Agency for Toxic Substances and Disease Registry
Case Studies in Environmental Medicine (CSEM) 

Nitrate/Nitrite Toxicity
What Are the Physiological Effects of Exposure to Nitrates/Nitrites?

Learning Objectives

Upon completion of this section, you will be able to

• describe the physiologic and pathologic effects of nitrates/nitrites.

Introduction

Unless conditions exist for reducing nitrate to nitrite in the gut (i.e., high pH and proper intestinal microbial flora), ingested nitrate (NO₃^-) is metabolized and excreted without producing apparent adverse effects. Nitrate in the diet may even enhance host defenses against gastrointestinal pathogens by modulating platelet activity, and possibly even gastrointestinal motility and microcirculation (37–39). The known toxic effects of nitrate exposure result from the conversion of nitrate to nitrite (22). The effects of nitrite (NO₂^-) are the same whether nitrite‑containing compounds are ingested or inhaled, or nitrite is produced in vivo from nitrate.

Hematologic Effects

Acute acquired methemoglobinemia is the most important adverse health effect caused by excessive nitrate or nitrite exposure. Methemoglobinemia may arise from various etiologies (40), including

• ingestion or skin exposure to an oxidizing drug or chemical
• systemic acidosis as a result of diarrhea and dehydration
• nitrate or nitrite ingestion in water
• genetic disorders presenting as cyanosis shortly after birth

Methemoglobinemia is a well-recognized hazard of ingestion of nitrates and nitrites (41, 42). The first reported case of fatal acquired methemoglobinemia in an infant due to ingestion of nitrate‑contaminated well water occurred in 1945 (43). In the following 25 years, about 2,000 similar cases of acquired methemoglobinemia in young infants were reported worldwide; about 10% of such cases resulted in death (44). Sporadic cases and occasional fatalities occurred through the 1980s and 1990s, most often resulting from ingestion of nitrate-contaminated well water by infants (33, 45, 46).

Hemoglobin molecules contain iron within a porphyrin heme structure. The iron in hemoglobin is normally found in the Fe²⁺ state. The iron moiety of hemoglobin can be oxidized to the Fe³⁺ state to form methemoglobin. Once it is formed, the molecule loses its ability to carry molecular oxygen. Because red blood cells are bathed in oxygen, a certain amount of physiologic methemoglobin formation occurs continuously. Several endogenous reduction systems exist to maintain methemoglobin in the reduced state. In normal individuals only about 1% of total hemoglobin is methemoglobin at any given time (40, 47).

Methemoglobin can be reduced back to hemoglobin by both spontaneous (NADH-dependent and to a lesser degree by NADPH-dependent) methemoglobin reductase enzymes. Depending on the percentage of total methemoglobin, the clinical picture is one of oxygen deprivation with cyanosis, cardiac dysrhythmias and circulatory failure, and progressive central nervous system (CNS) effects. CNS effects can range from mild dizziness and lethargy to coma and convulsions (33, 48, 49).

Cardiovascular Effects

Hypotension is the main cardiovascular effect seen with nitrate and nitrite medications. It is not commonly seen with ingestion of nitrates and nitrites in food and water.

Reproductive and Developmental Effects

Maternal exposure to environmental nitrates and nitrites may increase the risk of pregnancy complications such as anemia, threatened abortion/premature labor, or preeclampsia (29, 50). Recent epidemiologic data have suggested an association between developmental effects in offspring and the maternal ingestion of nitrate from drinking water; however, a definite conclusion on the cause-and-effect relationship cannot be drawn (33). The maternal transfer of nitrate, nitrite, and N-nitroso compounds, and the potential effect on fetal death and malformation have been described (51). A few studies have hinted at a role for nitrate intake in the risk for developing diabetes mellitus in childhood (52–54). All of these reproductive and developmental effects require further study.

Carcinogenicity

Some study results have raised concern about the cancer-causing potential of nitrates and nitrites used as preservatives and color-enhancing agents in meats (55). Nitrates can react with amino acids to form nitrosamines, which have been reported to cause cancer in animals (51). Elevated risk of non-Hodgkin’s lymphoma and cancers of the esophagus, nasopharynx, bladder, and prostate have been reported (56–59). An increased incidence of stomach cancer was observed in one group of workers with occupational exposures to nitrate fertilizer; however, the weight of evidence for gastric cancer causation is mixed (60, 61). Epidemiological investigations and human toxicological studies have not shown an unequivocal relationship between nitrate intake and the risk of cancer (31).

Key Points

• Acute acquired methemoglobinemia is the most important adverse health effect caused by excessive nitrate/nitrite exposure.
• Maternal exposure to environmental nitrates and nitrites may increase the risk of pregnancy complications such as anemia, threatened abortion/premature labor, or preeclampsia.

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