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

Nitrate/Nitrite Toxicity
How Should Patients Exposed to Nitrates/Nitrites Be Evaluated?

Learning Objectives

Upon completion of this section, you will be able to

• describe the clinical assessment of an infant exposed to nitrates/nitrites and
• describe the signs and symptoms of methemoglobinemia.

Introduction

The evaluation of nitrate/nitrite-related health effects most often presents as a clinical evaluation of an infant with cyanosis. Symptomatic methemoglobinemia is much less common in older children and adults.

Exposure History

The evaluation of a patient with suspected nitrate or nitrite exposure includes a complete medical and exposure history (1). Clues to potential exposure are often obtained by questioning the patient or family about the following topics (see Table 1 for a select list of methemoglobin inducers)

• location of the home (urban, suburban, or rural)
• drinking water source and supply (if well water: depth, location, type of well construction, and frequency of microbiologic and nitrate testing)
• nearby activities (agricultural or industrial) and proximity to drinking-water source
• type of sewer system (municipal or septic) and proximity to drinking-water source
• proximity of neighboring septic tanks or others upgradient to drinking water source
• recent flooding
• occupations, avocations, and hobbies of family members
• type of formula consumed by infant, feeding regimen, and source of dilution water
• types of food eaten, with a focus on prepared meats, carrots, spinach
• recent use of medications by infant and mother.

Medical History

Additional questions should be asked about the medical history including

• family history
• known blood or enzyme disorders
• nutritional status and growth history
• history of recent gastroenteritis with vomiting or diarrhea
• other episodes of cyanosis, recently or as a newborn
• history of tachypnea, tachycardia, or hypotension.

Physical Examination

All cyanotic patients should be assessed for possible cardiac and lung disease (cardiac murmurs, gallops, arrhythmias, rales, rhonchi, wheezes, dullness, or hyperresonance in the chest). A central chocolate‑brown or slate‑gray cyanosis that does not respond to administration of 100% oxygen is suggestive of methemoglobinemia (40, 63). In addition, two clinical observations may help

• the victim is often less ill than one would expect from the severity of 'cyanosis'
• the 'cyanosis' is unresponsive to oxygen therapy (48).

Physical examination should include special attention to the color of the skin and mucous membranes. In young infants, look for labored breathing, respiratory exhaustion, hypotension, below‑average weight gain, and failure to meet developmental indices. Gastroenteritis can increase the rates of production and absorption of nitrites in young infants and aggravate methemoglobinemia. If gastroenteritis is present—especially in infants—evaluate the patient for the possible presence of dehydration (i.e. , poor skin turgor, sunken fontanel, dry mucous membranes) (40, 64).

Contaminated well water
Meat preservatives
Vegetables: carrot juice, spinach
Silver nitrate burn therapy
Industrial salts
Contaminants of nitrous oxide canisters for anesthesia

Butyl/isobutyl nitrite
Amyl/sodium nitrite
Nitroglycerine

Room deodorizer propellants
Inhalant in cyanide antidote kit
Oral, sublingual, or transdermal pharmaceuticals for treatment of angina

Aniline/aminophenols
Nitrobenzene
Local anesthetics
Sulfonamides
Phenazopyridine
Antimalarials
Sulfones
p‑Aminosalicylic acid
Naphthalene copper sulfate
Resorcinol
Chlorates
Combustion products

Laundry ink
Industrial solvents, gun‑cleaning products Benzocaine, lidocaine, propitocaine, prilocaine
Antibacterial drugs
Pyridium
Chloroquin, primaquine
Dapsone
Bactericide (tuberculostatic)
Mothballs
Fungicide for plants, seed treatments
Antiseborrheic, antipruritic, antiseptic
Matches, explosives, pyrotechnics
Fires

Adapted from Dabney (62).

Correlation of Signs and Symptoms With MHg Levels

Signs and symptoms of methemoglobinemia can be roughly correlated with the percentage of total hemoglobin in the oxidized form (see Table 2). Unfortunately, because methemoglobin (MHg) is generally expressed as a percent of total hemoglobin, levels may not correspond with symptoms in some patients. For example, a patient with a MHg level of 20% and total hemoglobin of 15 g/dL still has 12 g/dL of functioning hemoglobin, whereas a patient with a MHg level of 20% and total hemoglobin of 8 g/dL has only 6.4 g/dL of functioning hemoglobin. Anemia, acidosis, respiratory compromise, and cardiac disease may make patients more symptomatic than expected for a given MHg level (40).

Due to the large excess capacity of the blood to carry oxygen, levels of MHg up to 10% typically do not cause significant clinical signs in an otherwise healthy individual. Levels above 10% may result in cyanosis, weakness, and rapid pulse (22). A chocolate-brown or slate-gray central cyanosis—involving the trunk and proximal portions of the limbs, as well as the distal extremities, mucous membranes, and lips—is one of the hallmarks of methemoglobinemia and can become noticeable at a concentration of 10%–15% of total hemoglobin (65–67). Dyspnea and nausea occur at MHg levels of above 30%, while lethargy and decreased consciousness occur as levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure, and neurological depression. Levels above 70% are often fatal (20). Features of toxicity may develop over hours or even days (48).

Central cyanosis of limbs/trunk; often asymptomatic but may have weakness, tachycardia

Central nervous system depression (headache, dizziness, fatigue), dyspnea, nausea

Lethargy, syncope, coma, arrhythmias, shock, convulsions

High risk of mortality

Adapted from Dabney (62)

Key Points

• The evaluation of nitrate/nitrite-related health effects most often presents as a clinical evaluation of an infant with cyanosis.
• Exposure history for infants should focus on formula preparation and the source of formula dilution water.
• Signs and symptoms of methemoglobinemia are roughly correlated with the percentage of oxidized hemoglobin in the blood.

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