitrosation is 2.5-3.3.) Several considerations should be included in model development: • Endogenous nitrate synthesis in the absence of infection or inflammation is constant over 24 hours. • Intake of exogenous nitrate from food and water occurs as a bolus. • Nitrate exposure from food is accompanied by exposure to antioxidants that inhibit N-nitrosation in the stomach. Estimating human cancer risk associated with nitrate in drinking water requires a physiologically based pharmacokinetic model that could be used to compute the relative input of nitrate from all sources, rates of input, and potential for N-nitroso compound formation. Data adequate to develop such a model are available.
1Actual
construction of the model was beyond the scope of the charge to the National Research Council.
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