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Toxicity, Nitrous Dioxide
Updated: Jun 10, 2008
Introduction
Background
Nitrogen dioxide (NO2) is a brownish gas that is produced primarily as a byproduct of high-temperature combustion.
- The American Chemical Society's Chemical Abstract Service (CAS) registry number for NO2 is CAS #10102-44-0.
- The United Nations/Department of Transportation number for NO2 is UN#1067.
- The National Institute of Occupational Safety and Health (NIOSH) Registry of Toxic Effects of Chemical Substances (RTECS) identifier for NO2 is QW 9800000.
Workers are exposed to combustion-produced NO2 in various occupations, including arc welders, firefighters, military and aerospace personnel, and those working with explosives. Nitric oxide (NO), NO2 and other oxides of nitrogen are formed from nitrogen and oxygen during high-temperature combustion. NO is oxidized to NO2, a precursor of ozone (O3). NO, NO2, and nitrogen tetroxide (N2 O4) almost always occur together; hence, the terms oxides of nitrogen and nitrogen oxides are used in literature to refer to these molecules. The term NOX is used most often in air pollution literature in reference to the oxides of nitrogen.
NO2 toxicity is also observed in environments where NO2 is formed from noncombustion sources. These include silo fillers, where nitrogen oxides are a byproduct of anaerobic fermentation of crops, and indoor ice skating rinks, where the gas is generated by the propane-driven ice cleaning machine, the Zamboni. In addition, NO2 from automobile exhaust smokestack emissions are thought to be a major contributor to the toxic effects of air pollution.
NO2 is a deep lung irritant that can produce pulmonary edema and fatality if inhaled at high concentrations. The effects of NO2 depend on the level and duration of exposure. Exposure to moderate NO2 levels (50 ppm) may produce cough, hemoptysis, dyspnea, and chest pain. Exposure to higher concentrations of NO2 (>100 ppm) can produce pulmonary edema that may be fatal or may lead to bronchiolitis obliterans. Some studies suggest that chronic exposure to NO2 may predispose individuals to the development of chronic lung diseases, including infection and chronic obstructive pulmonary diseases.
Recent literature on NO2 focuses on its association with nitrous acid (HONO), a molecule that can be formed as a primary product of gas combustion or by the reaction of NO2 with surface water.1,2,3,4 Although early data are inconclusive, some studies suggest HONO may contribute to the adverse health outcomes previously attributed to NO2. The theoretical health risks of HONO include damage to the mucous membranes and lungs by direct contact with the acid, creation of the carcinogenic nitrosamines secondary to HONO combination with amines, and oxygen free radical production through HONO photolysis in air. However, further studies are needed to examine the differential effects of NO2 and HONO.
Pathophysiology
The primary locus of NO2 toxicity is the lung. Exposure to NO2 induces pulmonary injury in a number of ways. NO2 is converted to NO, HNO3 (nitric acid), and HNO2 (nitrous acid) in the distal airways, where it exerts direct toxic effects on type I pneumocytes and ciliated airway cells. NO2 initiates free radical generation in the terminal bronchioles, resulting in protein oxidation, lipid peroxidation, and subsequent cell membrane damage. NO2 also alters macrophage and immune function, causing impaired resistance to infection.
Methemoglobinemia may also be induced with the inhalation of NO2 because NO is absorbed through the lungs and binds to hemoglobin, forming nitrosyl hemoglobin. NO has an affinity for hemoglobin that is several thousand times greater than that of carbon monoxide. This complex is readily oxidized to methemoglobin. Methemoglobinemia serves to compound the preexisting hypoxemia by causing a leftward shift of the oxygen-hemoglobin dissociation curve and further impairing tissue oxygenation. NO is synthesized endogenously from L -arginine by numerous cell types and has multiple physiologic roles.
Frequency
United States
Limited data in the United States and worldwide concerning the true prevalence of NO2 exposure and its contribution to morbidity and mortality are available. The multiple gases and particulates that comprise pollution and the spontaneous conversion of NO2 to other oxides make epidemiological studies difficult.
Mortality/Morbidity
NO2 poisoning may result in mortality or short-term and long-term morbidity. Manifestations of NO2 toxicity are related to the concentration inhaled, duration of exposure, and time since exposure.
Race
No epidemiologic studies have indicated that predilection to exposure or to the manifestations of exposure is attributable to race.
Sex
Historically, males are afflicted with the pulmonary sequelae more frequently than females because of their increased numbers in the predisposed occupations. However, no difference in physiologic response appears to be attributable to sex.
Clinical
History
The diagnosis of nitrogen dioxide (NO2) toxicity largely depends on the history of exposure. Query patients on this history if possible.
- Inquire about exposure and occupation. Welders, firefighters, military and aerospace personnel, individuals working with explosives, and farmers generally have higher risk of exposure than those in other occupations.
- Try to establish duration of exposure.
- In acute exposure, symptoms may range from mild cough to mucous membrane irritation to sudden fatality.
- Suspect methemoglobinemia in patients exposed to NO2 who exhibit cyanosis or dyspnea.
- The initial absence of significant symptoms does not exclude a subsequent development of serious disease.
- Following a delay of 2-48 hours, patients exposed to NO2 may develop the following symptoms:
- Dyspnea
- Cough
- Chest pain
- Clinical manifestations of noncardiogenic pulmonary edema
- The following may develop 2-6 weeks after initial exposure:
- Bronchiolitis obliterans, manifested as fever, cough, and dyspnea
- Diffuse reticulonodular or miliary pattern on chest radiography
Physical
Initial physical findings are sometimes mild but may progress over the following 72 hours to life-threatening respiratory distress.
- Pulmonary symptoms are the most common manifestation of NO2 toxicity.
- Cough
- Dyspnea
- Chest tightness
- Choking
- Wheezing
- Chest pain
- Rales
- Rhonchi
- Decreased breath sounds
- Stridor
- Other acute symptoms
- Light-headedness
- Loss of consciousness
- Restlessness
- Agitation
- Confusion
- Irritation of mucous membranes, including the eyes
- Conjunctival infection
- Weakness
- Fatigue
- Nausea
- Abdominal pain
- Skin burns, in cases of liquid N2 O4 exposure
- Delayed symptoms
- Tachypnea
- Headache
- Fever, chills
- Insomnia
- Myalgias
- Hemoptysis
- Palpitations
- Cyanosis
- Coma
Causes
- Occupational risk factors for NO2 exposure are high among farmers, particularly those who work near silos, firefighters, arc welders, military personnel, and aerospace workers (missile fuel). Any occupation that involves the production, transportation, or use of nitric acid is at risk.
- Other significant sources of risk include ice arenas with ice resurfacing (Zamboni) machines. Gas-fired and kerosene-fired household appliances and motor vehicle exhaust all pose significant risk of exposure.
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References
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Further Reading
Keywords
NO2, nitrous dioxide toxicity, nitrous dioxide poisoning, nitrogen dioxide poisoning, nitrogen dioxide toxicity, nitrogen dioxide, nitric oxide, nitrogen tetroxide, nitrous acid, NO2 exposure, nitrogen dioxide exposure, nitrous dioxide exposure, pulmonary edema, bronchiolitis obliterans, chronic obstructive pulmonary diseases, nitrous acid, HONO, methemoglobinemia, combustion-produced NO2
