This report contains the collective views of an international group of experts and does not necessarily represent the deci- sions or the stated policy of either the World I-Iea]th Organization or the United Nations Environment Programme Environmental Health Criteria 5 NITRATES, NITRITES, AND N-NITROSO COMPOUNDS Published under the joint sponsorship of ... the United Nations Environment Programme and the World Health Organization (6 Y. y I / t:3 / A World Health Organization Geneva, 1978 I 7 ISBN No. 92 4 154065 6 © World Health Organization 19711 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. For rights of reproduction or translation of WHO publications, in part or in tow, application should be made to the Office of Publications, World Health Organization, Geneva, Switzerland. The World Health Organization welcomes such applications. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply *-- that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are dislinguished by initial capital letters. PR1NTD IN UNITED KINGDOM CONTENTS Pg ENVIRONMENTAL HEALTH CRITERIA FOR NITRATES, NITRITES A N D N- N ITROSO COM POU N DS .................... II L. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES 13 1.1 Summary ............................ 13 1.1. 1 Analytical methods ................... 13 1 1.1.1 Nitrates and nitrites ................ 13 l 1.1.2 N-nitroso compounds ................. 13 1 1.2 Sources and occurrence in the environment ........... 14 1.1.2.1 Nitrates and nitrites ................. 14 1.12.2 N-nitroso compounds ................. 14 11.3 Metabolism ....................... 15 1.1.3.1 Nitratesand nitrites ................ 15 1.1.3.2 N-nitroso compounds ................. IS 1.14 Experimental studies in animals ................ IS 1.1.4.1 Nitrates and nitrites ................ 15 14.2 N-nitroso compounds ................ 16 1.1 5 Epidemiological studies .................. 16 1.1.5.1 Nitrates and nitrites ............... 16 1.1.5.2 N-nitrosocompounds ................. 17 .1.6 Evaluation of health risks .................. 17 .1.6. I Nitrates and nitrites ................. 17 1.1.62 N-nitrosoeompounds ................ 17 1.2 Recommendations for further studies ................ IS 12.1 Analyticalproblems .................... 18 12.1.1 Nitrates and nitrites ............. 18 121.2 N-nitrosocompounds ................ 18 12.2 Sources and levels in the environment ............. 18 12.2.1 Nitrates and nitrites ................ 18 12.2.2 N-nitroso compounds ................ 19 12.3 Metabolism ......................... 19 1.2.3.1 Nitrates and nitrites ............... 19 1.2.3.2 N-nitroso compounds ................. 20 1.2.4 Experimental studies .................... 20 12.5 Epidemiological and clinical studies ............. 20 1.2.5.1 Nitrates and nitrites ................. 20 1.2.5.2 N-nitroso compounds ................ 20 2. CHEMISTRY AND ANALYTICAL METHODS ............21 2.1 Chemical properties and reactions .................21 2.1.1 Nitrates and nitrites ..................2 I 11.2 N-nitrosocompounds ....................21 2.1.3 Formation of N-nitroso compounds in idro ........... 22 2.1 4 The effects of other substances on the formation of N-nitroso compounds ..................... 25 2.2 Analytical methods ......................26 2.2.1 Nitrates and nitrites .....................26 2.2.2 N-nitroso compounds ....................27 3 Page I SOURCES OF NITRATES, NiTRITES AND N-NITROSO COMPOUNDS IN AIR. WATER, SOIL, AND FOOD .................30 3.1 Natural occurrence .....................30 3.1.1 Nitrates and nitrites ...................30 3.1.2 2s-nitroso compounds .................30 3.2 Sources related to man's activities .................31 3.2.1 Nitrates and nitrites ....................II 3.2.1.1 Ecrtiliiers.....................11 3.2.1.2 Animal wastes ...................31 3.2.1.3 Municipal, industrial, and transport wastes ....... 32 3.2.1.4 Deliberate addition of nitrates and nitrites to food ..... 32 3.2.2 N-nitroso compounds .................. 33 3.2.2.1 Food .................... 33 3,2.2.2 Tobacco .................... 33 3.2.13 Industrial uses ..................... 4. TRANSPORT AND TRANSFORMATION IN ENVIRONMENTAL AND I4IOLOGICAL MEDIA .....................34 4,1 Nitrogen Cycle ........................ 4.2 Transformation in food ....................16 4.2.1 Reduction of nitratcs to nitrites .................16 4.2.2 Formation and degradation of N-nitroso compounds .......17 4.3 Formation of N-nitroso compounds from drugs and pesticides ....... 44 Formation ol \-flitroSo conipounds in animal organisms .........39 4.4.1 Formation of V-nitroso compounds in simulated gastric juice 39 4.4.2 Formation of ,•\-nitroso compounds in rig o ............19 4.5 Formation of A-nitroso compounds by microorganisms ........40 46 The effects of other chemicals on the formation of A-nitroso compounds - 40 5. FNVIRONMFNTAL LEVELS AND EXPOSURES ...........41 SI Nitrates and nitrites ................... 41 5 1.1 Ambieril air .................... 41 5.1.2 Water ......................... 41 5.I.3 Selected foods .................... 43 5.1.4 Estimate of general population exposure ............ 44 5.2 -\n1troso compounds .................... 45 5.2.1 Ambient air ..................... 45 5.22 Water ..................... 45 5.2.3 Selected foods ...................... 45 524 Tobacco and tobacco smoke ................. 49 5 Estimate of general population exposure .......... 49 5.2.6 Occupational exposure to A-'-nitroso compounds ....... 50 6. ME'I'ABOLISM OF NITRATES, NITRITES, AND ,.V-NITROSC) COMPOUNDS ..........................50 6 1 Gastrointestinal absorption ..................50 6.1.1 Nitrates and nitrites ...................50 6.1.2 2sunitroso compounds ...................SI 6.2 Biotransformation and eliminalion .................SI 6.2 I Nitrates and nitrites .................SI 6.2.2 V-nitroso compounds ................51 4 Pgc 7. EXPERIMENTAL ANIMAL STUDIES ON THE EFFECTS OF NITRATES, NITRITES.AND,V-NITROSOCOMPOUNDS .............. 52 7.1 Nitr tea and nitrites ....................... 52 7.1.1 Acute and subacute toxicity studies .............. 52 7.1.2 Chronic toxicity and carcinogcnicity studies .......... 54 7.1.3 Emhryotoxicity ..................... 55 7.1.4 Mutagenicity ........................56 7.1.5 Interaction with nutritional factors ............... 57 7.2 A-nitroso compounds ....................... 57 7.2, I Acute and subacute toxicity studies .............. 57 7.2.2 Careinogenicity ...................... 59 7.2.2.1 Interspecies variation in response ........... 61 7.2.2.2 Intraspecies variation in response ........... 61 7.2.2.3 Dose-response relationships of N-nitroso compounds 62 7.2.2.4 Tumour induction by combined administration of nitrites, and amines or am ides ................. 63 7.2.2.5 Dose-response relationship for combinations of nitrites and amines ...................... 65 7,2.2.6 Transplacental carcirlogenesis ............ 66 7.2.2.7 Morphological studies ............... 67 72.18 Biochemical mechanisms ............... 68 7.2.2.9 Interaction with various chemical factors ........ 68 7.2.2.1 t) Miscellaneous modilying factors ............ 70 7.2.3 Embryotoxicity and teratogenicity ..............71 7.2.4 Mutagenicity ......................71 8. EFFECTS OF NITRATES, NITRITES, AND N-NITROSO COMPOU NDS ON MAN .............................73 81 Nitrates and nitrites .......................73 8.1.1 Epidemiological studies..................73 8.1.1.1 Exposure through water ................74 8.1.1.2 F,xposure through vegetables ..............76 811.3 High accidental exposures ...............76 8.1.1.4 Ambient air exposures ...............76 8.1.2 Factors involved in susceptibility to nitrates ...........77 8.1.3 Dose-response relationships for nitrates and nitrites ........78 8.2 N-nitroso compounds ......................80 9. EVALUATION OF HEALTH RISKS TO MAN FROM EXPOSURE TO NITRATES. NITRITES. AND N-NITROSO COMPOUNDS ........ 81 9.1 Nitrates and nitrites ........................ 81 9.1.1 General considerations ................... 81 9.1.2 Assessment of health risks ................. 82 9.2 N-nitroso compounds ....................... 9.2.1 General considerations ................... 83 9.12 Assessment of health risks .................. 83 9.3 Reduction ofexposureth ....................... 84 REFERENCES ........................... 85 S NOTE TO READERS OF THE CRITERIA DOCUMENTS While every effort has been made to present information in the criteria documents as accurately as possible without unduly delaying their publication, mistakes might have occurred and are likely to occur in the future. In the interest of all users of the environmental health - criteria documents, readers are kindly requested to communicate any errors found to the Division of Environmental Health, World Health Organization, Geneva, Switzerland, in order that they may he included in corrigenda which will appear in subsequent