Toxicity Profiles

Condensed Toxicity Summary for NITRATES

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

AUGUST 1995

Prepared By: Andrew Francis, M.S., DABT, Chemical Hazard Evaluation Group, Biomedical Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.

Prepared for: Oak Ridge Reservation Environmental Restoration Program.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

Nitrates are produced by natural biological and physical oxidations and therefore are ubiquitous in the environment (Ridder and Oehme 1974). Most of the excess nitrates in the environment originate from inorganic chemicals manufactured for agriculture. Organic molecules containing nitrate groups are manufactured primarily for explosives or for their pharmacological effects (Stokinger 1982). Exposure to inorganic nitrates is primarily through food and drinking water, whereas exposure to organic nitrates can occur orally, dermally, or by respiration (Stokinger 1978). The primary toxic effects of the inorganic nitrate ion (NO3-) result from its reduction to nitrite (NO2-) by microorganisms in the upper gastrointestinal tract (Johnson and Kross 1990, Bouchard et al. 1992). Nitrite ions can also be produced with organic nitrate exposure; however, the primary effect of organic nitrate intake is thought to be dependent on the production of an active nitric oxide (NO-) radical (Waldman and Murad 1987). Organic nitrates are metabolized in the liver resulting in an increase in blood nitrites (Murad 1990). Nitrates and nitrites are excreted primarily in the urine as nitrates (Hartman 1982).

The primary toxic effect of inorganic nitrates is the oxidation of the iron in hemoglobin by excess nitrites forming methemoglobin. Infants less than 6 months old comprise the most sensitive population (Hartman 1982, Bouchard et al. 1992). Epidemiological studies have shown that baby formula made with drinking water containing nitrate nitrogen levels over 10 mg/L can result in methemoglobinemia, especially in infants less than 2 months of age. No cases of methemoglobinemia were reported with drinking water nitrate nitrogen levels of 10 mg/L or less (Bosch et al. 1950, Walton 1951, Shuval and Gruener 1972). A secondary target for inorganic nitrate toxicity is the cardiovascular system. Nitrate intake can also result in a vasodilatory effect, which can complicate the anoxia resulting from methemoglobinemia (Ridder and Oehme 1974). Decreased motor activity was reported in mice given up to 2000 mg nitrite/L in drinking water, and persistent changes in EEG recordings were observed in rats exposed to 100 to 2000 mg nitrite/L in drinking water. However, exposure of rats to 3000 mg nitrite/L in drinking water for 2 years did not result in any gross or microscopic changes in brain tissue. The data indicate that these central nervous system effects are not related to methemoglobin levels (Shuval and Gruener 1972).

The importance of the primary and secondary targets are reversed with organic nitrates, several of which have long been used for their vasodilatory effects in the treatment of angina pectoris in humans (Murad 1990). Large doses of organic nitrates, however, can also produce methemoglobinemia (Andersen and Mehl 1973). Epidemiological studies have shown that chronic or subchronic exposure to organic nitrates results in the development of tolerance to the cardiovascular effects of these compounds. This apparent biocompensation has caused serious cardiac problems in munitions workers exposed to organic nitrates when they are suddenly removed from the source of exposure (Carmichael and Lieben 1963).

An epidemiological study correlated the number of congenital malformations of the central nervous system and musculoskeletal system of babies with the amount of inorganic nitrate in the mother's drinking water (Dorsch et al. 1984). Other studies, however, do not support these associations, and the presence of unidentified teratogenic factors in the environment could not be ruled out. Inorganic nitrate and nitrite have been tested for teratogenicity in rats, guinea pigs, mice, hamsters, and rabbits. No teratogenic responses were reported; however, fetotoxicity attributed to maternal methemoglobinemia was observed at high doses (4000 mg nitrate/L in drinking water) (Sleight and Atallah 1968, Shuval and Gruener 1972, FDA 1972a, b, c).

A Reference Dose (RfD) of 1.60 mg/kg/day (nitrate nitrogen) for chronic oral exposure was calculated from a NOAEL of 10 mg/L and a LOAEL of 11-20 mg/L in drinking water, based on clinical signs of methemoglobinemia in 0-3-month-old infants (Bosch et al. 1950, Walton 1951). It is important to note, however, that the effect was documented in the most sensitive human population so no uncertainty or modifying factors were used (EPA 1994).

The possible carcinogenicity of nitrate depends on the conversion of nitrate to nitrite and the reaction of nitrite with secondary amines, amides, and carbamates to form N-nitroso compounds that are carcinogenic (Bouchard et al. 1992). Experiments with rats have shown that when given both components, nitrite and heptamethyleneimine, in drinking water, an increase in the incidence of tumors occurs (Taylor and Lijinsky 1975). Human epidemiological studies, however, have yielded conflicting evidence. Positive correlations between the concentration of nitrate in drinking water and the incidence of stomach cancer were reported in Columbia and Denmark (Cuello et al. 1976, Fraser et al. 1980). However, studies in the United Kingdom and other countries have failed to show any correlation between nitrate levels and cancer incidence (Forman 1985, Al-Dabbagh et al. 1986, Croll and Hayes 1988). Nitrate has not been classified as to its carcinogenicity by the EPA, although it is under review (EPA 1994).

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Last Updated 2/13/98