8
Nitrogen Dioxide
This chapter reviews the physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on nitrogen dioxide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine from exposure to nitrogen dioxide and to evaluate submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to nitrogen dioxide.
BACKGROUND INFORMATION
Nitrogen dioxide is a reddish-brown gas that is heavier than air. It typically exists in the atmosphere as an equilibrium mixture with nitrogen tetroxide. As a relatively stable free radical, it can be found in ambient air at high concentrations near a source such as automobile exhaust or an electric arc. High concentrations are also found in grain silos. The chemical and physical properties of nitrogen dioxide are summarized in Table 8–1.
The initial combustion product of nitrogen and oxygen is nitric oxide, which on further oxidation gradually turns into nitrogen dioxide. Atmospheric concen
TABLE 8–1 Physical and Chemical Properties for Nitrogen Dioxide
|
Characteristic |
Value |
|
Molecular formula |
NO2 |
|
Molecular weight |
46.01 |
|
CAS number |
10102–44–0 |
|
Physical state |
Gas |
|
Color |
Reddish brown |
|
Odor |
Sweet |
|
Odor threshold |
0.4 ppm (recognition) 4.0 ppm (<100% identification) |
|
Melting point |
–9.3 °C |
|
Boiling point |
21.15°C |
|
Solubility in water |
0.037 mL/mL at 35°C |
|
Vapor pressure |
720 torr at 20°C 800 mm Hg at 25°C |
|
Vapor density |
1.58 (air=1) |
|
Conversion factors |
1 ppm=1.88 mg/m3 |
|
25°C, 1 atm |
1 mg/m3=0.53 ppm |
|
Sources: EPA (1990, 1993); ACGIH (1991); Mohsenin (1994); Budavari et al. (1996). |
|
trations result from many natural and anthropogenic sources, including combustion of fossil fuels for heating and transportation, power generation, industrial processes, solid-waste disposal, and forest fires. In forested and rural areas of the United States, ambient nitrogen dioxide concentrations average less than 0.10 ppm (parts per million), whereas in urban areas peak levels may exceed 0.2 ppm, particularly in the late afternoon and evening (EPA 1993). As a major component of smog, nitrogen dioxide has been measured at concentrations of between 0.1 and 0.8 ppm (maximum hourly average) with short-term peaks of 1.27 ppm (Mohsenin 1994). Indoor air also can contain nitrogen dioxide at peak concentrations of 2–4 ppm as a result of the use of gas-burning appliances or kerosene heaters. Firefighters can encounter concentrations of up to 1 ppm, but rarely higher (Gold et al. 1978).
TOXICOKINETIC CONSIDERATIONS
Nitric oxide, a precursor of nitrogen dioxide, occurs naturally in the human body, where it acts as endothelial derived relaxing factor (EDRF), a neurotransmitter, and in unidentified ways in the nose, sinuses, and lower airways. Up to 15 ppm can be found normally in the nose and sinuses (DuBois et al. 1998). The substrate is l-arginine, and the enzymes consist of different forms of nitric oxide synthase, which turn arginine into citrulline. Inhaled nitric oxide gas is used at concentrations of up to 50 ppm to decrease pulmonary arterial pressure. Nitric oxide reacts in tissues to form nitrites and nitrates.
Nitrogen dioxide is relatively insoluble; however, its reactivity is sufficient to permit chemical interaction and absorption along the entire tracheobronchial tree (NRC 1985). In humans exposed at 0.29–7.2 ppm of nitrogen dioxide for approximately 30 min during quiet respiration and during exercise, the total respiratory tract absorption was measured at 81–90% and 91–92%, respectively, in healthy adults and 72% and 87%, respectively, in people with asthma (EPA 1993). In monkeys exposed to 0.30–0.91 ppm nitrogen dioxide for less than 10 min, 50–60% of the inhaled gas was retained during quiet respiration (Goldstein et al. 1977). The nitrogen dioxide was distributed throughout the lungs. In rats, nitrogen dioxide appears to be retained mostly in the upper respiratory tract (Russell et al. 1991). Pulmonary absorption of nitrogen dioxide could be the result of the nitrate-forming reaction between the inhaled gas and the pulmonary surface lining layer (Postlethwait and Bidani 1990, 1994; Saul and Archer 1983). Uptake of nitrogen dioxide is saturable. The reaction in the lungs is not known, but could involve hydrogen abstraction by readily oxidizable tissue components, such as proteins and lipids, to form lipid peroxides, nitrous acid, and nitrite radicals (Postlethwait and Bidani 1994). Alternatively, nitrogen dioxide might react with water to form nitrous and nitric acids (Goldstein et al. 1977).
Inhaled nitrogen dioxide and its metabolites are distributed throughout the body by the blood stream (Goldstein et al. 1977). The nitrite that is formed in the lungs diffuses into the vascular space and is oxidized to nitrate in interactions with red blood cells (Postlethwait and Mustafa 1981). In mice, the half-lives of nitrite and nitrate are several minutes and 1 h, respectively, and methemoglobin is not formed by nitrogen dioxide or nitrite in vivo, although it is formed in vitro (Oda et al. 1981). Urinary excretion of nitrate has been shown to be related linearly to the nitrogen dioxide concentration administered (Saul and Archer 1983).
HUMAN TOXICITY DATA
Outdoor air pollution studies on the effects of nitrogen dioxide in healthy adult humans do not conclusively show a relationship between ambient concentrations of nitrogen dioxide and respiratory effects. However, children and people with asthma appear to be at greater risk of respiratory effects.
Reports of workers who have been exposed to high concentrations as a result of industrial processes, such as welding, show increased incidence of respiratory illness, although in most cases the effects are reversible. Symptoms of exposure to nitrogen dioxide include dyspnea, cough, pulmonary edema, and irritation of the mucous membranes (Table 8–2).
Experimental Studies
Experimental studies of nitrogen dioxide exposure at concentrations of up to 5 ppm with healthy subjects and people with asthma have shown little if any adverse health effects. Exposures up to 0.6 ppm in healthy men and women, whether at rest or during exercise, do not appear to result in decreased pulmonary function although continuous exposure at 1.5 ppm for 3 h resulted in a slight but significant fall in forced expiratory volume (FEV) and forced vital capacity (FVC) response to carbachol (Frampton et al. 1991). Studies at higher concentrations suggest that a threshold for pulmonary function effects exists at approximately 5 ppm. Changes in bronchoalveolar lavage fluid and blood have been reported after exposure of healthy adults to nitrogen dioxide, with exposure at concentrations of 1–4 ppm for up to 5 h resulting in enzyme activity alterations (Devlin et al. 1992; Goings et al. 1989; Hackney et al. 1978; Linn and Hackney 1983; Rasmussen et al. 1992).
Several studies on people with asthma showed that low concentrations (0.12– 1 ppm) did not significantly affect pulmonary function in adults or adolescents, whether they were exercising or at rest (Kleinman et al. 1983; Koenig et al 1985, 1987; Linn and Hackney 1984; Mohsenin 1987; Utell and Morrow 1989; Roger et al. 1990; Rubinstein et al. 1990; Sackner et al. 1981; Vagaggini et al. 1996). However, Kerr et al. (1978) and Bauer et al. (1985) reported that exposure at 0.5 and 0.3 ppm for 2–4 h resulted in a slight reduction in forced expiratory volume in 1 s (FEV1) and specific airway conductance, headache, chest tightness, and wheezing. Studies on airway hyperreactivity in people with asthma also have been inconclusive and followed a pattern similar to that shown in pulmonary function studies.
TABLE 8–2 Human Toxicity Data, Exposure to Nitrogen Dioxide
|
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
EXPERIMENTAL STUDIES |
|||||
|
Healthy men and women |
Inhalation |
0.6 ppm |
1–3 h with intermittent or continuous exercise |
No effects in several studies. Continuous exposure to 1.5 ppm for 3 h resulted in slight fall in FEV1 and FVC response to carbachol. |
Folinsbee et al. 1978; Adams et al. 1987; Frampton et al. 1991; Hazucha et al. 1994 |
|
Healthy adults |
Inhalation |
1, 2, 2.3, 4, 5 ppm |
1.25–5 h |
No effects observed at 1–3 ppm for up to 5 h. At 4 ppm for 1.25 h, no effects with light or heavy exercise. At 5 ppm for 2 h, decreased alveolar oxygen partial pressure and increase in airway resistence in 6 of 11 subjects. |
Hackney et al. 1978; Devlin et al. 1992; Goings et al. 1989; Rasmussen et al. 1992; Linn and Hackney 1983; von Nieding and Wagner 1979 |
|
Volunteers |
Inhalation |
30 ppm |
2 h |
Burning sensation in nose and chest, cough, dyspnea, sputum production. |
NRC 1977 |
|
Healthy adults |
Inhalation |
2 ppm |
4, 6 h |
Influx of polymorphonuclear leukocytes in bronchoalveolar lavage fluid. |
Devlin et al 1992; Frampton et al. 1992 |
|
Healthy adults |
Inhalation |
2.3 ppm |
5 h |
Decrease in serum glutathione peroxidase activity. |
Rasmussen et al. 1992 |
|
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
Healthy adults |
Inhalation |
1–4 ppm |
3 h |
Decrease in red blood cell membrane acetylcholinesterase activity; increase in red blood cell lipids and glucose-6-phosphate dehydrogenase activity, higher concentration resulted in decrease in alpha-1-protease inhibitor activity but not overall enzyme activity in BALF. Mucociliary activity ceased after 45-min exposure to 1.5 and 3.5 ppm for 20 min. |
Devlin et al. 1992; Frampton et al. 1992; Rasmusen et al. 1992; Posin et al. 1978; Mohsenin and Gee 1987; Helleday et al. 1995 |
|
Adults and adolescents with asthma |
Inhalation |
0.12–4 ppm |
40 min—4 h |
No change in pulmonary function was noted in several studies of adult and adolescent, whether at rest or with intermittent exercise. |
Koenig et al. 1987; Koenig et al. 1985; Kleinman et al. 1983; Rubinstein et al. 1990; Vagaggini et al. 1996; Utell and Morrow 1989; Mohsenin 1987; Roger et al. 1990; Sackner et al. 1981; Linn and Hackney 1984 |
|
13 asthma patients |
Inhalation |
0.5 ppm |
2 h |
Slight burning of eyes and headache, chest tightness or labored breathing with exercise; no change in pulmonary function. |
Kerr et al. 1978 |
|
20 patients with chronic obstructive pulmonary disease |
Inhalation |
0.3 ppm |
4 h |
Reduced FEV1 and specific airway conductance after exercise. 1 of 6 had chest tighness and wheezing. |
Morrow et al. 1992 |
|
20 asthma patients |
Inhalation |
0.1 ppm |
1 h |
Increase in specific airway resistence and enhanced bronchoconstrictor effect of carbachol in 13 of 20 subjects. |
Orehek et al. 1976 |
|
Asthma patients |
Inhalation |
0.4 ppm |
1 or 6 h |
Decrease in FEV1 with challenge with house dust mite antigen after 1 h but not after 6 h when compared with nonasthma group. |
Tunnicliffe et al. 1994; Devalia et al. 1994 |
|
ACCIDENTAL EXPOSURES |
|||||
|
4 men |
Inhalation |
Unknown |
≤10 min |
Headache, cough, pulmonary edema, sinusitis, upper respiratory tract irritation, fever, chest tightness, shortness of breath; dypsnea. |
Tse and Bockman 1970 |
|
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
OCCUPATIONAL STUDIES |
|||||
|
17 grain silo workers |
Inhalation |
Unknown |
NR |
Dyspnea, cough, chest pain, eye irritation, rapid breathing, death with diffuse alveolar damage and edema. |
Douglas et al. 1989 |
|
1 worker |
Inhalation |
At least 90 ppm (acetylene torch) |
30 min |
Shortness of breath, pulmonary edema. |
Norwood et al. 1966 |
|
Welders |
Inhalation |
30 ppm |
40min |
Dyspnea, cough, headache, tightness or pain in chest, nausea, cyanosis, viral pneumonia, pulmonary edema. |
Morley and Silk 1970 |
|
Diesel bus garage workers |
Inhalation |
≥0.3 ppm |
NR |
Cough, itching, burning or watering eyes, difficult breathing, chest tightness, and wheeze but no reduction in pulmonary function. |
Gamble et al. 1987 |
|
Traffic officers |
Inhalation |
0.045–0.06 ppm |
NR |
Slight increase in bronchitis and colds compared with officers in low traffic area. |
Speizer and Ferris 1973 |
|
EPIDEMIOLOGY STUDIES |
|||||
|
Children and families living near TNT (trinitrotoluene) plant |
Inhalation |
0.083 ppm (average 24-h concentration) |
Several years |
Respiratory illness rates were consistently higher and lower FEV0.75 for people with higher exposures. Follow-up several years later found similar results. Reanalysis of data found inverse relationship between illness and nitrogen dioxide concentration in several subpopulations. |
Shy et al. 1970a,b; Love et al. 1982; Harrington and Krupnick 1985 |
|
Children |
Inhalation |
≥80 ppb hourly peak levels |
NR |
Increased occurrence of sore throats, colds and school absences in children exposed to unflued gas heating in classrooms. |
Pilotto et al. 1997 |
|
Adult asthma patients |
Inhalation |
>0.3 ppm |
Cooking on gas stove |
Slight decreases in FEV1 and peak expiratory flow. |
Goldstein et al. 1988 |
|
Abbreviations: FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; NR, not reported. |
|||||
Accidental Exposures
Death from accidental exposure to nitrogen dioxide occurs at concentrations generally greater than 150 ppm for healthy adults. Survivable exposures of brief duration at high concentrations of nitrogen dioxide have occurred from combustion of cordite in military vehicles (Elsayed 1994).
Occupational Studies
Silo filler’s disease is associated with the accumulation of nitrogen dioxide in grain silos that can reach concentrations of 200–4,000 ppm within 2 d. Respiratory effects among workers have been reported in the literature as far back as the 1950s (Grayson 1956; Lowry and Schuman 1956). In a report of 17 silo workers, 16 had dyspnea, cough, chest pain, eye irritation, and rapid breathing; one worker died with diffuse alveolar damage and pulmonary edema; and one worker developed bronchiolitis fibrosa obliterans years later (Grayson 1956; Lowry and Schuman 1956; Milne 1969).
Other occupations, such as welding with an acetylene torch, also have been found to result in exposure to nitrogen dioxide. Although most reports indicate that symptoms, such as dyspnea, cough, headache, chest pain and tightness, and cyanosis, are transient and respond to oxygen and antibiotic treatment, one welder died from viral pneumonia 43 d after exposure (Morley and Silk 1970). Concentrations might have been as high as 30 ppm for 40 min but not all welders were affected.
Epidemiologic Studies
Numerous reviews published since 1970 have examined the effects of nitrogen dioxide on humans; however, the evidence of adverse health effects from the studies cited in the reviews is inconclusive. EPA (1993) reviewed more than 20 studies on the epidemiology of nitrogen dioxide and other nitrogen oxides. In general studies showed that infants and children appear to have increased respiratory symptoms as a result of increased exposure to nitrogen dioxide, but a quantitative relationship could not be established. Studies that attempted to show a causal relationship between indoor and outdoor nitrogen dioxide exposure and long-term changes in pulmonary function were marginally significant. No studies were found that assessed short-term exposures for indoor nitrogen dioxide.
In a meta-analysis of the epidemiologic studies, EPA reported a 20% increase in the odds of respiratory illness in children exposed long-term to a nitrogen dioxide concentration of 0.01 ppm (Hasselblad et al. 1992).
EXPERIMENTAL ANIMAL TOXICITY DATA
The primary target of nitrogen dioxide is the lung, although it can produce changes in the blood and other organs as well (EPA 1993). Numerous studies have been conducted to assess the toxicity of exposure to nitrogen dioxide in experimental animals. Many of them are summarized below and in Table 8–3. A review of the data also is available in the Air Quality Criteria for Oxides of Nitrogen, Volume III (EPA 1993) and in the Emergency Exposure Guidance Levels, Volume 4 (NRC 1985).
Acute Exposure
For 5- to 60-min exposures, rat LC50 (the concentration that is lethal to 50% of test animals) range from 416 to 115 ppm in one study (Carson et al. 1962) and from 833 to 168 ppm in another study (Gray et al. 1954). A 15-min LC50 value for rabbits is 315 ppm (Carson et al. 1962). Hine et al. (1970) exposed rats, mice, dogs, rabbits, and guinea pigs to various concentrations of nitrogen dioxide. No mortality occurred up to 40 ppm. The first deaths were observed in rats and mice exposed at 50 ppm for 24 h, in dogs exposed at 76 ppm for 4 h, in rabbits exposed at 75 ppm for 1 h, and in guinea pigs exposed at 50 ppm for 1 h. Histologic signs in all species included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, and edema (Hine et al. 1970). Additional studies in rats, mice, monkeys, and dogs show that exposure to nitrogen dioxide causes pulmonary edema (e.g., alveolar and interstital edema) and histological changes (e.g., bronchiolitis, bronchiolar epithelial cell hyperplasia, loss of cells, necrosis of type I cells, and type II cell hyperplasia) (Carson et al. 1962; Dowell et al. 1971; Hayashi et al. 1987; Henry et al. 1969; Goldstein et al. 1973; Guth and Mavis 1985; Lehnert et al. 1994; Siegel et al. 1989; Stavert and Lehnert 1990; Stephens et al. 1972; Suzuki et al. 1982). In animals that did not die, the histopathologic changes were reversible, and the animals healed after a time. Enhanced susceptibility to infection was observed in mice exposed at 5 ppm for 6 h/d for 2 d (Rose et al. 1989) and in monkeys exposed at 50 ppm for 2 h (Henry et al. 1969).
TABLE 8–3 Experimental Animal Toxicity Data, Exposure to Nitrogen Dioxide 230
|
Species |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
|
ACUTE TOXICITY (LETHALITY) |
|||||
|
Rat |
Inhalation |
416 ppm |
5 min |
LC50; clinical signs included severe respiratory distress, eye irritation, 10–15% decrease in body weight; pathology showed darkened areas on surface of lung. |
Carson et al. 1962 |
|
Rat |
Inhalation |
201 ppm |
15 min |
LC50; clinical signs included severe respiratory distress, eye irritation, 10–15% decrease in body weight; pathology showed darkened areas on surface of lung. |
Carson et al. 1962 |
|
Rat |
Inhalation |
162 ppm |
30 min |
LC50; clinical signs included severe respiratory distress, eye irritation, 10–15% decrease in body weight; pathology showed darkened areas on surface of lung. |
Carson et al. 1962 |
|
Rat |
Inhalation |
115 ppm |
60 min |
LC50; clinical signs included severe respiratory distress, eye irritation, 10–15% decrease in body weight; pathology showed darkened areas on surface of lung. |
Carson et al. 1962 |
|
Rat |
Inhalation |
88–1,445 ppm |
2–240 min |
LC50 values for males (200–300 g): 1,445 for 2 min, 833 ppm for 5 min, 420 ppm for 15 min, 174 for 30 min, 168 ppm for 60 min, and 88 ppm for 240 min. Deaths attributable to pulmonary edema. |
Gray et al. 1954 |
|
Rat |
Inhalation |
25, 75, 125, 175, 200 ppm |
10 min |
No signs of toxicity at 25 ppm; at ≥75 ppm rats had dose-related increases in lung weight, subpleural hemorrhage, pale discoloration of lung, atypical pneumonia, edema, focal desquamation of the terminal bronchiolar epithelium, increased macrophages and neutrophilic leucocytes, and interstitial thickening of centriacinar speta (175 and 200 ppm only). Stertorous respirations were heard in animals exposed to 175 and 200 ppm. 1 of 6 and 1 of 9 rats died at two highest doses, respectively. |
Meulenbelt et al. 1992a,b |
|
Rat |
Inhalation |
175 ppm; 400 ppm |
10, 20, 30 min; 5, 10, 20 min |
All animals had stertorous respirations and lung weights were increased. At 175 ppm, 5 of 6 rats died at 20- and 30-min exposure groups. At 400 ppm, all 6 rats died in 10- and 20-min groups. Histology revealed foamy, serosanguinous fluid in trachea, subpleural bleeding, pale discoloration. |
Meulenbelt et al. 1992a,b |
|
Rat |
Inhalation |
5–250 ppm |
30 min-24 h |
At concentrations greater >40 ppm lacrimation, reddening of conjunctivae, and increased respiration noted. Mortality at 50 ppm after 24 h with gasping and lung edema. Histologic signs included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, edema. |
Hine et al. 1970 |
|
Species |
Route |
Concentration |
Duration |
Effect |
Reference |
|
Mouse |
Inhalation |
5, 20, 40 ppm |
12 h |
At two highest doses, body weight decreased. |
Hidekazu and Fujio 1981 |
|
Mouse |
Inhalation |
5–250 ppm |
30 min-24 h |
At concentrations >40 ppm lacrimation, reddening of conjunctivae, increased respiration noted. Mortality occurred at 50 ppm after 24 h, with gasping and lung edema. Histologic signs included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, edema. |
Hine et al. 1970 |
|
Dog |
Inhalation |
1,000 ppm 5,000 ppm 20,000 ppm |
136 min 5–45 min 15 min |
At 5,000 ppm for 35–45 min and at 20,000 ppm all dogs died due to pulmonary edema. One dog at 20,000 ppm had cyanosis attributable to methemoglobin formation. |
Greenbaum et al. 1967 |
|
Dog |
Inhalation |
5–250 ppm |
30 min-24 h |
At concentrations >40 ppm lacrimation, reddening of conjunctivae, increased respiration noted. Mortality occurred at 75 ppm after 4 h with gasping and lung edema. Histologic signs included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, edema. |
Hine et al. 1970 |
|
Rabbit |
Inhalation |
3 15 ppm |
15 min |
LC50; clinical signs of toxicity including severe respiratory distress, eye irritation, body weight decrease, and death at 30 min to 3 d. Pathology showed darkened areas on lung surface. |
Carson et al. 1962 |
|
Rabbit |
Inhalation |
5–250 ppm |
30 min-24 h |
At concentrations >40 ppm lacrimation, reddening of conjunctivae, increased respiration noted. Mortality occurred at 75 ppm at 60 min with gasping and lung edema. Histologic signs included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, edema. |
Hine et al. 1970 |
|
Rabbit |
Inhalation |
125, 175, 250, 400, 600, 800 ppm |
10 min |
2 of 3 animals at 800 ppm died 7–21 h after exposure. At 250 ppm and greater, lung weights were higher and lung homogenates contained increased protein, LDH, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. At ≥175 ppm, BAL also had increased protein, albumin, LDH, and angiotensin-converting enzyme activities and all exposed animals had increased neutrophilic leucocytes. Dose-related increases in pneumonitis, macrophage influx. Edema occurred at ≥250 ppm, hemorrhaging at ≥400 ppm, and desquamation of bronchiolar epithelium at ≥600 ppm. |
Meulenbelt et al. 1994 |
|
Guinea pig |
Inhalation |
5–200 ppm |
30 min-8 h |
At concentrations >40 ppm lacrimation, reddening of conjunctivae, increased respiration noted. Mortality occurred at 50 ppm after 1 h with gasping and lung edema. Histologic signs included bronchiolitis, desquamated bronchial epithelium, infiltration by polymorphonuclear cells, edema. |
Hine et al. 1970 |
|
Species |
Route |
Concentration |
Duration |
Effect |
Reference |
|
Guinea pig |
Inhalation |
2, 10 ppm |
3 d continuously |
At 10 ppm in 45-d old animals, toxicity included difficulty moving, reduced food and water consumption, hyperventilation. All exposed animals had reduced body weight after 45 d. 60% of 55-d old animals died at 10 ppm, most of them after 24 h exposure. |
Azoulay-Dupuis et al. 1983 |
|
ACUTE TOXICITY (NONLETHAL) |
|||||
|
Rat |
Inhalation |
10, 25, 50, 100 ppm |
5, 15, 30 min; 5, 15 min only |
Pulmonary injury determined by lung weight found no change for exposure to 10 ppm for 30 min or 25–50 ppm for 15 min. Increased lung weight seen at 50 ppm for 30 min and 100 ppm for 5 and 15 min. Histologic changes for 25 ppm for 30 min, and 50 and 100 ppm for all durations included accumulation of fibrin, increased polymorphonuclear leukocytes and macrophages, extravasated erythrocytes, and type 11 pneumocyte hyperplasia. |
Stavert and Lehnert 1990 |
|
Rat |
Inhalation |
25, 50, 75, 100, 150, 200, 250 ppm |
5–30 min |
Increased lung weights at ≥150 ppm for 5 min, 100 ppm for 15 min, 75 ppm for 30 min. Edema not proportional to duration. Histological changes, fibrin and type II cell hyperplasia seen at 50 ppm for 5 min. Severity increased proportionally. |
Lehnert et al. 1994 |
|
Rat |
Inhalation |
72, 90, 190 ppm |
5, 15, or 60 min |
Severe respiratory distress and eye irritation, increased lung-to-body-weight ratio increase, pulmonary edema, chronic murine pneumonia, darkened areas of lungs. Rats exposed to 104 ppm for 5 min, 65 ppm for 15 min, 28 ppm for 60 min, showed less respiratory distress, but increased weight ratios at 104 and 65 ppm, with no gross lesions, although pulmonary edema was evident. No clinical signs of toxicity at exposures of 74 and 33 ppm for 5 and 15 min, respectively. |
Carson et al. 1962 |
|
Rat |
Inhalation |
17 ppm |
48 h |
Histologic changes at 2 h included precapillary and postcapillary engorgement of alveoli, loss of cilia and alveolar type I cell swelling at 4 h, uniform terminal bronchiolar epithelium at 16 h, maximal macrophage numbers at 24 h, and cell hypertrophy and mitotic figure increases at 48 h. |
Stephens et al. 1972 |
|
Rat |
Inhalation |
20 ppm |
20 h |
Lung morphology changes included cytoplasmic blebbing in type I class, swelling and hyperplasia of type II cells, and interstitial edema at 5–15 d after exposure. Lungs normal at 35 d. |
Hayashi et al. 1987 |
|
Rat |
Inhalation |
10, 20, 30, 40 ppm |
4 h |
Alterations in lavage fluid seen at ≥ 20 ppm. |
Guth and Mavis 1985 |
|
Rat |
Inhalation |
100, 300, 1,000 ppm |
1–20min |
Reductions in VE increased with concentration. 7–15% for 15–20 min exposure to 100 ppm, and 20–28% reduction for 1–2 min exposure to 1,000 ppm. |
Lehnert et al. 1994 |
|
Species |
Route |
Concentration |
Duration |
Effect |
Reference |
|
Mouse |
Inhalation |
5, 10, 20 ppm |
24 h |
At 10 and 20 ppm, increased lung wet weight and lung water content, at 5 ppm accelerated gaseous exchange and metabolic rate of oxygen and carbon dioxide but at higher concentration gaseous exchange was inhibited. |
Suzuki et al. 1982 |
|
Mouse |
Inhalation |
20 ppm |
4 d |
Decreased food consumption and body weight, no deaths. |
Bouley et al. 1986 |
|
Mouse |
Inhalation |
20 ppm |
48 h |
Decreased splenic and thymic weights, cellularity, plaque-forming cell response, and hemagglutins, and decreased body weight.. |
Azoulay-Dupuis et al. 1985 |
|
Mouse |
Inhalation |
20, 40 ppm |
12 h |
Suppressed primary antibody response |
Hidekazu and Fujio 1981 |
|
Mouse |
Inhalation |
20 ppm |
24 h |
Minimal signs of irritation and behavior changes, questionable evidence of lung congestion and interstitial inflammation. |
Hine et al. 1970 |
|
Mouse |
Inhalation |
50–140 ppm |
1 h |
Immediately after exposure to 140 ppm, visible cell death in terminal bronchioles, increase in protease inhibitor activity, pulmonary protein, and lung wet weights. Histologic damage increased at 48 h with progressive edema, congestion of lungs, hypertrophy and hyperplasia of epithelial cells, obliteration of alveolar structure, increased intraalveolar macrophages and neutrophils. |
Siegel et al. 1989 |
|
Mouse |
Inhalation |
7, 9.2, 14.8 ppm; 2.3, 6.6 ppm |
4 h post-infection; 17 h prior to infection |
Decreased pulmonary bactericidal activity. Lungs of mice exposed to ≥ 9.2 ppm for 4 h had vascular hyperemia; those exposed to ≥ 2.3 ppm for 17 h had minor hyperemia and interstitial edema. |
Goldstein et al. 1973 |
|
Monkeys |
Inhalation |
10, 15, 35, 50 ppm |
2 h |
Squirrel monkeys exposed to nitrogen dioxide alone had increased respiratory rate and decreased tidal volume at 35 and 50 ppm, but only slight effects at 10 and 15 ppm. Histologic changes more evident at the 2 higher concentrations. Challenge with Kelbsiella pneumoniae 24 h after exposure resulted in 3 of 3 monkeys dying with 72 h at 50 ppm exposure. No deaths with nitrogen dioxide exposure only. |
Henry et al. 1969 |
|
Dog |
Inhalation |
39, 52, 53, 85, 125, 164 ppm |
5–60 min |
At 164 ppm for 5 min, 85 ppm for 15 min, and 53 ppm fo 60 min, signs of toxicity included respiratory distress during exposure, mild cough, eye irritation. At 125 pm for 5 min, 52 ppm for 15 min, or 39 ppm for 60 min, only mild sensory effects. No gross or microscopic lesions were seen in any dog. |
Carson et al. 1962 |
|
Dog |
Inhalation |
1,000 ppm; 5,000 pm |
136 min; 5–45 min |
No effects in one dog exposed to 1,000 ppm; at 5,000 ppm for 15 and 22 min, evident respiratory distress with anxiety lasted 2 h. |
Greenbaum et al. 1967 |
|
Dog |
Inhalation |
3–16 ppm |
1 h |
≥7 ppm, intraalveolar edema in most dogs, with ultrastructural alterations. At 3 ppm, formation in alveolar epithelium without biochemical or physiologic changes. |
Dowell et al. 1971 |
|
Species |
Route |
Concentration |
Duration |
Effect |
Reference |
|
REPEATED EXPOSURES |
|||||
|
Rat |
Inhalation |
3.6–14.4 ppm |
6–24 h/d, 3d |
Increases in protein content and cell types in lavage fluid. |
Gelzleichter et al. 1992 |
|
Mouse |
Inhalation |
5 ppm |
6 h/d, 4 d |
Enhanced susceptibility to infection by murine cytomegalovirus followed by exposure to 5 ppm for 6 h/d for 4 d. No evidence of lung injury. |
Rose et al. 1989 |
|
Mouse |
Inhalation |
4, 10, or 25 ppm |
6 h/d, 5 d/wk, up to 21 d |
At 4 ppm: no lesions in nasal cavity or lungs. At 10 ppm: no lesions in nasal cavity, increased cellularity of walls of bronchioles, alveolar duct, and adjacent alveoli by 21 d; hypertrophy or hyperplasia of small bronchi and bronchiolar epithelium by 7 d. At 25 ppm: no lesions in nasal cavity, hypertrophy or hyperplasia of small bronchi or bronchiolar epithelium by 7 d; increase in cellularity of walls of respiratory bronchioles, alveolar ducts, and adjacent alveoli by 7 d; some mononuclear infiltration of peribronchial areas. |
Hooftman et al. 1988 |
|
Abbreviations: BAL, bronchoalveolar lavage; LC50, median lethal concentration; LDH, lactic dehydrogenase; LOAEL, lowest observed adverse effect level; NOAEL, no observed adverse effect level; NR, not reported; VE, minute volume of ventilation. |
|||||
Repeated Exposure
Numerous repeated-exposure studies have been done with experimental animals (EPA 1993), although most have examined the effects of chronic exposures and thus are not relevant to setting SEALs. Several subchronic studies are summarized here. Gelzleichter et al. (1992) exposed rats at 3.6–14.4 ppm for 6–24 h/d for 3 d. The rats showed increases in protein content and cell types in lavage fluid. As mentioned above, mice exposed at 5 ppm for 6 h/d for 4 d exhibited enhanced susceptibility to infection by murine cytomegalovirus (Rose et al. 1989). Mice exposed at 10 or 25 ppm for 6 h/d, 5 d/wk for 21 d exhibited changes in their lungs (Hooftman et al. 1988). Mice exposed at 10 ppm had increased cellularity of the walls of the bronchioles, alveolar duct, and adjacent alveoli by 21 d and hypertrophy or hyperplasia of small bronchi and bronchiolar epithelium by 7 d; mice exposed at 25 ppm had hypertrophy or hyperplasia of small bronchi or bronchiolar epithelium by 7 d, an increase in cellularity of walls of respiratory bronchioles, alveolar ducts and adjacent alveoli by 7 d, and some mononuclear infiltration of peribronchial areas. Neither group nor another group exposed at 4 ppm had nasal lesions (Hooftman et al. 1988).
NAVY’S RECOMMENDED SEALS
The Navy proposes to set a SEAL 1 at 0.5 ppm and a SEAL 2 at 1 ppm. These levels were proposed to avoid even mild irritation to the eyes, nose, and upper respiratory tract.
RECOMMENDATIONS FROM OTHER ORGANIZATIONS
Recommended exposure guidance levels for nitrogen dioxide from other organizations are summarized in Table 8–4.
SUBCOMMITTEE ANALYSIS AND RECOMMENDATIONS
In animals that survive exposure to nitrogen dioxide, the ciliated epithelium is killed and later replaced during healing, as it is after influenza. Lung phospholipids show free radicals after nitrogen dioxide exposure, but recover. Type I alveolar cells are damaged and become replaced by type II alveolar cells during recovery. Protein and fluid leak into the alveolar spaces and are reabsorbed. Inflammatory processes attract white cells into the lung tissue, and later
TABLE 8–4 Recommendations from Other Organizations for Nitrogen Dioxide
|
Organization |
Type of Exposure Level |
Recommended Exposure Level, ppm |
Reference |
|
ACGIH |
TLV-TWA TLV-STEL |
3 ppm 5 ppm |
ACGIH 1991, 1998 |
|
DFG |
MAK (8h/d during 40-h workweek) |
5 ppm |
DFG 1997 |
|
|
Peak Limit (5 min maximum duration, 8 times per shift) |
10 ppm |
|
|
EPA |
Primary and secondary ambient air quality standards |
0.053 ppm, annual arithmetic mean concentration |
EPA 1993 |
|
NIOSH |
STEL IDHL |
1 ppm 20 ppm |
NIOSH 1994; Ludwig et al. 1994 |
|
OSHA |
Ceiling limit |
5 ppm |
OSHA 1996a |
|
aTable 2–1. Limits for Air Contaminants. 29 CFR Part 1910.1000. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; DFG, Deutsche Forschungsgemeinschaft; EPA, Environmental Protection Agency; IDLH, immediately dangerous to life and health; MAK, maximum allowable concentration in the workplace; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average. |
|||
this resolves. There is less resistance of the lungs to infection by bacteria and viruses, requiring medical treatment. These processes are similar to the ones described for injurious but recoverable processes.
A greater degree of inflammation can lead to permanent lung damage or death. The respiratory bronchioles become obliterated (bronchiolitis obliterans), the alveoli are filled with proteinaceous edema fluid (heavy, wet lungs), and the inflammatory process can turn into interstitial fibrosis.
Submarine Escape Action Level 1
On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 1 of 0.5 ppm for nitrogen dioxide is too conservative. The subcommittee recom-
mends a SEAL 1 for nitrogen dioxide of 5 ppm. The subcommittee’s recommended SEAL 1 was derived by reducing the SEAL 2 of 10 ppm (see below for derivation of SEAL 2) to 5 ppm to avoid health effects from continuous exposure of up to 10 d. That reduction was based on the knowledge that the toxicity of nitrogen dioxide is more dependent on concentration than on exposure duration.
Submarine Escape Action Level 2
On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 1 ppm for nitrogen dioxide is too conservative. The subcommittee recommends a SEAL 2 of 10 ppm for nitrogen dioxide. The subcommittee’s recommendation is based on a study in which volunteers exposed at 30 ppm for 2 h experienced a burning sensation in the nose and chest, cough, dyspnea, and sputum production (NRC 1977). Also, animals (rats, mice, guinea pigs, rabbits, and dogs) exposed at 20 ppm for 24 h showed respiratory irritation and changes in behavior, possible lung congestion, and interstitial inflammation (Hine et al. 1970). The subcommittee concludes that the crew of a disabled submarine should be able to tolerate the irritant effects from exposure to nitrogen dioxide at concentrations below 10 ppm for up to 24 h.
DATA GAPS AND RESEARCH NEEDS
Studies in humans and experimental animals should be conducted to better define the dose-response curve for exposures to nitrogen dioxide lasting 10 h to 10 d. Nitrogen dioxide is a particularly reactive gas and therefore, its interaction with other combustion gases likely to be found in a disabled submarine should be studied.
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