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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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).
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Review of Submarine Escape Action Levels for Selected Chemicals 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).
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Review of Submarine Escape Action Levels for Selected Chemicals 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.
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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.
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Review of Submarine Escape Action Levels for Selected Chemicals 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.
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Review of Submarine Escape Action Levels for Selected Chemicals 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).
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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.
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Review of Submarine Escape Action Levels for Selected Chemicals 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
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Review of Submarine Escape Action Levels for Selected Chemicals 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-
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Review of Submarine Escape Action Levels for Selected Chemicals 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. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Nitrogen Dioxide. Pp. 1108–1110 in Documentation of the Threshold Limit Values and Biological Exposure Indices, Vol. II, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 1998. Threshold Limit Values and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH.
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Review of Submarine Escape Action Levels for Selected Chemicals Adams, W.C., K.A.Brookes, and E.S.Schelegle. 1987. Effects of NO2 alone and in combination with O3 on young men and women. J. Appl. Physiol. 62(4):1698–1704. Azoulay-Dupuis, E., M.Torrres, P.Soler, and J.Moreau. 1983. Pulmonary NO2 toxicity in neonate and adult guinea pigs and rats. Environ. Res. 30(2):322–339. Azoulay-Dupuis, E., M.Levacher, M.Muffat-Joly, and J.J.Pocidalo. 1985. Humoral immunodepression following acute NO2 exposure in normal and adrenalectomized mice. J. Toxicol. Environ. Health 15(1):149–162. Bauer, M.A., M.J.Utell, P.E.Morrow, D.M.Speers, and F.R.Gibb. 1985. Route of inhalation influences airway responses to 0.30 ppm nitrogen dioxide in asthmatic subjects. Am. Rev. Respir. Dis. 131:A171. Bouley, G., E.Azoulay-Dupuis, and C.Gaudebout. 1986. Impaired acquired resistance of mice to Klebsiella pneumoniae induced by acute NO2 exposure. Environ. Res. 41(2):497–504. Budavari, S., M.J.O’Neil, A.Smith, P.E.Heckelman, and J.F.Kinneary, eds. 1996. Pp. 1135 in The Merck Index, 12th Ed. Rahway, NJ: Merck. Carson, T.R., M.S.Rosenholtz, F.T.Wilinski, and M.H.Weeks. 1962. The responses of animals inhaling nitrogen dioxide for single, short-term exposures. Am. Ind. Hyg. Assoc. J. 23:457–462. Devalia, J.L., C.Rusznak, M.J.Herdman, C.J.Trigg, H.Tarraf, and R.J.Davies. 1994. Effect of nitrogen dioxide and sulphur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 344(8938):1668–1671. Devlin, R., D.Horstman, S.Becker, T.Gerrity, M.Madden, and H.Koren. 1992. Inflammatory response in humans exposed to 2.0 ppm NO2. Am. Rev. Respir. Dis. 145:A 456. DFG (Deutsche Forschungsgemeinschaft). 1997. List of MAK and BAT Values 1997. Maximum Concentrations and Biological Tolerance Values at the Workplace, 1st Ed. Report No. 33. Weinheim: Wiley-VCH. Douglas, W.W., N.G.G.Hepper, and T.V.Colby. 1989. Silo-filler’s disease. Mayo Clin. Proc. 64(3):291–304. Dowell, A.R., K.H.Kilburn, and P.C.Pratt. 1971. Short-term exposure to nitrogen dioxide: Effects on pulmonary ultrastructure, compliance, and the surfactant system. Arch. Intern. Med. 128(1):74–80. DuBois, A.B., J.S.Douglas, J.T.Stitt, and V.Mohsenin. 1998. Production and absorption of nitric oxide gas in the nose. J. Appl. Physiol. 84(4):1219–1224. Elsayed, N.M. 1994. Toxicity of nitrogen dioxide: An introduction. Toxicology 89(3):161–174. EPA (U.S. Environmental Protection Agency). 1990. Research and Development: Health and Environmental Effects Document for Nitrogen Dioxide. ECAO-CING060. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH. 133 pp. March. EPA (U.S. Environmental Protection Agency). 1993. Air Quality Criteria for Oxides of Nitrogen, Vol. I-II. EPA600/8–91/049aF. EPA600/8–91/049bF. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Research Triangle Park, NC. August. Folinsbee, L.J., S.M.Horvath, J.F.Bedi, and J.C.Delehunt. 1978. Effect of 0.62 ppm
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Representative terms from entire chapter: