INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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 nitrogen dioxide is CAS #10102-44-0.

• The United Nations/Department of Transportation number for nitrogen dioxide is UN#1067.

• The National Institute of Occupational Safety and Health (NIOSH) Registry of Toxic Effects of Chemical Substances (RTECS) identifier for nitrogen dioxide is QW 9800000.

Workers are exposed to combustion-produced NO₂ in a variety of 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. Nitric oxide is oxidized to NO₂, a precursor of ozone (O₃). Nitric oxide, nitrogen dioxide, and nitrogen tetroxide (N₂O₄) 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.

Nitrogen dioxide 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.

Nitrogen dioxide 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 nitrogen dioxide 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. 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 tease out 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. Nitrogen dioxide 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. Nitrogen dioxide initiates free radical generation in the terminal bronchioles, resulting in protein oxidation, lipid peroxidation, and subsequent cell membrane damage. Nitrogen dioxide also alters macrophage and immune function, causing impaired resistance to infection.

Methemoglobinemia also may 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. Nitric oxide is synthesized endogenously from L-arginine by numerous cell types and has multiple physiologic roles.

Frequency:

• In the US: Limited data exist in the United States and worldwide concerning the true prevalence of NO₂ exposure and its contribution to morbidity and mortality. The multiple gases and particulates that comprise pollution and the spontaneous conversion of NO₂ to other oxides make epidemiological studies difficult.

Mortality/Morbidity: Nitrogen dioxide poisoning may result in mortality or short-term and long-term morbidity. Manifestations of nitrogen dioxide 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	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History: The diagnosis of nitrogen dioxide toxicity depends largely 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.

• Acute exposure - Symptoms may range from mild cough to mucous membrane irritation to sudden fatality.

• Suspect methemoglobin in patients exposed to nitrogen dioxide gas who exhibit cyanosis or dyspnea.

• The initial absence of significant symptoms does not exclude a subsequent development of serious disease.

• Latency period - Following a delay of 2-48 hours, patients exposed to nitrogen dioxide may develop the following symptoms:

• Dyspnea

• Cough

• Chest pain

• Clinical manifestations of noncardiogenic pulmonary edema

• Late sequelae - The following may develop 2-6 weeks after initial nitrogen dioxide exposure:

• Bronchiolitis obliterans, manifested as fever, cough, and dyspnea

• Diffuse reticulonodular or miliary pattern on chest x-ray

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 nitrogen dioxide 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 nitrogen tetroxide exposure

• Delayed symptoms
  • Tachypnea

  • Headache

  • Fever, chills

  • Insomnia

  • Myalgias

  • Hemoptysis

  • Palpitations

  • Cyanosis

  • Coma

Causes:

• Occupational risk factors for nitrogen dioxide 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 are ice arenas with ice resurfacing (Zamboni) machines. Gas- and kerosene-fired household appliances as well as motor vehicle exhaust all pose significant risk of exposure.