Cover Image

PAPERBACK
$64.25



View/Hide Left Panel

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).



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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).

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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).

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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-

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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,

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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).

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants piratory mechanics and bronchial susceptibility to acetylcholine in normal persons [in German]. Int. Arch. Occup. Environ. Health 38(1):31-44 (as cited in EPA 1993). Benemanskii, V.V., V.M. Prusakov, and M.E. Leshenko. 1981. Blastomogenic action of low concentration of nitrosodimethylamine, dimethylamine and nitrogen dioxide [in Russian]. Vopr. Onkol. 27(10):56-62 (as cited in EPA 1993). Blair, W.H., M.C. Henry, and R. Ehrlich. 1969. Chronic toxicity of nitrogen dioxide: II. Effect on histopathology of lung tissue. Arch. Environ. Health 18(2):186-192 (as cited in EPA 1993). Brunekreef, B., and S.T. Holgate. 2002. Air pollution and health. Lancet 360(9341):1233-1242. Budavari, S., M.J. O’Neil, A. Smith, and P.E. Heckelman, eds. 1989. P. 6528 in the Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck and Co. Carson, T.R., M.S. Rosenholtz, F.T. Willinski, 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. Chang, L., J.A. Miller, J.J. Ospital, and J.D. Crapo. 1986. Effects of subchronic inhalation of low concentrations of nitrogen dioxide. I. The proximal alveolar region of juvenile and adult rats. Toxicol. Appl. Pharmacol. 83(1):46-61 (as cited in EPA 1993). Costa, D.L., and M.O. Amdur. 1996. Air pollution. Pp. 857-882 in Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th Ed., C.D. Klaassen, ed. New York: McGraw Hill. Crapo, J.D., B.E. Barry, L. Chang, and R.R. Mercer. 1984. Alternations in lung structure caused by inhalation of oxidants. J. Toxicol. Environ. Health 13(2-3):301-321 (as cited in EPA 1993). Crawl, J.R. 2003. Review/Updating of Limits for Submarine Air Contaminants. Presentation at the First Meeting on Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, January 23, 2003, Washington, DC. Damji, K.S., and A. Richters. 1989. Reduction in T lymphocyte subpopulations following acute exposure to 4 ppm nitrogen dioxide. Environ. Res. 49(2):217-224. 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(4):A456. Douglas, W.W., N.G.G. Hepper, and T.V. Colby. 1989. Silo-filler’s disease. Mayo Clin. Proc. 64(3):291-304. Ehrlich, R., and M.C. Henry. 1968. Chronic toxicity of nitrogen dioxide: I. Effect on resistance to bacterial pneumonia. Arch. Environ. Health 17(6):860-865 (as cited in EPA 1993). Ehrlich, R., E. Silverstein, R. Maigetter, J.D. Fenters, and D. Gardner. 1975.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Immunologic response in vaccinated mice during long-term exposure to nitrogen dioxide. Environ. Res. 10(2):217-223 (as cited in EPA 1993). Ehrlich, R., J.C. Findlay, and D.E. Gardner. 1979. Effects of repeated exposures to peak concentrations of nitrogen dioxide and ozone on resistance to streptococcal pneumonia. J. Toxicol. Environ. Health 5(4):631-642. Elsayed, N.M. 1994. Toxicity of nitrogen dioxide: An introduction. Toxicology 89(3):161-174. Elsayed, N.M., N.V. Gorbunov, M.A. Mayorga, V.E. Kagan, and A.J. Januszkieicz. 2002. Significant pulmonary response to a brief high-level, nose-only nitrogen dioxide exposure: An interspecies dosimetry perspective. Toxicol. Appl. Pharmacol. 184(1):1-10. EPA (U.S. Environmental Protection Agency). 1993. Air Quality Criteria for Oxides of Nitrogen, Vol. III. EPA/600/8-91/049cF. Environmental Criteria and Assessment Office, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC. EPA (U.S. Environmental Protection Agency). 1995. Review of the National Ambient Air Quality Standards for Nitrogen Dioxide. Assessment of Scientific and Technical Information. OAQPS Staff Paper. EPA 452/R-95-005. Office of Air Quality, U.S. Environmental Protection Agency, Research Triangle Park. [Online]. Available: http://www.epa.gov/ttn/naaqs/standards/nox/data/noxsp1995.pdf [accessed March 18, 2004]. EPA (U.S. Environmental Protection Agency). 2004. Acute Exposure Guideline Levels (AEGLs). Nitrogen Dioxide Results (Proposed). Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency. [Online]. Available: http://www.epa.gov/oppt/aegl/chemlist.htm [Accessed March 9, 2004]. Evans, M.J., R.J. Stephens, L.J. Cabral, and G. Freeman. 1972. Cell renewal in the lungs of rats exposed to low levels of NO2. Arch. Environ. Health 24(3):180-188 (as cited in EPA 1993). Evans, J.N., D.R. Hemenway, and J. Kelley. 1989. Early markers of lung injury. Research Report No. 29. Cambridge, MA: Health Effects Institute (as cited in EPA 1993). Farrow, A., R. Greenwood, S. Preece, and J. Golding. 1997. Nitrogen dioxide, the oxides of nitrogen, and infants’ health symptoms. Arch. Environ. Health 52(3):189-194. Fenters, J.D., R. Ehrlich, J. Findlay, J. Spangler, and V. Tolkacz. 1971. Serologic response in squirrel monkeys exposed to nitrogen dioxide and influenza virus. Am. Rev. Respir. Dis. 104(3):448-451 (as cited in EPA 1993). Fenters, J.D., J.C. Findlay, C.D. Port, R. Ehrlich, and D.L. Coffin. 1973. Chronic exposure to nitrogen dioxide: Immunologic, physiologic, and pathologic effects in virus-challenged squirrel monkeys. Arch. Environ. Health 27(2):85-89. Folinsbee, L.J., S.M. Horvath, J.F. Bedi, and J.C. Delehunt. 1978. Effect of 0.62 ppm NO2 on cardiopulmonary function in young male nonsmokers. Environ. Res. 15(2):199-205.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Frampton, M.W., P.E. Morrow, C. Cox, R. Gibb, D.M. Speers, and M. Utell. 1991. Effects of nitrogen dioxide exposure on pulmonary function and airway reactivity in normal humans. Am. Rev. Respir. Dis. 143(3):522-527. Frampton, M.W., K.Z. Voter, P.E. Morrow, and N.J. Roberts, Jr., J.B. Garvas, and M.J. Utell. 1992. Effects of NO2 exposure on human host defense. Am. Rev. Respir. Dis. 145(4):A455 (as cited in NRC 2002). Frampton, M.W., J. Boscia, N.J. Roberts, Jr., M. Azadniv, A. Torres, C. Cox, P.E. Morrow, J. Nichols, D. Chalupa, L.M. Frasier, F.R. Gibb, D.M. Speers, Y. Tsai, and M.J. Utell. 2002. Nitrogen dioxide exposure: Effects on airway and blood cells. Am. J. Physiol. Lung. Cell. Mol. Physiol. 282(1):L155-L165. Freeman, G., N.J. Furiosi, and G.B. Haydon. 1966. Effects of continuous exposure of 0.8 ppm NO2 on respiration of rats. Arch. Environ. Health 13(4):454-456. Freeman, G., R.J. Stephens, S.C. Crane, and N.J. Furiosi. 1968. Lesion of the lung in rats continuously exposed to two parts per million of nitrogen dioxide. Arch. Environ. Health 17(2):181-192. Freeman, G., S.C. Crane, N.J. Furiosi, R.J. Stephens, M.J. Evans, and W.D. Moore. 1972. Covert reduction in ventilatory surface in rats during prolonged exposure to subacute nitrogen dioxide. Am. Rev. Respir. Dis. 106(4):563-579 (as cited in EPA 1993). Fujimaki, H., F. Shimizu, and K. Kubota. 1982. Effect of subacute exposure to NO2 on lymphocytes required for antibody responses. Environ. Res. 29(2):280-286 (as cited in EPA 1993). Fujimaki, H. 1989. Impairment of humoral immune responses in mice exposed to nitrogen dioxide and ozone mixtures. Environ. Res. 48(2):211-217 (as cited in EPA 1993). Furiosi, N.J., S. Crane, and G. Freeman. 1973. Mixed sodium chloride aerosol and nitrogen dioxide in air: biological effects on monkeys and rats. Arch. Environ. Health. 27(6):405-408. Fusco, D., F. Forastiere, P. Michelozzi, T. Spadea, B. Ostro, M. Arca, and C.A. Perucci. 2001. Air pollution and hospital admissions for respiratory conditions in Rome, Italy. Eur. Respir. J. 17(6):1143-1150. Gardner, D.E. 1980. Influence of exposure patterns of nitrogen dioxide on susceptibility to infectious respiratory disease. Pp. 267-288 in Nitrogen Oxides and Their Effects on Health, S.D. Lee, ed. Ann Arbor, MI: Ann Arbor Science Publishers, Inc. (as cited in EPA 1993). Gardner, D.E., F.J. Miller, J.W. Illing, and J.A. Graham. 1982. Non-respiratory function of the lungs: Host defenses against infection. Pp. 401-415 in Air Pollution by Nitrogen Oxides: Proceedings of the US-Dutch International Symposium, May, Maastricht, The Netherlands, T. Schneider and L. Grant, eds. Amsterdam, The Netherlands: Elsevier Scientific Publishing Company (as cited in EPA 1993). Garn, H., A. Siese, S. Stumpf, P.J. Barth, B. Muller, and D. Gemsa. 2003. Shift toward an alternatively activated macrophage response in lungs of NO2-exposed rats. Am. J. Respir. Cell. Mol. Biol. 28(3):386-396.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Goings, S.A., T.J. Kulle, R. Bascom, L.R. Sauder, D.J. Green, J.R. Hebel, and M.L. Clements. 1989. Effect of nitrogen dioxide exposure on susceptibility to influenza A virus infection in healthy adults. Am. Rev. Respir. Dis. 139(5):1075-1081. Goldstein, E., N.F. Peek, N.J. Parks, H.H. Hines, E.P. Steffey, and B. Tarkington. 1977. Fate and distribution of inhaled nitrogen dioxide in rhesus monkeys. Am. Rev. Resp. Dis. 115(3):403-412. Graham, J.A., D.E. Gardner, E.J. Blommer, D.E. House, M.G. Menache, and F.J. Miller. 1987. Influence of exposure patterns of nitrogen dioxide and modifications by ozone on susceptibility to bacterial infectious disease in mice. J. Toxicol. Environ. Health 21(1-2):113-125 (as cited in EPA 1993). Gregory, R.E., J.A. Pickrell, F.F. Hahn, and C.H. Hobbs. 1983. Pulmonary effects of intermittent subacute exposure to low-level nitrogen dioxide. J. Toxicol. Environ. Health 11(3):405-414 (as cited in EPA 1993). Greenbaum, R., J. Bay, M.D. Hargreaves, M.L. Kain, G.R. Kelman, J.F. Nunn, C. Prys-Roberts, and K. Siebold. 1967. Effects of higher oxides of nitrogen on the anaesthetized dog. Br. J. Anaesth. 39(5):393-404. Gross, P., R.T.P. deTreville, M.A. Babyak, M. Kaschak, and E.B. Tolker. 1968. Experimental emphysema: effect of chronic nitrogen dioxide exposure and papain on normal and pneumoconiotic lungs. Arch. Environ. Health 16(1): 51-58 (as cited in EPA 1993). Hackney, J.D., F.C. Thiede, W.S. Linn, E.E. Pederson, C.E. Speier, D.C. Law, and D.A. Fischer. 1978. Experimental studies on human health effects of air pollutants. IV. Short-term psychological and clinical effects of nitrogen dioxide exposure. Arch. Environ. Health 33(4):176-181. Hayashi, Y., T. Kohno, and H. Ohwada. 1987. Morphological effects of nitrogen dioxide on the rat lung. Environ. Health Perspect. 73:135-145. Haydon, G.B., G. Freeman, and N.J. Furiosi. 1965. Covert pathogenesis of NO2-induced emphysema in the rat. Arch. Environ. Health 11(6):776-783 (as cited in EPA 1993). Hazucha, M.J., L.J. Folinsbee, E. Seal, and P.A. Bromberg. 1994. Lung function response of healthy women after sequential exposures to NO2 and O3. Am. J. Respir. Crit. Care Med. 150(3):642-647. Hedberg, K., C.W. Hedberg, C. Iber, K.E. White, M.T. Osterholm, D.B.W. Jones, J.R. Flink, and K.L. MacDonald. 1989. An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. J. Am. Med. Assoc. 262(21):3014-3017. Henschler, D., A. Stier, H. Beck, and W. Neuman. 1960. Odor threshold of a few important irritant gases (sulfur dioxide, ozone, nitrogen dioxide) and the manifestations of the effect of small concentrations on man [in German]. Arch. Gewerbepathol. Gewerbehyg. 17:547-570. Henschler, D., and W. Lütge. 1963. Methemoglobin formation due to inhalation of low concentrations of nitroso gases [in German]. Int. Arch. Gewerbepathol. Gewerbehyg. 20:362-370.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants Henry, M.C., R. Ehrlich, and W.H. Blair. 1969. Effect of nitrogen dioxide on resistance of squirrel monkeys to Klebsiella pneumonaie infection. Arch. Environ. Health 18(4):580-587. Henry, M.C., J. Findlay, J. Spangler, and R. Ehrlich. 1970. Chronic toxicity of NO2 in squirrel monkeys. 3. Effect on resistance to bacterial and viral infection. Arch. Environ. Health 20(5):566-570. Hillam, R.P., D.E. Bice, F.F. Hahn, and C.T. Schnizlein. 1983. Effects of acute nitrogen dioxide exposure on cellular immunity after lung immunization. Environ. Res. 31(1):201-211. Hine, C.H., F.H. Meyers, and R.W. Wright. 1970. Pulmonary changes in animals exposed to nitrogen dioxide, effects of acute exposures. Toxicol. Appl. Pharmacol. 16(1):201-213. Holt, P.G., L.M. Findlay-Jones, D. Keast, and J.M. Papadimitriou. 1979. Immunological function in mice chromically exposed to nitrogen oxides (NOx). Environ. Res. 19(1):154-162 (as cited in EPA 1993). Hooftman, R.N., C.F. Kuper, and L.M. Appelman. 1988. Comparative sensitivity of histopathology and specific lung parameters in the detection of lung injury. J. Appl. Toxicol. 8(1):59-65. HSDB (Hazardous Substances Data Bank). 2003. Nitrogen dioxide. TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD. [Online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB [accessed March 9, 2004]. Ichinose, T., K. Fujii, and S. Masaru. 1991. Experimental studies on tumor promotion by nitrogen dioxide. Toxicology 67(2):211-225. Isomura, K., M. Chikahira, K. Teranishi, and K. Hamada. 1984. Induction of mutations and chromosomes aberrations in lung cells following in vivo exposure of rats to nitrogen oxides. Mutat. Res. 136(2):119-125. Ito, K. 1971. Effect of nitrogen dioxide inhalation on influenza virus infection in mice [in Japanese]. Nippon Eiseigaku Zasshi 26:304-314 (as cited in EPA 1993). Kerr, H.D., T.J. Kulle, M.L. McIlhany, and P. Swidersky. 1979. Effects of nitrogen dioxide on pulmonary function in human subjects: An environmental chamber study. Environ. Res. 19(2):392-404 (as cited in NRC 2002). Kim, S.U., J.Q. Koeing, W.E. Pierson, and Q.S. Hanley. 1991. Acute pulmonary effects of nitrogen dioxide exposure during exercise in competitive athletics. Chest 99(4):815-819. Kleinerman, J., M.P.C. Ip, and R.E. Gordon. 1985. The reaction of the respiratory tract to chronic NO2 exposure. Pp. 200-210 in The pathologist and the environment, D.G. Scarpelli, J.E. Craighead, and N. Kaufman, eds. International Academy of Pathology Monograph no. 26. Baltimore, MD: Williams and Wilkins (as cited in EPA 1993). Kleinman, M.T., R.M. Bailey, W.S. Linn, K.R. Anderson, J.D. Whynot, D.A. Shamoo, and J.D. Hackney. 1983. Effects of 0.2 ppm nitrogen dioxide on pulmonary function and response to bronchoprovocation in asthmatics. J. Toxicol. Environ. Health 12(4-6):815-826.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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. Koenig, J.Q., D.S. Covert, S.G. Morgan, G. van Belle, and W.E. Pierson. 1987. The effects of ozone and nitrogen dioxide on pulmonary function in healthy and in asthmatic adolescents. Am. Rev. Respir. Dis. 136(5):1152-1157. Koike, E., T. Kobayashi, and R. Utsunoaiya. 2001. Effect of exposure to nitrogen dioxide on alveolar macrophage - mediated immunosuppressive activity in rats. Toxicol. Lett. 121(2):135-143. Kripke, B., and R.P. Sherwin. 1984. Nitrogen dioxide exposure - Influence on rat testes. Anesth. Analg. (NY) 63(5):526-528 (as cited in EPA 1993). Kyono, H., and K. Kawai. 1982. Morphometric study on age-dependent pulmonary lesions in rats responses. J. Toxicol. Environ. Health 17(2-3):241-248 (as cited in EPA 1993). Lefkowitz, S.S., J.J. McGrath, and D.L. Lefkowitz. 1986. Effects of NO2 on immune responses. J. Toxicol. Environ. Health 17(2-3):241-248 (as cited in EPA 1993). Lehnert, B.E., D.C. Archuleta, T. Ellis, W.S. Session, N.M. Lehnert, L.R. Gurley, and D.M. Stavert. 1994. Lung injury following exposure of rats to relatively high mass concentrations of nitrogen dioxide. Toxicology 89(3):239-277. Lewis, R.J., Sr., ed. 1993. Pp. 828 in Hawley's Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Rheinhold. Linn, W.S., and J.D. Hackney. 1984. Short-term human respiratory effects of nitrogen dioxide: Determination of Quantitative Dose-Response Profiles, Final Report, Phase 2. Exposure of Asthmatic Volunteers to 4 ppm NO2. CRC-CAPM-48-83. (1-82). NTIS PB85-104388. Rancho Los Amigos Hospital, Inc, Downey, CA. Linn, W.S., D.A. Shamoo, C.E. Spier, L.M. Valencia, U.T. Aznar, T.G. Venet, E.L. Avol, and J.D. Hackney. 1985. Controlled exposure of volunteers with chronic obstructive pulmonary disease to nitrogen dioxide. Arch. Environ. Health 40(6):313-317. Lowry, T. and L.M. Schuman. 1956. “Silo-filler’s disease”- A syndrome caused by nitrogen dioxide. J. Am. Med. Assoc. 162(3):153-160 (as cited in NRC 2002). Mauderly, J.L. 1989. Susceptibility of young and aging lungs to inhaled pollutants. Pp. 148-161 in Susceptibility to Inhaled Pollutants. ASTM special technical publication no. 1024. Philadelphia, PA: American Society for Testing and Materials. Mauderly, J.L., D.E. Bice, Y.S. Cheng, N.A. Gillett, R.F. Henderson, J.A. Pickrell, and R.K. Wolff. 1987. Effects of Inhaled Nitrogen Dioxide and Diesel Exhaust on Developing Lung. Research Report No. 8. Cambridge, MA: Health Effects Institute (as cited in EPA 1993). Mauderly, J.L., D.E. Bice, Y.S. Cheng, N.A. Gillett, R.F. Henderson, J.A. Pickrell,

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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. Mercer, R.R., D.L. Costa, and J.D. Crapo. 1995. Effects of prolonged exposure to low doses of nitric oxide or nitrogen dioxide on the alveolar septa of the adult rat lung. Lab. Invest. 73(1):20-28. Messiha, F.S., J. McGrath, J. Early, M.J. Hughes, and D.F. Rector. 1983. Biochemical and morphological aspects of nitrogen dioxide toxicity and the effect of ethanol intake. J. Environ. Sci. Health Part A 18:571-581 (as cited in EPA 1993). Meulenbelt, J., J.A.M.A. Dormans, A.B.T.J. Boink, and B. Sangster. 1992a. Rat model to investigate the treatment of acute nitrogen dioxide intoxication. Hum. Exp. Toxicol. 11:179-187 (as cited in NRC 2002). Meulenbelt, J., L. van Bree, J.A.M.A. Dormans, A.B.T.J. Boink, and B. Sangster. 1992b. Biochemical and histological alterations in rats after acute nitrogen dioxide intoxication. Human Exp. Toxicol. 11(3):189-200 (as cited in NRC 2002). Miller, F.J., J.A. Graham, J.A. Raub, J.W. Illing, M.G. Menache, D.E. House, and D.E. Gardner. 1987. Evaluating the toxicity of urban patterns of oxidant gases. II. Effects in mice from chronic exposure to nitrogen dioxide. J. Toxicol. Environ. Health 21(1-2):99-112 (as cited in EPA 1993). Mohsenin, V. 1987. Airway responses to nitrogen dioxide in asthmatic subjects. J. Toxicol. Environ. Health 22(4):371-380. Mohsenin, V. 1988. Airway responses to 2.0 ppm nitrogen dioxide in normal subjects. Arch. Environ. Health 43(3):242-246. Mohsenin, V., and J.B. Gee. 1987. Acute effect of nitrogen dioxide exposure on the functional activity of alpha-1-protease inhibitor in bronchoalveolar lavage fluid of normal subjects. Am. Rev. Respir. Dis. 136(3):646-650. Morley, R., and S.J. Silk. 1970. The industrial hazard from nitrous fumes. Ann. Occup. Hyg. 13(2):101-107. Morrow, P.E., and M.J. Utell. 1989. Responses of susceptible subpopulations to nitrogen dioxide. Res. Rep. Health Eff. Inst. 23:1-45 (as cited in NRC 2002). NAC (National Advisory Committee). 2003. Acute Exposure Guideline Levels (AEGLs) for Nitrogen Dioxide, Proposed 1: 1/2003. National Advisory Committee/AEGL, U.S. Environmental Protection Agency, Washington, DC. NIOSH (National Institute for Occupational Safety and Health). 1976. Occupational Exposure to Oxides of Nitrogen (Nitrogen Dioxide and Nitric Oxide): Criteria for a Recommended Standard. NIOSH 76-149. National Institute for Occupational Safety and Health, U.S. Department of Health, Education, and Welfare, Washington, DC.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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. Norwood, W.D., D.E. Wisehart, C.A. Earl, F.E. Adley, and D.E. Anderson. 1966. Nitrogen dioxide poisoning due to metal-cutting with oxyacetylene torch. J. Occup. Med. 8(6):301-306. NRC (National Research Council). 1977. Nitrogen Oxides: Medical and Biologic Effects of Environmental Pollutants. Washington, DC: National Academy of Science. NRC (National Research Council). 1985. Pp. 83-95 in Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 4. Washington, DC: National Academy Press. NRC (National Research Council). 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: National Academies Press. Oda, H., H. Nogami, and T. Nakajima. 1980. Reaction of hemoglobin with nitric oxide and nitrogen dioxide in mice. J. Toxicol. Environ. Health 6(3):673-678. Oda, H., H. Tsubone, A. Suzuki, T. Ichinose, and K. Kubota. 1981. Alterations of nitrite and nitrate concentrations in the blood of mice exposed to nitrogen dioxide. Environ. Res. J. 25(2):294-301 (as cited in EPA 1993). 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. Peters, J.M., E. Avol, W. Navidi, S.J. London, W.J. Gauderman, F. Lurman, W.S. Linn, H. Margolis, E. Rappaport, H. Vora, H. Gong, Jr., and D.C. Thomas. 1999b. A study of twelve southern California communities with differing levels and types of air pollution. II. Effects on pulmonary function. Am. J. Resp. Crit. Care Med. 159(3):768-775. Pilotto, L.S., R.M. Douglas, R.G. Attewell, and S.R. Wilson. 1997. Respiratory effects associated with indoor nitrogen dioxide exposure in children. Int. J. Epidemiol. 26(4):788-796. Posin, C., R.D. Buckley, K. Clark, J.D. Hackney, M.P. Jones, and J.V. Patterson. 1978. Nitrogen dioxide inhalation and human blood biochemistry. Arch. Environ. Health 33(6):318-324. Postlethwait, E.M., and A. Bidani. 1990. Reactive uptake governs the pulmonary air space removal of inhaled nitrogen dioxide. J. Appl. Physiol. 68(2):594-603. Postlethwait, E.M., and A. Bidani. 1994. Mechanisms of pulmonary NO2 absorption. Toxicology 89(3):217-237. Postlethwait, E.M. and M.G. Mustafa. 1981. Fate of inhaled nitrogen dioxide in isolated perfused rat lung. J. Toxicol. Environ. Health 7(6):861-872. Proust, B., G. Lacroix, G.F. Rabidel, M. Mariliene, A. Lecomte, and V.B. Vargaftig. 2002. Interference of a short-term exposure to nitrogen dioxide

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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). Roger, L.J., D.H. Horstman, W. McConnell, H. Kehrl, P.J. Ives, E. Seal, R. Chapman, and E. Massaro. 1990. Pulmonary function, airway responsiveness, and respiratory symptoms in asthmatics following exercise in NO2. Toxicol. Ind. Health 6(1):155-171 (as cited in NRC 2002). Rombout, P.J.A., J.A.M.A. Dormans, M. Marra, and L. van Esch. 1986. Influence of exposure regimen on nitrogen dioxide-induced morphological changes in the rat lung. Environ. Res. 41(2):466-480 (as cited in EPA 1993). Rose, R.M., J.M. Fuglestad, W.S. Skornik, S.M. Hammer, S.F. Wolfthal, B.D. Beck, and J.D. Brain. 1988. The pathophysiology of enhanced susceptibility to murine cytomegalovirus respiratory infection during short-term exposure to 5 ppm nitrogen dioxide. Am. Rev. Respir. Dis. 137(4):912-917. Rose, R.M., P. Pinkston, and W.A. Skornik. 1989. Altered susceptibility to viral respiratory infection during short-term exposure to nitrogen dioxide. Res. Rep. Health Eff. Inst. 24:1-24. Rubinstein, I., B.G. Bigby, F. Reiss, and H.A. Boushey, Jr. 1990. Short-term exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects. Am. Rev. Respir. Dis. 141(2):381-385. Sackner, M.A., S. Birch, A. Friden, and B. Marchetti. 1981. Effects of breathing low levels of nitrogen dioxide for four hours on pulmonary function of asthmatic adults. Am. Rev. Respir. Dis. 123(4):151 (as cited in NRC 2002). 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.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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. Schlesinger, R.B. 1987. Intermittent inhalation of nitrogen dioxide: Effects of rabbit alveolar macrophages. J. Toxicol. Environ. Health 21(1-2):127-139. Selgrade, M.K., M.J. Daniels, and E.C. Grose. 1991. Evaluation of immunotoxicity of an urban profile of nitrogen dioxide: acute, subchronic, and chronic studies. Inhal. Toxicol. 3(4):389-403. Sherwin, R.P., and V. Richters. 1982. Hyperplasia of type 2 pneumocytes following 0.34 ppm nitrogen dioxide exposure: Quantitation by image analysis. Arch. Environ. Health 37(5):306-315 (as cited in EPA 1993). Siegel, P.D., B.E. Bozelka, C. Reynolds, and W.J. George. 1989. Phase-dependent response of the lung to NO2 irritant insult. J. Environ. Path. Toxicol. Oncolog. 9(4):303-315 (as cited in NAC 2003). Steadman, B.L., R.A. Jones, D.E. Rector, and J. Siegel. 1966. Effects on experimental animals of long- term continuous inhalation of nitrogen dioxide. Toxicol. Appl. Pharmacol. 9(1):160-170 (as cited in EPA 1993). Stephens, R.J., G. Freeman, S.C. Crane, and N.J. Furiosi. 1971a. Ultrastructural changes in the terminal bronchiole of the rat during continuous, low-level exposure to nitrogen dioxide. Exp. Mol. Pathol. 14(1):1-19 (as cited in EPA 1993). 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). Stephens, R.J., G. Freeman, and M.J. Evans. 1972. Early response of lungs to low levels of nitrogen dioxide: Light and electron microscopy. Arch. Environ. Health 24(3):160-179 (as cited in EPA 1993). Stephens, R.J., M.F. Sloan, D.G. Groath, D.S. Negi, and K.D. Lunan. 1978. Cytologic response of postnatal rat lungs to O3 or NO2 exposure. Am. J. Pathol. 93(1):183-200. 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). Tse, R.L., and A.A. Bockman. 1970. Nitrogen dioxide toxicity. Report of four cases in firemen. J. Am. Med. Assoc. 212(8):1341-1344. 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. van Bree, L., I. Reitjens, A.M. Alink, J. Dormans, M. Marra, and P.J. Rombout. 2000. Biochemical and morphological changes in lung tissues and isolated lung cells of rats induced by short-term nitrogen dioxide exposure. Hum. Exp. Toxicol. 19(7):392-401.

OCR for page 223
Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants 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). von Nieding, G., and H.M. Wagner. 1979. Effects of NO2 on chronic bronchitis. Environ. Health Perspect. 29:137-142. von Nieding, G., H.M. Wagner, H. Casper, A. Beuthan, and U. Smidt. 1980. Effect of experimental and occupational exposure to NO2 in sensitive and normal subjects. Pp. 315-331 in Nitrogen Oxides and Their Effects on Health, S.D. Lee, ed. Ann Arbor, MI: Ann Arbor Science Publishers, Inc. (as cited in EPA 1993). Wagner, W.D., B.R. Duncan, P.G. Wright, and H.E. Stokinger. 1965. Experimental study of threshold limit of NO2. Arch. Environ. Health 10(3):455-466 (as cited in EPA 1993). Wong, T.W., W.S. Tam, T.S. Yu, and A.H.S. Wong. 2002. Associations between daily mortalities from respiratory and cardiovascular diseases and air pollution in Hong Kong, China. Occup. Environ. Med. 59(1):30-35. Yokoyama, E., I. Ichikawa, and K. Kawai. 1980. Does nitrogen dioxide modify the respiratory effects of ozone? Pp. 217-229 in Nitrogen Oxides and Their Effects on Health, S.D. Lee, ed. Ann Arbor, MI: Ann Arbor Science Publishers, Inc. (as cited in EPA 1993). Yuen, T.G.H., and R.P. Sherwin. 1971. Hyperplasia of type 2 pneumocytes and nitrogen dioxide (10 ppm) exposure: A quantitation based on electron photomicrographs. Arch. Environ. Health 22(1):178-188 (as cited in EPA 1993).