B2 Ammonia

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Ammonia is a colorless gas with a sharp, burning odor (ACGIH, 1986).

Formula:

NH3

CAS number:

7664-41-7

Molecular weight:

17.0

Boiling point:

−33.5°C

Melting point:

−77,7°C

Vapor pressure:

8.5 atm at 20°C for liquid NH3

Conversion factors at 25°C, 1 atm:

1 ppm = 0.69 mg/m3

1 mg/m3= 1.44 ppm

OCCURRENCE AND USE

Ammonia can be used in coolant loops as a refrigerant. There is an internal biological source of ammonia from amino acid metabolism (White et al., 1978). It is difficult to predict the exposure levels in the spacecraft. On the shuttle, a large amount of ammonia is used in the coolant loop and it is triply contained.



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants B2 Ammonia King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Ammonia is a colorless gas with a sharp, burning odor (ACGIH, 1986). Formula: NH3 CAS number: 7664-41-7 Molecular weight: 17.0 Boiling point: −33.5°C Melting point: −77,7°C Vapor pressure: 8.5 atm at 20°C for liquid NH3 Conversion factors at 25°C, 1 atm: 1 ppm = 0.69 mg/m3 1 mg/m3= 1.44 ppm OCCURRENCE AND USE Ammonia can be used in coolant loops as a refrigerant. There is an internal biological source of ammonia from amino acid metabolism (White et al., 1978). It is difficult to predict the exposure levels in the spacecraft. On the shuttle, a large amount of ammonia is used in the coolant loop and it is triply contained.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants PHARMACOKINETICS AND METABOLISM The principal internal source of ammonia is the oxidation of glutamate by glutamate dehydrogenase in tissues, in particular the liver (White et al., 1978). Minor internal sources include oxidative and nonoxidative deaminations of amino acids in the liver and kidney. Another source of ammonia is the bacterial degradation of urea in the large intestine (Diamondstone, 1982). Ammonia averages about 100 µg/100 mL in blood (Diamondstone, 1982). Once formed inside the body, ammonia is used in the syntheses of glutamine, asparagine, and carbamoyl phosphate, which is utilized in arginine synthesis (White et al., 1978). The body eliminates ammonia in two major ways, both of which proceed indirectly via amino acid metabolism. One way is the hepatic metabolism of arginine into urea, which is excreted in the urine (White et al., 1978). The second major way is the renal metabolism of glutamine into free ammonia, which is excreted in the urine for maintaining the body's acid-base balance (Diamondstone, 1982). Ammonia could be excreted in the urine at 680 mg or 40 mEq per day in humans (Eastman, 1963). A minor elimination pathway is via exhalation. Ammonia vapor has been measured in the expired air from the mouth of rabbits ranging from 0.014 to 1.09 ppm (Vollmuth and Schlesinger, 1984). When exposed to ammonia gas, the human nose retains 83% of ammonia inhaled at a ventilation rate corresponding to light activity (Landahl and Herrmann, 1950). Being extremely water soluble, ammonia gas readily dissolves in the moisture present on the mucosa that comes in contact with it (Helmers et al., 1971; O'Kane, 1983). TOXICITY SUMMARY Mechanisms of Tissue Injuries Ammonia's principal toxic effect is to irritate mucous membranes, causing burning sensation in the eyes, nose, and throat with little systemic toxicity, but sensory fatigue develops toward the irritation with continuous or repetitive exposure (Hatton et al., 1979). In accidental massive exposures, ammonia harms the tissue it comes in contact in two ways (Arwood et al., 1985). One is via the ammonium hydroxide formed when ammonia

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants dissolves in the liquid lining the mucous membrane, causing liquefaction of tissues in a manner similar to that seen in alkali burns. The second mechanism of tissue injury is the release of heat in the solvation of ammonia in the liquid on the mucous membrane. Mucosal Irritation in Naive Subjects Ammonia's irritation response depends on whether the subject has adapted to it. Based on their experiences in manufacturing facilities for ammonia, nitrate, and urea in Italy, Vigliani and Zurlo (1956) reported that unadapted workers found 20-ppm ammonia irritating to the mucous membranes, but adapted workers did not complain of any irritating sensation upon long-term exposures to 20 ppm. However, there was a slight redness on the conjunctiva of the adapted workers after the 20-ppm exposures. The irritation data on unadapted workers reported by other investigators are summarized here. MacEwen et al. (1970) studied the subjective irritation of a 10-min exposure of five or six unadapted human volunteers to 30 or 50 ppm ammonia (MacEwen et al., 1970). Two of five subjects found 30 ppm to be faintly irritating (the irritation was just perceptible, but not painful). In contrast, four of six subjects found 50 ppm to be moderately irritating. Only one of six subjects felt that 50 ppm was faintly irritating and this subject did not find 30 ppm irritating (MacEwen et al., 1970). Irritation data of ammonia exposures at concentrations higher than 50 ppm, lasting longer than 10 min, have been reported by Verberk (1977), who compared the irritation responses of eight students who did not know ammonia's toxicity with those of eight “experts” who were familiar with ammonia's toxicity. Since neither the students nor the “experts” were accustomed to ammonia's effects by personal contact before the study, the data of the two groups are combined and summarized in Table 2-1. It can be concluded from the data of Vigliani and Zurlo (1956), MacEwen et al. (1970), and Verberk (1977) that ammonia vapor could produce irritation sensation on mucous membranes in unadapted human subjects at as low as 20 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 2-1 Irritation Data from Verberk (1977)   1h 2h NH3 Conc. Eye Irritation Throat Irritation Eye Irritation Throat Irritation 50 ppm Just perceptible Just perceptible Just perceptible Just perceptible 80 ppm In between just perceptible and distinctively perceptible Just perceptible In between just perceptible and distinctively perceptible In between just perceptible and distinctively perceptible 110 ppm In between distinctively perceptible and nuisance In between distinctively perceptible and nuisance In between distinctively perceptible and nuisance In between distinctively perceptible and nuisance 140 ppm Nuisance In between just perceptible and offensive Incomplete data Incomplete data

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Mucosal Irritation in Adapted Subjects Holness et al. (1989) reported that, in 58 soda ash workers, who have been continually exposed to ammonia on the job, an exposure to 9.2-ppm ammonia on the first and last workdays of their workweek did not produce any symptoms, effects on the sense of smell, or effects on lung functions, such as forced expiratory volume in 1 s and forced vital capacity (Douglas and Coe, 1987). Ferguson et al. (1977) showed that, in several subjects exposed to 25-100-ppm ammonia daily for 2-6 h for 5 d in the previous week, only one of four subjects developed mild mucosal irritation (pinkish red mucosa upon examination by a physician) when exposed to 25-ppm ammonia, 2 h a day for 5 d. However, at a more severe exposure of 50-pm ammonia, 4 or 6 h/d for 5 d, all six subjects developed mild mucosal irritation. Based on their experiences in manufacturing plants for ammonia, nitrate, and urea, Vigliani and Zurlo (1956) reported that workers, presumably adapted, could not breathe 100-ppm ammonia for too long without developing irritation of the upper respiratory tract and the conjunctiva. In conclusion, in adapted human subjects, ammonia at 9 ppm is not irritating, but whether 25 ppm or 50 ppm produces irritation symptoms is unknown. Nevertheless, based on an objective sign of irritation (mucosal erythema), 25 ppm is barely irritating, and 50 ppm is definitely irritating, albeit only mildly, in adapted subjects. Mucosal Irritation in Subjects Of Unknown Adaptation Status This section summarizes the irritation data on individuals with unknown adaptation status. Weatherby (1952) reported that five or six members of his laboratory staff, upon inhaling the exhaust from a chamber in which guinea pigs were exposed to 140-200-ppm ammonia, gave their opinion that no person would voluntarily remain in such an atmosphere for any length of time because of the respiratory distress and disagreeable odor. Henderson and Haggard (1943) reported that it took at least 408-ppm ammonia to cause immediate throat irritation. Other reports indicate that ammonia could produce immediate eye injury at 700 ppm and laryngospasm at 1700 ppm (Helmers et al., 1971; Grant, 1974). Death is possible at 2500 ppm (Helmers et al., 1971).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Toxic Effects of Massive Exposures As the exposure concentration increases, ammonia affects not only the upper airways, it can also cause pulmonary or alveolar injuries (Hatton et al., 1979). All our knowledge of the toxic effects of ammonia at high concentrations in humans is generated from our experiences with accidental ammonia releases, in which there are no data on the exposure concentrations. However, via qualitative characterization of the exposure and response, the toxic effects of massive ammonia exposures can be separated into six groups. Most accidental ammonia releases involved a rupture of refrigerant storage tanks, tank trucks, or railroad tank cars containing many gallons of anhydrous liquid ammonia (Price et al., 1983; Close et al., 1980; Montague and Macneil, 1980; Kass et al., 1972; Flury et al., 1983). In the first group of cases, the victims were situated close enough to the ruptured tank that they came in direct contact with anhydrous ammonia and also inhaled the ammonia vapor at presumably very high concentrations (Close et al., 1980). According to Close et al., victims in this group died shortly afterward with severe chemical burns over most of the body, full-thickness chemical burns of the entire tracheobronchial tree, and extensive pulmonary edema. In the second group, the fatal course was more prolonged than in the first group (Arwood et al., 1985; Price et al., 1983). Immediately after the accident, the victims developed chemical burns over the face, eyes, oropharynx, back, and legs. Arwood et al. reported that some of them rapidly developed corneal opacities. Within a day, according to Price et al., some of them were coughing up large quantities of greenish mucus. Both studies reported severe respiratory distress, tachypnea, dyspnea, pulmonary edema, crackles or wheezing over the lung fields, and bilateral pulmonary infiltrates in chest x-ray. Hypoxemia began in the first or second day and remained until death. The hypoxemia showed a variable course of steady deterioration, oscillating between deterioration and improvement, or remaining constant with time. The victims died in 10 d to 12 w. The two victims who died in 10-16 d were oliguric a few days before death, and their autopsies showed lung congestion with purulent exudates in smaller bronchi, necrotizing bronchitis with ulceration and membrane formation, and severe intraalveolar fibroblastic proliferation (Arwood et al., 1985). For the victim who died 12 w after the exposure, an autopsy revealed

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants patchy ulceration and squamous metaplasia of bronchi, whose mucosa were partially replaced by granulation tissue, bronchiectasis, peribronchiolar fibrosis, patchy congestion and edema of the alveolar region (Price et al., 1983). Similarly, Kass et al. (1972) reported radiological studies showing bronchiectatic changes in two victums 2 y after a massive exposure to ammonia. Unlike the victims who died in 10-16 d in the study of Arwood et al. (985), Price et al. (1983) reported that the victim who died in 12 w did not have fibrosis of the alveolar region. This victim also developed severe airflow obstruction, which got worse with time, in the last 8 w. Airflow obstruction was also detected by Kass et al. (1972) and Flury et al. (1983) in three victims 1-2 y after a massive exposure to ammonia. The victims of the remaining three groups did not die from the ammonia exposure. The third group of victims were also exposed to anhydrous ammonia cutaneously and to ammonia vapor via inhalation, but they survived. They sustained chemical burns of the face and the mucous membranes of the upper airway (Close et al., 1980). There was also acute upper airway obstruction. Close et al. postulated that the upper airway obstruction might have protected the remainder of the tracheobronchial tree from the harmful effects of ammonia vapor. Although the acute airway obstruction was life-threatening, the victims probably did not die from that because they were rescued and hospitalized after less than 30 min of exposure, when emergency airways were created for them (Close et al., 1980). These victims developed inspiratory wheezing, rhonchi, and rales. They recovered in 1-2 mo and did not develop any pulmonary sequelae afterward. The fourth group of victims were in the vicinity of the ruptured tank without coming in direct contact with the liquid ammonia, but they did inhale the gaseous ammonia for longer than 30 min (Close et al., 1980). Close et al. reported that they all had first-degree chemical burns of the eyes, face, and exposed skin, but they had no acute upper airway obstruction. Initially the victims appeared to have sustained very little internal injuries because, upon hospital admission, both the chest examination and x-ray were normal and only one of nine of the victims developed hypoxemia. Because the victims did not develop upper airway obstruction acutely, their lungs were not protected against ammonia at concentrations too low to cause acute lung damage but sufficient to lead to insidious lung damage. During the next 2 to 6 mo, obstructive pulmonary function gradually developed, followed by a slight improvement and then stabiliza-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants tion. The moderate obstructive pulmonary function with considerable bronchoalveolar perfusion deficits remained constant for the next 2 y (Close et al., 1980). Both the fifth and sixth groups of victims were exposed to high concentrations of gaseous ammonia for several seconds to several minutes (Montague and Macneil, 1980). Montague and Macneil reported that in day 1 both groups had inflammation of conjunctiva and pharynx, pain in the pharynx and chest, cough, and dyspnea, but there were no chest x-ray abnormalities. The major difference between the fifth and sixth groups was their results in chest examinations. Based on this study, Montague and Macneil concluded that, in terms of predicting the clinical course of ammonia inhalation, chest x-ray is of little value, and chest examinations are much more important (Montague and Macneil, 1980). In chest examinations, the fifth group exhibited abnormalities, such as rales, rhonchi, or wheezing, while the sixth group had no abnormalities. The fifth group developed moderate hypoxemia, but the sixth group had only mild hypoxemia. In addition, the fifth group had tachypnea and tachycardia. The sixth group recovered on the second day after the exposure. In contrast, the fifth group developed airway obstruction and productive cough in the next several days. The fifth group finally recovered about 1 w after the exposure (Montague and Macneil, 1980). In summary, massive ammonia exposures usually cause chemical burns of the face, eyes, pharynx, or even the torso; some degree of mucosal injury of the tracheobronchial tree; productive cough; and hypoxemia. Airway obstruction is produced either acutely or as a sequelae. If the exposure is severe, there can be deep lung injuries, resulting in acute rales, rhonchi, or wheezing and bronchiectasis later. Animal Models of Ammonia's Respiratory Damage Niden (1968) demonstrated ultrastructural damage to the respiratory system of mice exposed to an extremely high concentration of ammonia, an exposure probably similar to that of the first group of human victims. He exposed mice to 28% ammonia, which killed the mice in 3 to 60 min. He found an increase in the number of secretory granules in Clara cells and the ballooning of Clara cells. Mitochondrial and endoplasmic swelling in

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants type II pneumocytes, extensive swelling of the alveolar epithelium with edema fluid, and intracapillary platelet thrombosis in the lung also occurred. The biphasic nature of ammonia's damage to the respiratory system seen in the fourth group of human victims has been reproduced somewhat by Dodd and Gross (1980) in cats exposed to 1000 ppm ammonia for 10 min. In the first day after exposure, the cats exhibited necrotizing bronchitis primarily in the large bronchi, but the bronchioles were hardly damaged and the centriacinus was normal, indicating that the bronchoconstriction reflexes protected deep parts of the lung. Pulmonary function reflected the pathology in these cats. Increases in the work of breathing, airway resistance, and pulmonary tissue resistance agreed with pathological changes in the air conducting pathways, and a lack of change in the functional residual capacity agreed with the lack of central lung damage. On the seventh day after exposure, the mucosal lesions were healed, but pulmonary congestion, edema, and interstitial emphysema still existed. The increases in the work of breathing and airway resistance disappeared on the seventh day. However, both pulmonary resistance and pulmonary tissue resistance were increased. On the 21st day after exposure, bronchitis, bronchiolitis, early bronchopneumonia, and scattered bulbous emphysema had developed, which the investigators felt represented sequelae of the initial chemical insult (Dodd and Gross, 1980). Even though there were no differences, compared with the values before exposure, in airway resistance, increases were seen in the functional residual capacity, work of breathing, pulmonary resistance, and pulmonary tissue resistance on the 21st day (Dodd and Gross, 1980). Metabolic Acidosis Although mucosal irritation is its major toxicity, ammonia could cause a systemic effect. Manninen et al. (1988) exposed rats to ammonia at 25 or 300 ppm, 6 h/d for 5, 10, or 15 d. They found metabolic acidosis after 5 d of exposure at both concentrations. However, the metabolic disturbance is not long lasting because it disappeared in later time points. After a 15-d exposure to 25 or 300 ppm, Manninen et al. failed to find any treatment-related histopathology in the lung, liver, and kidney.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 2-2 Toxicity Summarya Concentration Exposure Duration Species Effects Reference 2.8 ppm 35 d Human No changes in blood cells and acid-base equilibrium. Petruk et al., 1980 9.2 ppm Up to 12 y Worker (adapted) No increase in irritation complaints and respiratory symptoms. No change in pulmonary function. Holness et al., 1989 19 ppm 7-8 h Human Increases of urea and ammonia in blood and urine. Kustou, 1967 20 ppm N.S.b Worker (unadapted) Eye and respiratory discomfort. Vigliani and Zurlo, 1956 20 ppm N.S. Worker (adapted) Slight conjunctival erythema, but no discomfort. Vigliani and Zurlo, 1956 20-25 ppm N.S. Worker Maximal concentration not leading to significant complaints in a survey. Hatton et al., 1979 25 ppm 2 h Worker (inured) Mucosal irritation in 1 of 4 workers. Grant, 1974 30 ppm 10 min Human (uninured) Mucosal irritation just perceptible in 2 of 5 subjects. MacEwen et al., 1970 32 ppm 5 min Human Slight nasal dryness in 10% of the subjects. (Industrial Bio-Test Laboratories, 1973) 50 ppm 5 min Human Slight nasal dryness in 20% of the subjects. (Industrial Bio-Test Laboratories, 1973) 50 ppm 10 min Human (uninured) Moderate irritation in 4 of 6 subjects; just perceptible in 1 of 6. MacEwen et al., 1970 50 ppm 2 h Human (uninured) Irritation just perceptible. Verberk, 1977 55 ppm 15 s Human Lachrymation. Douglas and Coe, 1987

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 72 or 134 ppm 5 min Human Irritation of eyes, nose, throat, and chest. (Industrial Bio-Test Laboratories, 1973) 72 ppm N.S. Human Reduction in respiratory rate and minute volume during exercise. Cole et al., 1977 80 ppm 2 h Human (uninured) Irritation in between just perceptible and distinctively perceptible. Verberk, 1977 85 ppm 10 breaths Human Bronchoconstriction if breathed through the mouth with the nose clipped. Douglas and Coe, 1987 100 ppm h Human Tolerated. Helmers et al., 1971 110 ppm 2 h Human (uninured) Irritation in between distinctively perceptible and a nuisance. Verberk, 1977 130-150 ppm N.S. Human (adapted) Tolerated. Ferguson et al., 1977 140 ppm 1 h Human (uninured) Eye irritation became a nuisance. Throat irritation was in between just perceptible and offensive. Verberk, 1977 140 ppm N.S. Human Slight eye irritation. Grant, 1974 300 ppm 30 s Human (adapted) Barely tolerated. Ferguson et al., 1977 408 ppm N.S. Human Throat irritation. Helmers et al., 1971 495 ppm N.S. Human Reduction in minute volume, rapid shallow breathing during submaximal exercise. Cole et al., 1977 500 ppm 30 min Human Severe irritation of eyes, nose, and throat; increased tidal volume and respiratory rate. Silverman, 1949 700 ppm N.S. Human Severe eye irritation. Grant, 1974 1700 ppm N.S. Human Laryngospasm. Helmers et al., 1971

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 2500 ppm 0.5 h Human Death is possible. Helmers et al., 1971 2500-6500 ppm N.S. Human Severe eye irritation, bronchospasm, dypsnea and lung irritation. Hatton et al., 1979 3 ppm N.S. Rat Cilia stopped beating in respiratory tract. Dalhamn, 1956 25 ppm 6 h/d, 15 d Rat Metabolic acidosis on day 5, recovery on day 15. Manninen et al., 1988 50 ppm, followed by 100 ppm 2.5-3 h Rabbit Decrease in respiratory rate, increases in respiratory depth and blood urea nitrogen. Mayan and Merilan, 1972 57 ppm 24 h/d, 114 d Monkey, dog, rabbit, guinea pig, rat No significant histological change. Coon et al., 1970 100 ppm N.S. Rabbit Beating of cilia in trachea affected. Dalhamn and Sjoholm, 1963 100 ppm and 7 mg/m3 of carbon 6 mon Rats Synergism: severe mucosal damage and ciliary impairment. Dalhamn and Reid, 1967 100 or 300 ppm 6 h Mouse, rat Reduction in wheel running activity. Tepper et al., 1985 180 ppm 24 h/d, 90 d Rat No adverse histological effects. Coon et al., 1970 219 ppm 8 h/d, 5 d/w, 6 w Monkey, dog, rabbit, guinea pig, rat No adverse histological effects. Coon et al., 1970

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants 303 ppm 6 h/d, 5 d Mouse Microscopic injury of the nasal mucosa. Buckley et al., 1984 305 ppm 4 h Rat No effect on pulmonary surfactant activity. Sraubaev and Ivanov, 1976 371 ppm 24 h/d, 90 d Rat Mild nasal discharge. Coon et al., 1970 643 ppm 24 h/d, 90 d Rat 50/51 mortality, mild signs of dypsnea and nasal irritation. Coon et al., 1970 665 ppm 24 h/d, 90 d Monkey, dog, rabbit, guinea pig, rat Marked eye irritation, nasal discharge, interstitial pneumonitis, some deaths of rats and guinea pigs. Coon et al., 1970 1089 ppm 8 h/d, 5 d/w, 6 w Monkey, dog, rabbit, guinea pig, rat No histological changes that could definitely be attributed to the exposure. Coon et al., 1970 2000 ppm 4 h Rat Half died. NIOSH, 1987 4230 ppm 1 h Mouse Half died. Kapeghian et al., 1982 7338 ppm 1 h Rat Half died. Vernot et al., 1977 16,600 ppm 60 min Rat Half died. Appelman et al., 1982 20,300 ppm 40 min Rat Half died. Appelman et al., 1982 21,430 ppm 39 min Mouse Half died. Hilado et al., 1977 28,595 ppm 20 min Rat Half died. Appelman et al., 1982 40,300 ppm 10 min Rat Half died. Appelman et al., 1982 a Only the results from inhalation studies were included. b N.S. = not specified.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 2-3 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 25 (TWA) OSHA's PEL 50 (TWA) NIOSH's REL 50 (5-min ceiling) NIOSH's IDLH 50 NRC's 1-h EEGL 100 NRC's 24-h EEGL 100 NRC's CEGL 50 TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. REL = recommended exposure limit. IDLH = immediately dangerous to life and health. EEGL = emergency exposure guida nce level. CEGL = continuous exposure guidance level. TABLE 2-4 Spacecraft Maximum Allowable Concentrations Durationa ppm mg/m3 Target Toxicity 1 h 30 20 Irritation 24 h 20 14 Irritation 7 db 10 7 Irritation 30 d 10 7 Irritation 180 d 10 7 Irritation a These SMACs are ceiling values. b The current 7-d SMAC = 25 ppm. RATIONALE The SMACs for ammonia should be set based on mucosal irritation, which is the major toxic end point of ammonia inhalation at low-to-moderate concentrations. Vigliani and Zurlo (1956) noted that the adaptation status of workers played an important role in ammonia's irritation response. Based on their industrial experiences (they studied the health effects in workers and measured the ammonia concentrations in various industrial plants), Vigliani and Zurlo reported that 20-ppm ammonia could produce eye and nose discomfort in unadapted workers, but no complaints in adapted workers. Although 20 ppm elicited no complaints from the

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants adapted workers, there was conjunctival erythema (Vigliani and Zurlo, 1956). That means ammonia can cause mild inflammation in a person who has adapted to ammonia's irritation sensation. Therefore, the irritation sensation of adapted workers should not be used to set SMACs for ammonia because unadapted astronauts could be sensitive to levels tolerated by adapted workers. Consequently, in setting the SMACs, an emphasis is placed on irritation data on unadapted subjects. 1-h SMAC and 24-h SMAC The 1-h and 24-h SMACs are intended for emergencies, so a potential of some discomfort is acceptable. However, the 1-h and 24-h SMACs should not be set at levels that produce more than slight mucosal irritation. In eight uninured human volunteers studied by Verberk, 50-ppm ammonia was found to cause irritation that was, on the average, “just perceptible ” in 2 h (Verberk, 1977). When the individual eye-irritation responses of the eight uninured volunteers exposed to 50-ppm ammonia for 2 h in Verberk's study were examined, it was discovered that the individual responses ranged from “no sensation,” “just perceptible,” “distinctively perceptible,” to “nuisance.” Although none of the eight uninured volunteers experienced “offensive” eye irritation in the 2-h exposure at 50 ppm, it is obvious that 50 ppm could be irritating in some people. Without citing any data, Ellenhorn and Barceloux (1988) stated that, upon an ammonia exposure, “eye and nasal irritation begins near 50 ppm.” According to Ellenhorn and Barceloux, ammonia concentrations below 50 ppm should be nonirritating. However, the lack of data support casts doubt on the accuracy of the statement of Ellenhorn and Barceloux. Indeed, there were investigators who contradicted their statement by reporting irritation at ammonia concentrations below 50 ppm. For instance, MacEwen et al. (1970) reported that 30-ppm ammonia caused just perceptible mucosal irritation in two of five uninured human subjects in 10 min. Ferguson et al. (1977) cited an industrial hygiene report made by Mangold at the Puget Sound Naval Shipyard that workers engaged in diazo copying complained of discomfort and annoyance with 20 ppm of ammonia. Vigliani and Zurlo (1956) also reported that 20-ppm ammonia could cause eye and respiratory discomfort in unadapted workers. These human data on ammonia's mucosal irritation are tabulated in Table 2-5.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants TABLE 2-5 Ammonia's Mucosal Irritation in Humans Concentration, ppm Time Exposed Subjects Effect Reference 20 Occupational Unadapted workers in manufacturing plants for NH3, nitrate, and urea Eye and respiratory discomfort Vigliani and Zurlo, 1956 20 Occupational Workers in a naval shipyard Discomfort and annoyance Ferguson et al., 1977 30 10 min 2 of 5 unadapted subjects Irritation just perceptible MacEwen et al., 1970 Because 30-ppm ammonia caused only just perceptible irritation in 10 min, it is not expected to produce more than mild irritation in 1 h. The 1-h SMAC is, therefore, set at 30 ppm. Although some irritation is acceptable for the 24-h SMAC, it should be set lower than the 1-h SMAC to reduce the degree of slight irritation astronauts have to endure in a 24-h contingency. Since 20-ppm ammonia has been shown to produce only eye and nose discomfort in workers (Vigliani and Zurlo, 1956; Ferguson et al., 1977), the 24-h SMAC is set at 20 ppm. It should be noted that, even though the 1-h SMAC was based on the response in only five subjects, no adjustment for a “small n” is needed owing to the fact that a certain degree of mucosal irritation is acceptable in a 1-h or 24-h contingencies, so a smaller margin of safety is acceptable in the derivation of the 1-h and 24-h SMACs based on irritation. 7-d SMAC There are no data on the effect of ammonia on humans after long-term continuous exposures. A continuous exposure to ammonia at 57 ppm for 114 d or 180 ppm for 90 d produced no adverse histological effects on monkeys, dogs, rats, and rabbits (Coon et al., 1970). However, the 7-d, 30-d, and 180-d SMACs are not set relying on these animal data because the data provide no information on irritation sensation of ammonia.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants The 7-d SMAC should be set at the maximum nonirritating level. Unfortunately, there are no data on that level. We know that 20 ppm caused some discomfort in workers in Italy (Vigliani and Zurlo, 1956), so the 7-d SMAC should be lower than 20 ppm. Although 20 ppm is the lowest-observed-adverse-effect level (LOAEL), the traditional factor of 10 to derive a no-observed-adverse-effect level (NOAEL) from a LOAEL will not be used because there are concentration-response data. In the study of Verberk, when the 1-h ammonia concentration was reduced 43% from 140 ppm to 80 ppm, the eye irritation went from “nuisance” to between “just perceptible” and “distinctly perceptible” (Verberk, 1977). In the same study, a 37% decrease in ammonia concentration from 80 ppm to 50 ppm caused the irritation sensation to drop from being between “just perceptible” and “distinctively noticeable” to “just noticeable.” In another report, as the 10-min inhalation concentration is reduced by 40% from 50 ppm to 30 ppm, the irritation decreases from “moderate” to “just perceptible” (MacEwen et al., 1970). Although the irritation effects were characterized subjectively and qualitatively in these studies, as long as we compare the effects within the same study group, the qualitative differences should give us an idea of the concentration response of ammonia. From these comparisons, it can be concluded that a 50% reduction of the 20-ppm discomfort level (Vigliani and Zurlo, 1956) should yield a level that does not produce irritation or discomfort. Ten parts per million is selected as the 7-d NOAEL. Because the 7-d NOAEL was derived from the experience of Vigliani and Zurlo with workers in various manufacturing plants with ammonia exposures in Italy (Vigliani and Zurlo, 1956), the NOAEL is based on a sufficiently large human population, requiring no “small n” adjustment. Accordingly, the 7-d SMAC is set at the 7-d NOAEL of 10 ppm. 30-d SMAC and 180-d SMAC Because of adaptation, a level that is nonirritating in 7 d should remain nonirritating up to 180 d. Consequently, the 30-d and 180-d SMACs are also set at 10 ppm. Ten parts per million appears to be appropriate because workers exposed to ammonia at 9.2 ppm for up to 12 y did not complain of irritation any more than nonexposed workers did (Holness et

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants al., 1989). Finally, because mucosal irritation is a surface response, the SMACs need not be adjusted for any microgravity-induced physiological changes. REFERENCES ACGIH. 1986. Threshold Limit Values and Biological Exposure Indices for 1986-87. American Conference of Governmental Industrial Hygienists , Cincinnati, Ohio. Appelman, L.J., W.F. ten Berge, and P.G.J. Reuzel. 1982. Acute inhalation toxicity study of ammonia in rats with variable exposure periods. Am. Ind. Hyg. Assoc. J. 43:662-665. Arwood, R., J. Hammond, and G. Gillon. 1985. Ammonia inhalation. Trauma 25:444-447. Buckley, L.A., X.Z. Jiang, R.A. James, K.T. Morgan, and C.S. Barrow. 1984. Respiratory tract lesions induced by sensory irritants at the RD50 concentration. Toxicol. Appl. Pharmacol. 74:417-429. Close, L.G., F.I. Catlin, and A.M. Cohn. 1980. Acute and chronic effects of ammonia burns of the respiratory tract. Arch. Otolaryngol. 106:151-158. Cole, T.J., J.E. Cotes, G.R. Johnson, H.D. Martin, J.W. Reed, and J.E. Saunders. 1977. Ventilation, cardiac frequency and pattern of breathing during exercise in men exposed to 0-chlorobenzylidene melononitrile (CS) and ammonia gas in low concentrations. Q.J. Exp. Physiol. Cogn. Med. Sci. 62:341-51. Coon, R.A., R.A. Jones, L.J. Jenkins, Jr., and J. Siegel. 1970. Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol. Appl. Pharmacol. 16:646-655. Dalhamn, T. 1956. Mucous flow and ciliary activity in the trachea of healthy rats and rats exposed to respiratory irritant (SO2, NH3, HCHO). VIII. The reaction of the tracheal ciliary activity to single exposure to respiratory irritant gases and studies of the pH. Acta Physiol. Scand. Suppl. 123:93-97. Dalhamn, T. and L. Reid. 1967. P. 299 in Inhaled Particles and Vapours II. C.N. Davies , ed. Pergamon, New York, N.Y. Dalhamn, T. and J. Sjoholm. 1963. Studies on SO2 and NH3—Effect on ciliary activity in the rabbit trachea of single in vitro exposure and

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants resorption in rabbit nasal cavity. Acta Physiol. Scand. 58:287-91. Diamondstone, T.I. 1982. Amino acid metabolism. I. P. 544 in Textbook of Biochemistry with Clinical Correlations. T.M. Devlin , ed. John Wiley & Sons. New York, N.Y. Dodd, K.T. and D.R. Gross. 1980. Ammonia inhalation toxicity in cats: A study of acute and chronic respiratory dysfunction. Arch. Environ. Health 35:6-14. Douglas, R.B. and J.E. Coe. 1987. The relative sensitivity of the human eye and lung to irritant gases. Ann. Occup. Hyg. 31:265-267. Eastman, R.D. 1963. P. 13 in Biochemical Values in Clinical Medicine. Wright, Bristol, U.K. Ellenhorn, M.J. and D.G. Barceloux. 1988. Airborne toxins. P. 871 in Medical Toxicology. Diagnosis and Treatment of Human Poisoning. Elsevier, New York, N.Y. Ferguson, W.S., W.C. Koch, L.B. Webster, and J.B. Gould. 1977. Human physiological response and adaptation to ammonia. J. Occup. Med. 19:319- 326. Flury, K.E., D.E. Dines, J.R. Rodarte, and R. Rodgers. 1983. Airway obstruction due to inhalation of ammonia. Mayo Clin. Proc. 58:389-393. Grant, W.M. 1974. Pp. 121-128 in Toxicology of the Eye. Charles Thomas, Springfield, Ill. Hatton, D.V., C.S. Leach, A.L. Beaudet, R.O. Dillman, and N. Di Ferrante. 1979. Collagen breakdown and ammonia inhalation. Arch. Environ. Health 34:83-87. Helmers, S., F.H. Top, and L.W. Knapp. 1971. Ammonia injuries in agriculture. J. Iowa Med. Soc. 61:271-280. Henderson, Y. and H.W. Haggard. 1943. Noxious Gases and the Principles of Respiration Influencing Their Action. Chemical Catalog , New York, N.Y. Hilado, C.J., C.J. Casey, and A. Furst. 1977. Effect of ammonia on Swiss albino mice. J. Combust. Toxicol. 4:385-388. Holness, D.L., J.T. Purdham, and J.R. Nethercott. 1989. Acute and chronic respiratory effects of occupational exposure to ammonia. Am. Ind. Hyg. Assoc. J. 50:646-650. Industrial Bio-Test Laboratories. 1973. Irritation Threshold Evaluation Study with Animals. Report to International Institute of Ammonia Refrigeration. IBT 663-03161 , March 1973.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Kapeghian, J.C., H.H. Mincer, A.B. Jones, A.J. Verlangieri, and I.W. Waters. 1982. Acute inhalation toxicity of ammonia in mice. Bull. Environ. Contam. Toxicol. 29:371-378. Kass, I., N. Zamel, C.A. Dobry, and M. Holzer. 1972. Bronchiectasis following ammonia burns of the respiratory tract. Chest 62:282-285. Kustou, U.U. 1967. Means of Measuring the Maximum Allowable Concentrations of Toxic Products of Natural Human Metabolism. NASA Report, Oct. 1967. Landahl, H.D. and R.G. Herrmann. 1950. Retention of vapors and gases in the human nose and lung. Arch. Ind. Hyg. Occup. Med. 1:36-45. MacEwen, J.D., J. Theodore, and E.H. Vernot. 1970. Human exposure to EEL concentrations of monomethylhydrazine. Proc. 1st Ann. Conf. Environ. Toxicol. , AMRL-TR-70-102, Paper 23, Sept. 1970. Wright-Patterson Air Force Base, Dayton, Ohio. Manninen, A., S. Anttila, and H. Savolainen. 1988. Rat metabolic adaptation to ammonia inhalation. Proc. Soc. Exp. Biol. Med. 187:278-281. Mayan, M.H. and C.P. Merilan. 1972. Effects ammonia inhalation on respiration rate of rabbits. J. Animal Sci. 34:448-452. Montague, T.J. and A.R. Macneil. 1980. Mass ammonia inhalation. Chest 77:496-498. NIOSH. 1987. Registry of the Toxic Effects of Chemical Substances. DHHS (NIOSH) Publ. No. 87-114. National Institute for Occupational Safety and Health, Cincinnati, Ohio. Niden, A.H. 1968. Effects of Ammonia inhalation on the terminal airways. Pp. 41-44 in Proceedings of the 11th Aspen Emphysema Conference. Aspen, Colo. O'Kane, G.J. 1983. Inhalation of ammonia vapour. Anaesthesia 38:1208-1213. Petruk, Y.A., I.D. Makulova, and I.M. Suvorov. 1980. Evaluation of the effect of prolonged and continuous exposure of a human subject to low (2 mg/m3) ammonia concentrations under conditions of an airtight chamber. Gig. Tr. Prof. Zabol. 12:63. Price, S.K., J.E. Hughes, S.C. Morrison, and P.D. Potgieter. 1983. Fatal ammonia inhalation. A case report with autopsy findings. Sa. Mediese. Tydskrif. 64:952-955. Silverman, L. 1949. Physiological response of man to ammonia at low concentrations. J. Ind. Hyg. Toxicol. 31:74-78.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Sraubaev, E.N. and N.G. Ivanov. 1976. [Study of the activity of the pulmonary surfactant in determining the threshold of the irritating action of industrial poisons]. Gig. Tr. Prof. Zabol. 10:47-48 . Tepper, J.S., B. Weiss, and R.W. Wood. 1985. Alterations in behavior produced by inhaled ozone or ammonia. Fund. Appl. Toxicol. 5:1110-1118 . TLV Committee. 1986. Documentation of TLV's and BEI's. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Verberk, M.M. 1977. Effects of ammonia in volunteers. Int. Arch. Occup. Environ. Health 39:73-81 . Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42:417-423 . Vigliani, E.C. and N. Zurlo. 1956. Ehfahrungen der clinica del lavoro mit einigen maximalen arbeitsplatzkonzentrationen (MAK) ven industrieniften. Arch. Gewerbepathol. Gewerbehyg. 13:528-534 . Vollmuth, T.A. and R.B. Schlesinger. 1984. Measurement of respiratory tract ammonia in the rabbit and implications to sulfuric acid inhalation studies. Fund. Appl. Toxicol. 4:455-464 . Weatherby, J.H. 1952. Chronic toxicity of ammonia fumes by inhalation. Proc. Soc. Exp. Biol. Med. 81:300-301 . White, A., P. Handler, E.L. Smith, R.L. Hill, and I.R. Lehman. 1978. Amino acid metabolism. II. Pp 695-700 in Principles of Biochemistry. McGraw-Hill, New York, N.Y.

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