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,[1] 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.[2, 3, 4, 5] 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.
Epidemiology
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.
Exposure to nitrogen dioxide in an indoor ice arena - new hampshire, 2011. MMWR Morb Mortal Wkly Rep. Mar 2 2012;61:139-42. [Medline].
Jarvis DL, Leaderer BP, Chinn S, Burney PG. Indoor nitrous acid and respiratory symptoms and lung function in adults. Thorax. Jun 2005;60(6):474-9. [Medline].
Jones GR, Proudfoot AT, Hall JI. Pulmonary effects of acute exposure to nitrous fumes. Thorax. Jan 1973;28(1):61-5. [Medline].
Lee K, Xue J, Geyh AS, et al. Nitrous acid, nitrogen dioxide, and ozone concentrations in residential environments. Environ Health Perspect. Feb 2002;110(2):145-50. [Medline].
van Strien RT, Gent JF, Belanger K, et al. Exposure to NO2 and nitrous acid and respiratory symptoms in the first year of life. Epidemiology. Jul 2004;15(4):471-8. [Medline].
Hesterberg TW, Bunn WB, McClellan RO, et al. Critical review of the human data on short-term nitrogen dioxide (NO2) exposures: evidence for NO2 no-effect levels. Crit Rev Toxicol. 2009;39(9):743-81. [Medline].
US Food and Drug Administration. FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available at http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. Accessed July 27, 2011.
Becker S, Soukup JM. Effect of nitrogen dioxide on respiratory viral infection in airway epithelial cells. Envir Res. 1999;81(2):159-66. [Medline].
Douglas WW, Hepper NG, Colby TV. Silo-filler's disease. Mayo Clin Proc. Mar 1989;64(3):291-304. [Medline].
Elsayed NM. Toxicity of nitrogen dioxide: an introduction. Toxicology. May 20 1994;89(3):161-74. [Medline].
Evans MJ, Stephens RJ, Cabral LJ, Freeman G. Cell renewal in the lungs of rats exposed to low levels of NO2. Arch Environ Health. Mar 1972;24(3):180-8. [Medline].
Hajela R, Janigan DT, Landrigan PL, et al. Fatal pulmonary edema due to nitric acid fume inhalation in three pulp- mill workers. Chest. Feb 1990;97(2):487-9. [Medline].
Hedberg K, Hedberg CW, Iber C, et al. An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. JAMA. Dec 1 1989;262(21):3014-7. [Medline].
Horowitz RS. Nitrogen oxides and silo-filler's disease. In: Viccellio P, Bania T, eds. Emergency Toxicology. 2nd ed. Lippincott Williams & Wilkins; 1998:959-64.
Mayorga MA. Overview of nitrogen dioxide effects on the lung with emphasis on military relevance. Toxicology. May 20 1994;89(3):175-92. [Medline].
Papi A, Amadesi S, Chitano P, et al. Bronchopulmonary inflammation and airway smooth muscle hyperresponsiveness induced by nitrogen dioxide in guinea pigs. Eur J Pharmacol. Jun 18 1999;374(2):241-7. [Medline].
Prutz WA, Monig H, Butler J, Land EJ. Reactions of nitrogen dioxide in aqueous model systems: oxidation of tyrosine units in peptides and proteins. Arch Biochem Biophys. Nov 15 1985;243(1):125-34. [Medline].
Sagai M, Ichinose T. Lipid peroxidation and antioxidative protection mechanism in rat lungs upon acute and chronic exposure to nitrogen dioxide. Environ Health Perspect. Aug 1987;73:179-89. [Medline].
van Bree L, Rietjens I, Alink GM, et al. Biochemical and morphological changes in lung tissue and isolated lung cells of rats induced by short-term nitrogen dioxide exposure. Hum Exp Toxicol. Jul 2000;19(7):392-401. [Medline].
Veeramachaneni NK, Harken AH, Cairns CB. Clinical implications of hemoglobin as a nitric oxide carrier. Arch Surg. Apr 1999;134(4):434-7. [Medline].
Weller BL, Witschi H, Pinkerton KE. Quantitation and localization of pulmonary manganese superoxide dismutase and tumor necrosis factor alpha following exposure to ozone and nitrogen dioxide. Toxicol Sci. Apr 2000;54(2):452-61. [Medline].
World Health Organization. Nitrogen oxides. In: Recommended Health-Based Occupation Exposure Limits for Respiratory Irritants. 1984:73-114.
Print
