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Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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10
Nitrogen Dioxide

This chapter summarizes the relevant epidemiologic and toxicologic studies on nitrogen dioxide (NO2). Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation exposure levels from the National Research Council (NRC) and other agencies are also presented. The subcommittee considered all of that information in its evaluation of the Navy’s current and proposed 1-hour (h), 24-h, and 90-day exposure guidance levels for NO2. The subcommittee’s recommendations for NO2 exposure levels are provided at the conclusion of this chapter along with a discussion of the adequacy of the data for defining those levels and research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

NO2 is a reddish-brown gas that decomposes in water to form nitric acid and nitric oxide (NO) (Budavari et al. 1989). The odor threshold for recognition of NO2 in air is 0.1 to 0.4 parts per million (ppm) (NIOSH 1976). Most individuals become tolerant of or desensitized to the odor as exposure duration is increased. Selected physical and chemical properties are summarized in Table 10-1.

OCCURRENCE AND USE

NO2 has a number of industrial applications (Lewis 1993). It is an intermediate in nitric acid production, a nitrating agent in explosives, a polymerization inhibitor for acrylates, and an oxidizing agent in rocket fuels. It has been used to bleach flour (Budavari et al. 1989).

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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TABLE 10-1 Physical and Chemical Data on Nitrogen Dioxidea

Synonyms

CAS registry number

10102-44-0

Molecular formula

NO2

Molecular weight

46.01

Boiling point

21.15°C

Melting point

−9.3°C

Flash point

Explosive limits

Specific gravity

1.448 at 20°C/4°C (liquid)

Vapor pressure

908 mmHg at 25°C

Solubility

Soluble in concentrated sulfuric and nitric acids

Conversion factors

1 ppm = 1.88 mg/m3; 1 mg/m3 = 0.53 ppm

aData on vapor pressure were taken from HSDB (2003); all other data were taken from Budavari et al. (1989).

Abbreviations: mg/m3, milligrams per cubic meter; mmHg, millimeters of mercury; ppm, parts per million; —, not available or not applicable.

NO2 is a component of smog and a precursor of ozone (Costa and Amdur 1996). Motor-vehicle exhaust and emissions from other commercial and industrial combustion processes are the major anthropogenic sources of NO2 (HSDB 2003). Natural sources include forest fires and atmospheric lightning discharges (HSDB 2003). The Navy has indicated that the primary sources of NO2 on board submarines are the vent fog precipitator, the diesel generator, and cigarette smoking (Crawl 2003).

SUMMARY OF TOXICITY

NO2 irritates mucous membranes, inciting cough and dyspnea. Higher concentrations of NO2 produce changes in lung function in healthy subjects and lesions in the pulmonary tract of animals. Increased airway resistance has been reported to occur when exposures to NO2 exceed 2.5 ppm (Beil and Ulmer 1976; von Nieding et al. 1979, 1980; von Nieding and Wagner 1979). However, other investigators have not observed any NO2-induced changes in airway resistance or spirometry at concentrations between 2 and

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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4 ppm (Linn et al. 1985; Mohsenin 1987, 1988; Sandström et al. 1990). Below 1 ppm, the evidence for changes in lung volumes, flow-volume characteristics of the lungs, or airway resistance in healthy subjects is very weak. Asthmatic patients and individuals with respiratory disease are considered to be more sensitive to inhaled NO2 at concentrations greater than 1-2 ppm than are healthy individuals.

The following information comes from a comprehensive review by the U.S. Environmental Protection Agency (EPA 1993). NO2 appears to have its primary pulmonary effects on the distal bronchioles, proximal alveolar ducts, and alveolar parenchyma. Sufficiently high concentrations of NO2 produce subtle to major changes in pulmonary function depending on concentration and duration of exposure. The terminal conducting airways and adjacent alveolar ducts and alveoli are most sensitive to the toxic effects of NO2. The ciliated cells of the bronchiolar epithelium and the type I cells of the alveolar epithelium are highly susceptible to NO2-induced injury. The ciliated bronchioles can become denuded of cilia, and nonciliated bronchiolar cells (in rodents) lose their dome-like luminal surface projections. The type I cells in the alveoli become necrotic and slough, and type II cells proliferate to replace them. Pulmonary edema is the hallmark of severe NO2 toxicosis. Death results from bronchospasm or pulmonary edema. NO2 is not considered to be a directly acting carcinogen in animals or humans.

The immune system appears to be a secondary target of repeated exposures to NO2(EPA 1993). Animals treated with NO2 and subsequently challenged with either pathogenic bacteria or viruses were less resistant to infection compared with untreated animals. Humoral immune responses were also affected. In NO2-treated animals, there was a reduction in circulating antibody and antibody producing cells. The cellular (T-cell) immune response appeared to be less affected by NO2 than the humoral (B-cell) response.

The toxicity of air pollutants, notably NO and NO2, may be influenced by the pattern of exposure as well as concentration and duration in that cyclical peak exposures, such as those associated with rush-hour traffic, have been shown to enhance the toxic effects of NO and NO2 in animals (EPA 1993; Mercer et al. 1995). No information on pattern of exposure on submarines was provided to the subcommittee. The influence of exposure pattern on toxicity highlights the critical importance of continuous monitoring to characterize the submarine atmosphere.

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Effects in Humans

Accidental Exposures

Inhaled NO2 can produce a syndrome known as silo-filler’s disease. Gas that accumulates above silage in silos contains a mixture of nitrogen oxides that can attain NO2 concentrations of 200-4,000 ppm within 2 days (Lowry and Schuman 1956; Douglas et al. 1989). Silo-filler’s disease can progress from an immediate cough, dyspnea, and a choking sensation to a 2-3 week period of apparent remission, followed by fever, progressively severe dyspnea, cyanosis, cough, inspiratory and expiratory rales, neutrophilic leukocytosis, and discrete nodular densities in the lungs. Seventeen patients examined after being exposed to silo gas developed similar symptoms. Autopsy of one patient who died revealed diffuse alveolar damage with hyaline membranes, hemorrhagic pulmonary edema, and acute edema of the airways (Douglas et al. 1989).

An accidental acute exposure of hockey players and spectators to NO2 from a malfunctioning motor on an ice resurfacer resulted in onset of cough, hemoptysis, or dyspnea during or within 48 h of the exposure (Hedberg et al. 1989). No spirometry effects were identified in the hockey players at 10 days or 2 months following exposure. NO2 concentrations were not measured in the arena.

Experimental Studies

Healthy individuals exposed to NO2 at <1.5 ppm generally show no symptoms or effects on pulmonary function (Folinsbee et al. 1978; Adams et al. 1987; Frampton et al. 1991; Kim et al. 1991; Hazucha et al. 1994). Although exposure at 1.5 ppm for 3 h did not significantly affect pulmonary function, there were slight but significant decreases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) when subjects were challenged with carbachol (Frampton et al. 1991). However, no changes were observed in the pulmonary airway reactivity or in symptoms of irritation in healthy adults exposed to NO2 at 1 ppm for 2 h, at 2 ppm for 3 h (Hackney et al. 1978), at 2 ppm for 4 h (Devlin et al. 1992), at 3 ppm for 2 h (Goings et al. 1989), or at 2.3 ppm for 5 h (Rasmussen et al. 1992). When normal subjects were exposed to NO2 at 2 ppm for 1 h and challenged with methacholine, there was an increase in airway reactivity, but there were no changes in lung volume or spirometry (Mohsenin 1988).

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Biochemical effects have also been noted in healthy adults exposed to NO2. Exposures at 1-4 ppm for 3-4 h have caused (1) increases in recovery of polymorphonuclear leukocytes in bronchoalveolar lavage fluid (Devlin et al. 1992; Frampton et al. 1992), (2) decreases in serum glutathione peroxidase activity (Rasmussen et al. 1992), (3) decreases in red blood cell membrane acetylcholinesterase activity and increases in peroxidized red blood cell lipids and glucose-6-phosphate dehydrogenase activity (Posin et al. 1978), (4) decreases in alpha-1-protease inhibitor activity (Mohsenin and Gee 1987), and (5) small reductions in red blood cell counts (Frampton et al. 2002).

Healthy volunteers exposed to NO2 at 10 ppm for 6 h or at 20 ppm for 2 h noted an odor upon entering the exposure chamber (Henschler and Lütge 1963). At the 20-ppm concentration, minor scratchiness of the throat was reported by all subjects after 50 minutes (min), and three of the eight volunteers experienced a slight headache towards the end of the 2-h exposure (Henschler and Lütge 1963). Methemoglobin levels were unaffected in the 10-ppm exposure group and increased 1% on average in the 20-ppm exposure group. In another study involving exposures to 10-14 healthy volunteers, no symptoms of irritation occurred in those exposed to NO2 at 20 ppm for 2 h, if they had been exposed to several lower concentrations of NO2 during the preceding days (Henschler et al. 1960). An exposure at 30 ppm for 2 h, however, caused definite discomfort. Subjects experienced a burning sensation and an increasingly severe cough for most of the second hour of exposure, although the cough began to improve near the end of the exposure period. As the exposure continued, the burning sensation migrated into the lower airways and deep into the chest and was accompanied by marked sputum secretion and dyspnea. Near the end of 2 h, the exposure was described as barely tolerable.

Several studies have been conducted to assess the effects of NO2 on pulmonary function in asthmatic individuals and patients with chronic lung disease or bronchitis. However, most of the results from studies on pulmonary function and airway hyperactivity in asthmatic humans have been inconclusive and conflicting. Nevertheless, humans with asthma appear to be at greater risk for the respiratory effects of NO2 exposure than healthy individuals are. For example, it has been reported that asthmatic individuals exposed to NO2 at 0.3 or 0.5 ppm for 2-4 h exhibited slight reductions in FEV1 and specific airway conductance and experienced wheezing and tightness of the chest (Kerr et al. 1979; Bauer et al. 1985). However, in several other studies, exposures of asthmatic subjects to concentrations of NO2 at 0.13-1.0 ppm did not significantly affect pulmonary function in

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

adolescents or adults during exercise or rest (Sackner et al. 1981; Kleinman et al. 1983; Linn and Hackney 1984; Koenig et al. 1985, 1987; Mohsenin 1987; Morrow and Utell 1989; Roger et al. 1990; Rubinstein et al. 1990; Vagaggini et al. 1996).

Occupational and Epidemiologic Studies

As mentioned above, silo-filler’s disease is an occupational hazard to farmers (Lowry and Schuman 1956; Douglas et al. 1989). Welders are exposed to a mixture of fumes, gases, and NO2. An acetylene-torch welder developed shortness of breath and chest discomfort while welding for about 30 min in a confined space. Eighteen hours after the incident, chest X-rays revealed pulmonary edema. Simulation of the incident produced a concentration of NO2 of at least 90 ppm within 40 min and total oxides of nitrogen in excess of 300 ppm (Norwood et al. 1966). Morley and Silk (1970) measured NO2 at 30 ppm during a 40-min welding job. No adverse effects were observed in the six people present. Morley and Silk (1970) also described 11 cases, including one resulting in death, of “nitrous fume gassing” of workers in the chemical, engineering, and shipbuilding industries whose symptoms included choking, cough, dyspnea, cyanosis, headache, chest pain and tightness, nausea, and pulmonary edema. Similar signs and symptoms occurred in four firemen who were exposed to an unknown amount of NO2 (Tse and Bockman 1970).

In a review of epidemiologic studies, the U.S. Environmental Protection Agency (EPA 1993) determined that there was insufficient evidence to make a conclusion about the long- or short-term health effects of exposure to NO2. The studies reviewed included investigations of (1) lung function, respiratory symptoms, and various respiratory diseases in relation to gas-stove use in the home (a surrogate for NO2 exposure) and (2) lung function, respiratory symptoms, various respiratory diseases, and mortality in relation to both indoor and outdoor NO2 concentrations. The majority of the studies did not include individual exposure measurements or estimates. The literature indicates that infants and adults respond similarly to NO2, but children 5-12 years of age and people with pre-existing disease appear to be more sensitive to low-level NO2 exposures (EPA 1995). Recent investigations of similar design and type have yielded similar results (Farrow et al. 1997; Pilotto et al. 1997; Schindler et al. 1998; Peters et al. 1999a,b; Fusco et al. 2001; Brunekreef and Holgate 2002; Wong et al. 2002). Epidemiologic studies, by design, identify associations between health effects and expo-

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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sures but are usually inadequate for defining continuous-exposure concentrations pertinent to the setting of EEGLs and CEGLs for submariners.

Effects in Animals

Acute Toxicity

Hine et al. (1970) studied the effects of NO2 at varying concentrations and exposure durations in mice, rats, guinea pigs, rabbits, and dogs. At 40 ppm for varying durations, lacrimation, conjunctivitis, and increased respiration occurred in all five species. When all species were exposed to NO2 at 20 ppm for 24 h, they exhibited minimal signs of irritation and changes in behavior, and histologic examination revealed lung congestion and interstitial inflammation. Lethality was first noted in guinea pigs exposed at 50 ppm for 1 h, in rats and mice exposed at 50 ppm for 24 h, and in rabbits and dogs exposed at 75 ppm for 1 and 4 h, respectively.

Wistar rats were exposed to NO2 at 25, 75, 125, 175, or 200 ppm for 10 min (Meulenbelt et al. 1992a,b). No signs of toxicity were observed at 25 ppm. At 75 ppm, there were significant increases in lung weights and in subpleural hemorrhages accompanied by pale discoloration of the lung. Histopathology revealed atypical pneumonia, edema, focal desquamation of the terminal bronchiolar epithelium, and increased numbers of macrophages and neutrophilic lymphocytes. The lesions increased in severity at the higher concentrations, and interstitial thickening of the centriacinar septa was present in the 175-ppm and 200-ppm exposure groups. When the rats were exposed at 175 ppm for 20 min, five of six of them died.

The lung weights of male Fischer 344 rats were increased significantly following exposures to NO2 at 150 ppm for 5 min, 100 ppm for 15 min, and 75 ppm for 30 min (Lehnert et al. 1994). Rats exposed at 90 ppm for 15 min or 72 ppm for 60 min showed severe signs of respiratory distress and eye irritation lasting about 2 days, and they showed significantly increased lung-to-body weight ratios during the first 48 h after exposure (Carson et al. 1962). Histopathology revealed pulmonary edema and an increased incidence of chronic murine pneumonia. Rats exposed at 65 ppm for 15 min or 28 ppm for 60 min had mild signs and symptoms, whereas those exposed at 33 ppm for 15 min had no adverse clinical signs of toxicity or pathologic changes. Histopathologic changes have been noted in the type I and type II cells of the lungs of Wistar rats exposed to NO2 at 20 ppm for 20 h (Hayashi et al. 1987). Other studies have noted similar changes as well as alveolar

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

and interstitial edema, bronchiolitis, bronchiolar epithelial cell hyperplasia, and loss of cilia 1-3 days following exposure at 26 ppm for 24 h (Schnizlein et al. 1980; Hillam et al. 1983) or at 20 ppm for 24 hours (Rombout et al. 1986).

When Sprague-Dawley rats were exposed to NO2 at 14 ppm for 24 h, 48 h, or 72 h, Stephens et al. (1978) observed minor loss of cilia from the epithelial cells lining the terminal airways. In another study of Wistar rats exposed to NO2 at 2 or 10 ppm for 3 days, the tracheal and bronchiolar epithelium were sporadically deciliated and fibrinous deposits were observed in the alveoli at the 10-ppm concentration (Azoulay-Dupuis et al. 1983).

Changes in minute-ventilation have been evaluated in Fischer 344 rats exposed to NO2 at 100, 300, or 1,000 ppm for 1-20 min (Lehnert et al. 1994) or at 200 ppm for 15 min (Elsayed et al. 2002). As concentrations increased, there were decreases in the minute-ventilation, which were considered to be the result of declines in tidal volume but not in breathing frequency.

Respiratory function was monitored in squirrel monkeys exposed to NO2 at 10-50 ppm for 2 h (Henry et al. 1969). Only slight effects on respiratory function and mild histopathologic changes in the lungs were noted at the 10 and 15 ppm concentrations. At the 35- and 50-ppm concentrations there were marked increases in respiratory rate and decreases in tidal volume. Histopathologic changes in the lungs were severe.

Repeated Exposures and Subchronic Toxicity

Alveolar macrophages have an immunosurveillance role in the lungs. The effects of NO2 on resident alveolar macrophages have been inconsistent. Wistar rats exposed to NO2 at 10 ppm for 28 days exhibited inhibition of the immunosuppressive activity of alveolar macrophages (Koike et al. 2001). In a study of New Zealand rabbits exposed to NO2 at 0.3 ppm for 2 h per day for 13 days, there was a decrease in macrophage phagocytic capacity, although exposure at 1.0 ppm for 2 days increased phagocytic capacity (Schlesinger 1987). No effects were observed after 6 days of exposure at 1.0 ppm. In two studies with Fischer 344 rats, there was a trend toward increased numbers of alveolar macrophages and increased cell volume when the rats were exposed to base concentrations of NO2 at 0.5 ppm and 2.0 ppm for 22 h per day, 7 days per week and to two 1-h peak concentrations of 1.5 ppm and 6.0 ppm on 5 of 7 days for 6 weeks (Crapo et al.

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

1984; Chang et al. 1986). An increase in alveolar macrophages was noted in the lungs of Wistar rats exposed to NO2 at 2.7 ppm for 4 weeks, but not in rats exposed at 1.3 or 0.5 ppm (Rombout et al. 1986). An increase in alveolar macrophages was also observed in Fischer 344 rats exposed to NO2 at 5 ppm for up to 15 weeks (Gregory et al. 1983) and in Wistar rats exposed at 10 ppm for 21 days (Hooftman et al. 1988). Phagocytic activity was reduced in the alveolar macrophages after exposure to NO2 at 25 ppm for 14 and 21 days (Hooftman et al. 1988). However, in Fischer 344 rats, suppression of phagocytic activity occurred after 7 days of exposure at 4 ppm and 5 days of exposure at 8 ppm, but activity returned to normal following 10 days of exposure at those concentrations (Suzuki et al. 1986). In Fischer 344 rats exposed to NO2 at 10 ppm for 1, 3, and 20 days, the numbers of inflammatory cells and the total protein concentrations were increased in the bronchoalveolar lavage. Tumor necrosis factor-alpha was markedly reduced, and interleukin-10 and interleukin-6 were increased in alveolar macrophages (Garn et al. 2003).

In mice treated with NO2 at either 1 or 5 ppm for 6 h on 2 consecutive days, a concentration-dependent decrease in alveolar macrophage phagocytosis was observed in the lower respiratory tract (Rose et al. 1989). However, when the exposure concentration was increased to 15 ppm for the same duration, no further affect on alveolar macrophage phagocytosis was noted. A significant increase in vital capacity of the lung occurred in rats exposed to NO2 at 0.5 ppm for 6 h per day, 5 days per week for 4 weeks, but no effects were noted at the 1-ppm concentration (Evans et al. 1989). When Wistar rats were exposed to NO2 at 5.4 ppm for 3 h per day for 30 days, there was a tendency toward increased lung volume (Yokoyama et al. 1980), although a definite increase in lung volume was observed in Fischer 344 rats exposed at 9.5 ppm for 24 months (Mauderly et al. 1990). Decreases in tidal volume and increases in respiratory rate were observed in squirrel monkeys exposed continuously (24 h per day) to NO2 at 5 ppm for 2 months (Henry et al. 1970).

There was mild loss of bronchiolar cilia and fibrin deposition in the alveoli of Wistar rats exposed to NO2 at 10 ppm for 3 days (Azoulay-Dupuis et al. 1983). No lesions were observed at the 2-ppm concentration for 3 days or when Sprague-Dawley rats were exposed at 5 ppm for 3 days (Messiha et al. 1983). Hypertrophy and hyperplasia of type II cells were noted in the lungs of Swiss-Webster mice exposed to NO2 at 0.34 ppm for 6 h per day, 5 days per week for 6 weeks (Sherwin and Richters 1982). No pathology was noted in five species of animals (guinea pig, rabbit, dog,

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

squirrel monkey, or rat) continuously exposed to NO2 at 0.53 ppm for 90 days (Steadman et al. 1966).

No pulmonary pathology was seen in Wistar rats continuously exposed at up to 1.3 ppm for 28 days (Rombout et al. 1986). At 2.7 ppm, there was focal thickening of the centriacinar septa, progressive loss of cilia in the trachea and main bronchi, and hypertrophy of the bronchiolar epithelium and epithelial cells. Those lesions were more severe at the 10.6-ppm concentration and included extensive shortening and loss of cilia in the trachea and bronchioles, necrosis of type I cells, an increase in the number of type II cells, thickening of the proximal alveolar septa, alveolar dilatation, and increased numbers of macrophages in the bronchioles (Rombout et al. 1986). Wistar rats exposed to NO2 at 10.6 ppm for 4 days had significantly increased pulmonary activities of glucose-6-phosphate dehydrogenase, glutathione reductase, and glutathione peroxidase and increased numbers of type II cells (van Bree et al. 2000).

No lesions were noted in the nasal cavities or lungs of Wistar rats exposed to NO2 at 4 ppm for 6 h per day, 5 days per week for up to 21 days (Hooftman et al. 1988). At 10 ppm, there were increases in the cellularity of the bronchiolar walls, alveolar ducts, and adjacent alveoli. Hypertrophy or hyperplasia of small bronchi and bronchiolar epithelium was observed. These lesions were exacerbated at the 25-ppm concentration. Three other studies revealed lesions in the lungs of Wistar rats (Hayashi et al. 1987), JCL:SD rats (Kyono and Kawai 1982), and guinea pigs (Yuen and Sherwin 1971) continuously exposed to NO2 at 10 ppm for 14 days, 1 month, and 6 weeks, respectively.

Chronic Toxicity

In several studies in which rats were exposed to NO2 at 2 ppm continuously for 360-763 days, no inflammation was observed, but the rats exhibited loss of cilia in bronchioles, decreased numbers of ciliated cells, hypertrophy and hyperplasia of bronchiolar epithelium, increased thickness of collagen fibrils, alveolar distention, and variability of alveolar sizes (Freeman et al. 1968; Stephens et al. 1971a,b, 1972; Evans et al. 1972). Rats exposed continuously at 0.8 ppm during their natural lifetimes grew normally but showed elevated respiratory rates and occasional minimal changes in the morphology of bronchiolar epithelial cells (Freeman et al. 1966).

Bronchial epithelial hyperplasia was observed in Sprague-Dawley

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

rats continuously exposed to NO2 at 4 ppm for 16 weeks (Haydon et al. 1965). Fischer 344 rats exposed to NO2 at 9.5 ppm for 7 h per day, 5 days per week for 6 months had no histologic changes (Mauderly et al. 1987; Mauderly 1989). However, by 24 months of exposure, mild hyperplasia of the epithelium in terminal bronchioles and extension of bronchiolar epithelial cell types into proximal alveoli were observed (Mauderly et al. 1989; Mauderly et al. 1990). An occasional alveolus contained a slight mixed inflammatory-cell infiltrate.

Monkeys (Macaca species) exposed to NO2 at 2 ppm continuously for 14 months revealed bronchiolar epithelial hypertrophy and changes to cuboidal cells in the proximal bronchiolar epithelium (Furiosi et al. 1973). Several monkeys exposed at 5 ppm continuously for 2 months had normal minute respiratory volumes but had depressed tidal volumes and a compensatory increase in respiratory rate (Henry et al. 1970). There were mild effects in tidal volume, minute-volume, and respiration rates in squirrel monkeys exposed at 1.0 ppm for 493 days (Fenters et al. 1973).

EPA (1993) includes a discussion of the potential for chronic NO2 exposures to cause emphysema in animals. Intermittent or continuous exposures to NO2 ranging from 1 to 90 ppm for 12-33 months have yielded positive or equivocal results in squirrel monkeys, Wistar rats, hamsters, and guinea pigs (Gross et al. 1968; Freeman et al. 1972; Fenters et al. 1973). In Fenters et al. (1973), only monkeys challenged with influenza virus in addition to the NO2 exposure developed histopathologic changes indicating slight emphysema. Studies with negative results for emphysema from exposures to NO2 ranged from 0.5 to 30 ppm with intermittent or continuous exposures from 12-25 months to mongrel dogs, mice, rats, rabbits, hamsters, and guinea pigs (Wagner et al. 1965; Freeman et al. 1968; Blair et al. 1969; Kleinerman et al. 1985; Mauderly et al. 1989, 1990). The relevance of some of the studies to human emphysema was questioned because of differences in the clinical definitions of emphysema for humans and animals (EPA 1993).

Reproductive Toxicity in Males

No information was found regarding the reproductive toxicity of NO2 in humans. In animals, no effects on spermatogenesis or germinal or interstitial testicular cells were observed in male LEW/fmai rats exposed to NO2 at 1.0 ppm for 7 h per day, 5 days per week for 21 days (Kripke and Sherwin 1984).

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Immunotoxicity

Several studies have investigated the effects of NO2 on the immune system and on host resistance to infectious agents. Mice exposed to NO2 at concentrations ranging from 0.5 to 10 ppm continuously for 15 days to 12 months exhibited increased mortality when challenged with Streptococcus species (Ehrlich et al. 1979; Gardner 1980; Gardner et al. 1982; Graham et al. 1987; Miller et al. 1987). Similar results were observed in mice exposed at 0.5 ppm continuously for 3 months and challenged with Klebsiella pneumoniae (Ehrlich and Henry 1968) or exposed to the viral agents A/PR/8 (Henry et al. 1970; Ito 1971) or cytomegalovirus (Rose et al. 1988, 1989).

Two studies evaluating humoral immunity in the CD-1 mouse and the squirrel monkey reported reduced serum neutralizing antibody titers, but there was no change in hemagglutination inhibition titers (Fenters et al. 1971; Fenters et al. 1973; Ehrlich et al. 1975). The mice were exposed to a 0.5-ppm base concentration of NO2 plus a 1-h daily 2-ppm peak for 3 months, and the monkeys were exposed to NO2 at either 1 or 5 ppm continuously for 16 months or 169 days, respectively. Several other studies did not report significant effects on antibody responses (Antweiler et al. 1975; Lefkowitz et al. 1986; Fujimaki 1989; Rose et al. 1989). A decrease in the plaque-forming cell response was observed in mice exposed at 1.5 ppm for 14 days (Lefkowitz et al. 1986), at 1.6 ppm continuously for 4 weeks (Fujimaki et al. 1982), or at 20 ppm for 48 h (Azoulay-Dupuis et al. 1985).

When BALB/c mice were exposed to NO2 at 10 ppm for 2 h per day for 30 weeks, there was a marked depression in the ability of T cells to respond to nonspecific stimuli (Holt et al. 1979). Others have noted an alteration in T lymphocyte subpopulations and a tendency toward suppression in the percentages of total T cells or subpopulations of T cells (Richters and Damji 1988; Damji and Richters 1989; Selgrade et al. 1991; Frampton et al. 2002).

The role of NO2 in allergic responses in animals is unclear. In a recent study in which BALB/c mice were challenged with ovalbumin and exposed to NO2 at 5 or 20 ppm for 3 h, it was determined that NO2 can both exacerbate and inhibit some features of the development of allergic disease in mice (Proust et al. 2002).

NO2 has immunosuppressive effects on both the local (pulmonary) and systemic immune responses in laboratory animals. Those effects can occur at relatively low concentrations of NO2 but usually require long durations of exposure. Although there is sufficient evidence to suggest that NO2 could

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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increase the severity of pulmonary infections in animals, it is unclear whether that effect would occur in humans.

Genotoxicity

No information was found regarding the genotoxicity of NO2 in humans. A concentration-dependent increase in chromosome aberrations was observed in Sprague-Dawley rats exposed to NO2 at 8, 15, 21, or 27 ppm for 3 h (Isomura et al. 1984). Lung cells isolated from the rats and exposed to concentrations of NO2 at 15 ppm and greater showed a concentration-related increase in mutation to ouabain resistance.

Carcinogenicity

No relevant information was found regarding the carcinogenicity of NO2 in humans. There is no evidence that exposure to NO2 induces neoplasia in laboratory rodents. However, NO2 was a weak promoter of tumor development in initiation-promotion experiments (Benemanskii et al. 1981; Richters and Richters 1989; Ichinose et al. 1991).

TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

About 70-80% of inspired NO2 is absorbed by the respiratory tract in healthy adult humans (EPA 1993). Pulmonary absorption of NO2 appears to be regulated by a reaction between inhaled NO2 and constituents of the pulmonary surface lining layer that forms nitrite (Saul and Archer 1983; Postlethwait and Bidani 1990, 1994). It is thought that NO2 causes pulmonary injury by lipid peroxidation, either through a reaction that involves hydrogen abstraction by readily oxidizable tissue components to form nitrous acid and an organic radical (Postlethwait and Bidani 1994; EPA 1995) or through reaction with water which forms nitrous and nitric acid (Greenbaum et al. 1967; Goldstein et al. 1977). The peroxide products formed disrupt cellular membranes that are essential for maintaining cellular integrity and function, and they probably account for the epithelial damage to the lungs and the pulmonary edema (EPA 1995).

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

The reactive products of inhaled NO2 are distributed throughout the body via the blood stream (Goldstein et al. 1977). When nitrite that is formed deep in the lungs by absorption of NO2 interacts with red blood cells, the nitrite is oxidized to nitrate (Postlethwait and Mustafa 1981). Thus, inhaled NO2 produces nitrosylhemoglobin but not methemoglobin (Oda et al. 1980). After exposure, the half-life of nitrite is several minutes, whereas that of nitrate is about 1 h (Oda et al. 1981).

NO2 is an irritant to the mucous membranes that causes coughing and dyspnea that can persist for a few hours following exposure (NIOSH 1976). More severe effects of exposure to NO2 include cyanosis, chest pain, moist rales, and pulmonary edema (NIOSH 1976; Douglas et al. 1989). Death results from bronchospasm and pulmonary edema associated with hypoxemia, respiratory acidosis, metabolic acidosis, and a shift of the oxyhemoglobin dissociation curve to the left (Douglas et al. 1989). It is not uncommon in the acute phase of NO2 intoxication to have an apparent recovery followed by late-onset bronchiolar injury that develops into bronchiolitis fibrosa obliterans (NIOSH 1976; NRC 1977; Douglas et al. 1989).

Acute exposures to high concentrations of NO2 can result in immediate death, delayed symptoms with pulmonary edema within 48 h, or apparent recovery followed by chronic pulmonary disease of varying severity (NIOSH 1976; NRC 1977). An investigation of the morphologic and biochemical changes in the lungs of mice exposed to NO2 at 140 ppm for 1 h (Siegel et al. 1989) revealed acute cell death in areas adjacent to the distal terminal bronchioles accompanied by a significant increase in protease inhibitor activity, lung protein content, and lung wet weights. Two days following exposure, hypertrophy and hyperplasia of the epithelial cells, increased numbers of intraalveolar macrophages and neutrophils, complete obliteration of the alveolar structure with progressive congestion and edema of the lungs, and further biochemical changes, including increases in B-glucuronidase, lactate dehydrogenase, and choline kinase activities, were observed. Other lesions included the loss of ciliated cells, disruption of capillary junctions, degeneration of type I cells, and proliferation of type II cells (Siegel et al. 1989; Elsayed 1994).

INHALATION EXPOSURE LEVELS FROM THE NRC AND OTHER ORGANIZATIONS

Several agencies have established or proposed inhalation exposure levels for NO2. Selected values are summarized in Table 10-2.

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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TABLE 10-2 Selected Inhalation Exposure Levels for Nitrogen Dioxide from NRC and Other Agenciesa

Organization

Type of Level

Exposure Level (ppm)

Reference

Occupational

 

 

 

ACGIH

TLV-TWA

3

ACGIH 2002

 

TLV-STEL

5

 

NIOSH

REL-STEL

1

NIOSH 2004

OSHA

PEL-Ceiling

5

29 CFR 1910.1000

Submarine

 

 

 

NRC

SEAL-1 (10 days)

5

NRC 2002

 

SEAL-2 (24 h)

10

 

General Public

 

 

 

NAC/NRC

Proposed AEGL-1 (1 h)

0.5

EPA 2004

 

Proposed AEGL-1 (8 h)

0.5

 

 

Proposed AEGL-2 (1 h)

12

 

 

Proposed AEGL-2 (8 h)

6.7

 

NRC

SPEGL (1 h)

1

NRC 1985

 

SPEGL (24 h)

0.04

 

aThe comparability of EEGLs and CEGLs with occupational and public health standards or guidance levels is discussed in Chapter 1, section “Comparison to Other Regulatory Standards or Guidance Levels.”

Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; h, hour; NAC, National Advisory Committee; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; ppm, parts per million; REL, recommended exposure limit; SEAL, submarine escape action level; SPEGL, short-term public emergency exposure guidance level; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

SUBCOMMITTEE RECOMMENDATIONS

The subcommittee’s recommendations for EEGL and CEGL values for NO2 are summarized in Table 10-3. The current and proposed U.S. Navy values are provided for comparison.

1-Hour EEGL

Upon entering the chamber, healthy male volunteers exposed to NO2 at 30 ppm for 2 h noted an intense odor; however, that odor was unnotice-

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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TABLE 10-3 Emergency and Continuous Exposure Guidance Levels for Nitrogen Dioxide (ppm)

Exposure Level

U.S. Navy Values

 

Current

Pro posed

NRC Recommended Values

EEGL

 

 

 

 

 

1 h

1

3

10

 

24 h

1

1

2

CEGL

 

 

 

 

 

90 days

0.5

0.5

0.7

Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; h, hour; NRC, National Research Council; ppm, parts per million.

able by 25-40 min postentry (Henschler et al. 1960). For the first hour of exposure, one individual complained of a slight tickling of the mucous membranes of the nose and throat after 30 min, and two others reported the same nose and throat symptoms after 40 min. No other symptoms were experienced until 70 min of exposure, when all subjects experienced a burning sensation and an increasingly severe cough that began to decrease after an exposure duration of 100-120 min. When healthy male volunteers were exposed at either 10 ppm for 6 h or 20 ppm for 2 h, minor scratchiness of the throat was noted after 50 min, and three of eight subjects reported slight headaches toward the end of the exposure period (Henschler and Lütge 1963).

The 2-h, 30-ppm concentration exposure in humans was used to derive the 1-h EEGL (Henschler et al. 1960). During the first hour of exposure in that study, three subjects complained of a slight tickling of the mucous membranes of the nose and throat. An intraspecies uncertainty factor of 3 was applied, resulting in a 1-h EEGL of 10 ppm. The intraspecies uncertainty factor was used because of the small number of human subjects studied and the mild symptoms observed in three subjects within the first hour.

24-Hour EEGL

In the absence of appropriate human studies, the subcommittee relied on the animal toxicology literature to set the 24-h EEGL. Five different species of laboratory animals (mice, rats, guinea pigs, rabbits, and dogs)

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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exposed to NO2 at 20 ppm for 24 h exhibited minimal signs of irritation and changes in behavior and some congestion and interstitial inflammation in the lungs (Hine et al. 1970). Histopathologic changes observed in rats exposed at 20 ppm for 20 h included changes in type I and type II cells (Hayashi et al. 1987). Other studies reported changes in type I and II cells, alveolar and interstitial edema, bronchiolitis, bronchiolar epithelial cell hyperplasia, and loss of cilia occurring at 1-3 days following exposure to NO2 at 26 ppm for 24 h (Schnizlein et al. 1980; Hillam et al. 1983) or at 20 ppm for 24 h (Rombout et al. 1986). In another study (Stephens et al. 1978), Sprague-Dawley rats exposed to NO2 at 14 ppm for 24, 48, or 72 h exhibited minor losses of cilia from the epithelial cells lining the terminal airways.

Thus, 20 ppm was selected to develop a 24-h EEGL. Applying an interspecies uncertainty factor of 3 and an intraspecies uncertainty factor of 3 resulted in a composite uncertainty factor of 10. The 24-h EEGL is 2 ppm. This value is supported by several observations in healthy human volunteers, indicating that concentrations of NO2 in excess of 2 ppm can incite functional changes in the lungs (EPA 1993).

90-Day CEGL

In the absence of long-term quantitative human data, the nonhuman primate data was used to develop the 90-day CEGL. Monkeys exposed to NO2 at 2 ppm continuously for 14 months had bronchiolar epithelial hypertrophy forming cuboidal epithelium in the proximal bronchioles (Furiosi et al. 1973). In squirrel monkeys exposed to NO2 at 1 ppm for 493 days, there were mild effects in tidal volume, minute-volume, and respiration rates. Slight emphysema was observed but only in monkeys also challenged with influenza virus (Fenters et al. 1973). Thus, minimal effects are observed in nonhuman primates exposed to NO2 continuously for longer than 1 year. Continuous exposure at 5 ppm for 2 months in squirrel monkeys did not affect minute respiratory volume, but depressed tidal volume, producing a compensatory increase in respiratory rate (Henry et al. 1970). In addition, rats exposed to NO2 at 2 ppm continuously for a lifetime exhibited slight changes in pulmonary morphology but had normal life-spans (Freeman et al. 1968). No pathology was noted in five species of laboratory animals exposed to NO2 at 0.53 ppm continuously for 90 days (Steadman et al. 1966).

The subcommittee began with an NO2 concentration of 2 ppm, which

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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is a concentration associated with only mild respiratory effects over a 14-month continuous exposure. The subcommittee applied an interspecies uncertainty factor of 3 yielding a 90-day CEGL recommendation of 0.7 ppm. No additional uncertainty factors were applied given research indicating that there is minimal variation in the mild respiratory effects sometimes observed in healthy and asthmatic populations at exposure concentrations <1 ppm.

DATA ADEQUACY RESEARCH NEEDS

Sufficient data were available, having a fairly high degree of confidence, to develop 1-h and 24-h exposure limits for NO2. The 90-day exposure limit was based on long-term exposures in nonhuman primates, which could result in conservative values. Thus, continuous subchronic and chronic exposure data are needed to improve the subcommittee’s confidence in the 90-day exposure limit determined.

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Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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Koenig, J.Q., D.S. Covert, M.S. Morgan, M. Horike, N. Horike, S.G. Marshall, and W.E. Pierson. 1985. Acute effects of 0.12 ppm ozone or 0.12 ppm nitrogen dioxide on pulmonary function in healthy and asthmatic adolescents. Am. Rev. Respir. Dis. 132(3):648-651.

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Mauderly, J.L., D.E. Bice, Y.S. Cheng, N.A. Gillett, R.F. Henderson, J.A. Pickrell,

Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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and R.K. Wolff. 1989. Influence of Experimental Pulmonary Emphysema on Toxicological Effects from Inhaled Nitrogen Dioxide and Diesel Exhaust. Research Report No. 30. Cambridge, MA: Health Effects Institute (as cited in EPA 1993).

Mauderly, J.L., Y.S. Cheng, N.A. Gillett, W.C. Griffith, R.F. Henderson, J.A. Pickrell, and R.K. Wolff. 1990. Influence of preexisting pulmonary emphysema on susceptibility of rats to chronic inhalation exposure to nitrogen dioxide. Inhal. Toxicol. 2:129-150.

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NIOSH (National Institute for Occupational Safety and Health). 2004. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) No. 2004-103. National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH.

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Peters, J.M., E. Avol, W. Navidi, S.J. London, W.J. Gauderman, F. Lurman, W.S. Linn, H. Margolis, E. Rappaport, H. Gong, Jr., and D.C. Thomas. 1999a. A study of twelve southern California communities with differing levels and types of air pollution. I. Prevalence of respiratory morbidity. Am. J. Resp. Crit. Care Med. 159(3):760-767.

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Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
×

with allergic airways responses to allergic challenges in BALB/C mice. Mediators Inflamm. 11(4):215-260.

Rasmussen, T.R., S.K. Kjaergaard, U. Tarp, and O.F. Pedersen. 1992. Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans. Am. Rev. Respir. Dis. 146(3):654-659.

Richters, A., and K.S. Damji. 1988. Changes in T-lymphocyte subpopulations and natural killer cells following exposure to ambient levels of nitrogen dioxide. J. Toxicol. Environ. Health 25(2):247-256 (as cited in EPA 1993).

Richters, A., and J. Richters. 1989. Nitrogen dioxide (NO2) inhalation formation of microthrombi in lungs and cancer metastasis. J. Environ. Pathol. Toxicol. Oncol. 9(1):45-51 (as cited in EPA 1993).

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Sandström, T., M.C. Andersson, B. Kolmodin-Hedman, N. Stjernberg, and T. Angström. 1990. Bronchoalveolar mastocytosis and lymphocytosis after nitrogen dioxide exposure in man: A time-kinetic study. Eur. Respir. J. 3(2):138-143.

Saul, R.L., and M.C. Archer. 1983. Nitrate formation in rats exposed to nitrogen dioxide. Toxicol. Appl. Pharmacol. 67(2):284-291.

Schindler, C., U. Ackerman-Liebrich, P. Leuenberger, C. Monn, R. Rapp, G. Bolognini, J.P. Bongard, O. Brändli, G. Domenighetti, W. Karrer, R. Keller, T.G. Medici, A.P Perruchoud, M.H. Schöni, J.M. Tschopp, B. Villiger, and J.P. Zellweger. 1998. Associations between lung function and estimated average exposure to NO2 in eight areas of Switzerland. The SPALDIA Team. Epidemiology 9(4):405-411.

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Schnizlein, C.T., D.E. Bice, A.H. Rebar, R.K. Wolf, and R.L. Beethe. 1980. Effect of lung damage by acute exposure to nitrogen dioxide on lung immunity in the rat. Environ. Res. 23(2):362-370.

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Stephens, R.J., G. Freeman, and M.J. Evans. 1971b. Ultrastructural changes in connective tissue in lungs of rats exposed to NO2. Arch. Intern. Med. 127(5): 873-883 (as cited in EPA 1993).

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Suzuki, T., S. Ikeda, T. Kanoh, and I. Mizoguchi. 1986. Decreased phagocytosis and superoxide anion production in alveolar macrophages of rats exposed to nitrogen dioxide. Arch. Environ. Contam. Toxicol. 15(6):733-739 (as cited in EPA 1993).

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Vagaggini, B., P.L. Paggiaro, D. Gianni, A. Di Franco, S. Cianchette, S. Carnevali, M. Taccola, E. Bacci, E. Bancalari, F.L. Dente, and C. Giuntini. 1996. Effect of short-term NO2 exposure on induced sputum in normal, asthmatic and COPD subjects. Eur. Respir. J. 9(9):1852-1857.

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Suggested Citation:"10 Nitrogen Dioxide." National Research Council. 2007. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/11170.
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von Nieding, G., H.M. Wagner, H. Krekeler, H. Loellgen, W. Fries, and A. Beuthan. 1979. Controlled studies of human exposure to single and combined action of NO2, O3, and SO2. Int. Arch. Occup. Environ. Health 43(3):195-210 (as cited in EPA 1993).

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U.S. Navy personnel who work on submarines are in an enclosed and isolated environment for days or weeks at a time when at sea. Unlike a typical work environment, they are potentially exposed to air contaminants 24 hours a day. To protect workers from potential adverse health effects due to those conditions, the U.S. Navy has established exposure guidance levels for a number of contaminants. The Navy asked a subcommittee of the National Research Council (NRC) to review, and develop when necessary, exposure guidance levels for 10 contaminants.

Overall, the subcommittee found the values proposed by the Navy to be suitable for protecting human health. For a few chemicals, the committee proposed levels that were lower than those proposed by the Navy. In conducting its evaluation, the subcommittee found that there is little exposure data available on the submarine environment and echoed a previous recommendation from an earlier NRC report to conduct monitoring that would provide a complete analysis of submarine air and data on exposure of personnel to contaminants.

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