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9
Sulfur Dioxide

This chapter reviews the physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on sulfur dioxide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to sulfur dioxide.

BACKGROUND INFORMATION

Sulfur dioxide is a colorless, water-soluble irritant gas (Costa and Amdur 1996). It can be detected by taste at concentrations of 0.35–1.05 ppm (parts per million) and has an immediate pungent irritating odor at a concentration of 3.5 ppm (WHO 1984). It has been termed a “mild irritant” (Amdur 1969). Ambient sulfur dioxide can react with oxygen to form sulfur trioxide, which then reacts with water (on moist surfaces) to produce sulfuric acid. Sulfur dioxide also can react with water to form sulfurous acid, which dissociates to sulfite and bisulfite ions. The chemical and physical properties of sulfur dioxide are presented in Table 9–1.



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Review of Submarine Escape Action Levels for Selected Chemicals 9 Sulfur Dioxide This chapter reviews the physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on sulfur dioxide. The Subcommittee on Submarine Escape Action Levels used this information to assess the health risk to Navy personnel aboard a disabled submarine and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and recommends research relevant for determining the health risk attributable to exposure to sulfur dioxide. BACKGROUND INFORMATION Sulfur dioxide is a colorless, water-soluble irritant gas (Costa and Amdur 1996). It can be detected by taste at concentrations of 0.35–1.05 ppm (parts per million) and has an immediate pungent irritating odor at a concentration of 3.5 ppm (WHO 1984). It has been termed a “mild irritant” (Amdur 1969). Ambient sulfur dioxide can react with oxygen to form sulfur trioxide, which then reacts with water (on moist surfaces) to produce sulfuric acid. Sulfur dioxide also can react with water to form sulfurous acid, which dissociates to sulfite and bisulfite ions. The chemical and physical properties of sulfur dioxide are presented in Table 9–1.

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 9–1 Physical and Chemical Properties for Sulfur Dioxide Characteristic Value Molecular formula SO2 Synonyms Sulfurous anhydride, sulfurous oxide, sulfur oxide, sulfurous acid anhydride Molecular weight 64.07 CAS number 7446–09–5 Solubility Soluble in water, alcohol, acetic acid, sulfuric acid, ether, and chloroform Density 2.811 g/L Vapor pressure 3×10–3 mm Hg at 25°C Saturated vapor pressure 0.47 lb/ft3 at 15°C Melting point –72°C Boiling point –10°C Conversion factors in air, 1 atm 1 ppm=2.6 mg/m3 1 mg/m3=0.38ppm Abbreviation: CAS, Chemical Abstracts Service. Source: NRC (1984); Budavari (1989); ACGIH (1994); ATSDR (1998); HSDB (2000). Sulfur dioxide is formed when materials containing sulfur are burned. It is a primary air pollutant emitted by smelters and electrical power plants that burn coal or oil. Sulfur dioxide is found at concentrations of 1–10 parts per billion (ppb) in clean ambient air, and at 20–200 ppb in polluted air (Seinfeld 1986). Sulfur dioxide also is used in treating wood pulp for paper manufacturing; in ore and metal refining; in extraction of lubricating oils; as a bleaching, disinfecting, and fumigating agent; as a food additive and preservative; and as a reducing agent. Sulfur dioxide is a precursor to acid sulfates, which generally are more toxic; therefore, recent research has focused on those compounds (Costa and Amdur 1996). TOXICOKINETIC CONSIDERATIONS Absorption Sulfur dioxide is primarily an upper airway and eye irritant. In the airways, it produces bronchoconstriction and mucous secretion. Because of its high water

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Review of Submarine Escape Action Levels for Selected Chemicals solubility, sulfur dioxide appears to react in airway and lung fluids to produce sulfite (SO32–) or bisulfite (HSO3–) ions, but itself can be rapidly absorbed. The bisulfite ion is a direct irritant and it inhibits mucociliary transport (Costa and Amdur 1996). The irritation results in parasympathetic stimulation producing smooth muscle contraction and mucous secretion (HSDB 2000). Studies in humans and animals suggest that 40–90% of inhaled sulfur dioxide is absorbed in the upper respiratory tract (WHO 1979). Two factors affect the efficiency of absorption in the respiratory tract: the mode of breathing (oral versus oronasal) and the ventilation rate. Penetration of sulfur dioxide to the lungs is greater during mouth breathing than during nose breathing, as sulfur dioxide is readily removed during passage through the upper respiratory tract. An increase in ventilation rate, for example during exercise, increases penetration of sulfur dioxide to the deeper lung (Costa and Amdur 1996). In rabbits exposed to 100, 200, or 300 ppm, 90–95% of the sulfur dioxide was found to be absorbed by tissues in the upper respiratory tract (Dalhamn and Strandberg 1961), and the rate of absorption in the nasal cavity was greater than that in the mouth or pharynx. Strandberg (1964) determined that in rabbits, the amount of sulfur dioxide absorbed depends on concentration. Rabbits exposed to high concentrations (≥100 ppm) had ≥90% absorption; at low concentrations (≥0.1 ppm), absorption was about 40%. The reasons for these different rates of absorption with varying concentration are not clear. In dogs, more than 99% of inhaled sulfur dioxide is absorbed by the nose at exposure of 2.9–140 mg/m3 (1–50 ppm). Similar absorption rates have been observed in studies of human volunteers who were exposed to concentrations ranging from 2.9 to 420 mg/m3 (1–140 ppm) for a few minutes at the higher concentrations and for 30–40 min at the lower concentrations (WHO 1979). Speizer and Frank (1966) observed that, in human subjects breathing through a mask and exposed to 16.1 ppm for 30 min, 12% of the sulfur dioxide taken up by the tissues in inspiration reentered the airstream in expiration and that another 3% was desorbed during the first 15 min after the end of the exposure. The authors concluded that 12–15% of sulfur dioxide absorbed on nasal mucosa is desorbed and exhaled. The remaining sulfur dioxide and metabolites are absorbed into the systemic circulation or are delivered to the lower respiratory system by repeated absorption and desorption from mucosa (Frank et al. 1969). Frank et al. (1967) reported sulfur dioxide in the lungs of dogs that apparently was carried by the blood after nasal deposition. Systemic absorption of sulfur dioxide metabolites from tissues of the upper respiratory tract has been demonstrated in animals. In dogs a small segment of trachea was isolated and perfused with radiolabeled sulfur dioxide (35SO2) while the lungs were ventilated with auto prevent entry of the 35SO2 (Balchum et al. 1959). Detection of 35S in lungs, liver, spleen, and kidneys indicated systemic absorption from the tracheal mucosa.

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Review of Submarine Escape Action Levels for Selected Chemicals Distribution Most inhaled sulfur dioxide is absorbed into the bloodstream, widely distributed throughout the body, and rapidly metabolized to sulfate by the sulfite oxidase enzyme system. Sulfate is then primarily excreted by way of the urinary tract (HSDB 2000). However, results from studies that used 35S indicate that some residual sulfur dioxide can persist in the respiratory system for a week or more after exposure possibly as a result of the sulfur binding with protein (Yokoyama et al. 1971 as cited in Costa and Amdur 1996). In rabbits and human subjects, sulfite (metabolite of sulfur dioxide) that reaches the plasma has been shown to form S-sulfonate products (R-S-SO3–) by reacting with the disulfide bonds of proteins (Gunnison and Palmes 1974). Gunnison and Palmes (1974) exposed human subjects continuously to 0.3, 1.0, 3.0, 4.2, or 6.0 ppm sulfur dioxide for up to 12 h, determined that plasma sulfonate concentrations had a positive correlation with air concentrations of sulfur dioxide. Although the biochemical significance of these S-sulfonate products is not currently understood, their formation represents a biochemical alteration (Costa and Amdur 1996). Studies with dogs suggest that absorbed sulfur dioxide metabolites are readily distributed throughout the body (Frank et al. 1967; Yokoyama et al. 1971). Frank et al. (1969) exposed dogs to 22±2 ppm 35SO2 for 30–60 min and deteched radioactivity in the blood 5 min after the onset of exposure. It was estimated that 5% to 18% of the radioactive compound administered to the dogs was contained in the blood by the end of exposure. Balchum et al. (1959, 1960 a,b) examined radioactivity in dogs administered 35SO2. Dogs that inhaled 35SO2 through the nose and mouth at concentrations of 1–141 ppm had significant radioactivity in the upper airways; lower rates were exhibited in the trachea, lungs, hilar lymph nodes, liver, and spleen. Metabolism Although the primary effects of sulfur dioxide are on the respiratory tract, inhaled sulfur dioxide can be transferred into the systemic circulation. After its rapid absorption, inhaled sulfur dioxide is rapidly converted to a mixture of sulfite, bisulfite, and sulfur trioxide (ATSDR 1998):

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Review of Submarine Escape Action Levels for Selected Chemicals Sulfite and bisulfite ions can be oxidized to form plasma protein S-sulfonates. Bisulfite is further detoxified by sulfite oxidase, which is found primarily in liver mitochondria (Gunnison et al. 1987) and is excreted as sulfate ion in the urine. Sulfite oxidase also has been detected in other tissues, including kidney and heart (Cabre et al. 1990). Sulfite oxidase concentrations vary in animals and humans, and the efficiency of sulfite oxidation depends primarily on sulfite oxidase activity (Gunnison and Palmes 1974). Cohen et al. (1973) observed sulfite oxidase activity to be lower in the livers of young versus mature rats, sulfite oxidase activity in 1-d-old rats was one-tenth that of adults. Decreased activity of sulfite oxidase in sulfite-oxidase-deficient rats resulted in higher in vivo concentrations of sulfite, whereas sulfite-oxidase-competent rats exposed to sulfur dioxide lacked sulfite in the plasma (Gunnison et al. 1987). In humans, age-related differences have been observed in metabolism of sulfite to sulfate and in formation of sulfur trioxide (Constantin et al. 1996). Constantin et al. (1996) measured sulfur trioxide radicals and sulfite oxidase activity in polymorphonuclear leukocytes (PMNs) from four groups: young adults (average age 25), older adults (average age 65), 3 centenarians (older than 100), and Down syndrome patients. They found significantly increased amounts of sulfur trioxide radicals in PMNs from healthy adults who had low sulfite oxidase activity. In centenarians and Down syndrome patients, generation of the sulfur trioxide radical was the primary mechanism for detoxification of sulfite. There was no correlation between the sulfur trioxide radical and sulfite oxidase activity. Langley-Evans et al. (1996) observed decreased glutathione concentrations in the lungs of rats exposed to sulfur dioxide, suggesting that glutathione could operate in the detoxification process. Kågedal et al. (1986) conducted in vitro experiments demonstrating that sulfites—metabolites of sulfur dioxide—react with reduced glutathione to form S-sulfoglutathione. Elimination Studies on humans and dogs show that sulfur dioxide is excreted primarily in the urine as sulfate (Savic et al. 1987; Yokoyama et al. 1971). Yokoyama et al. (1971) exposed dogs via inhalation to 35SO2 and determined that 35S was excreted primarily in the urine as sulfate. An average of 84.4% of the urinary radioactivity was exhibited as inorganic sulfate; 92.4% was total sulfate. In humans it is estimated that 12–15% of sulfur dioxide absorbed to mucous membranes is desorbed and exhaled (Speizer and Frank 1966). Plasma S-sulfonates are relatively long-lived in the body, with half-life clearance of 4.1 d in rabbits exposed to 10 ppm sulfur dioxide (Gunnison and Palmes 1974).

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Review of Submarine Escape Action Levels for Selected Chemicals HUMAN TOXICITY DATA Many studies have examined the human health effects from exposure to sulfur dioxide. The next section examines the effects of experimental, accidental, occupational, and community exposures; however, more complete reviews are available in the Toxicological Profile for Sulfur Dioxide (ATSDR 1998); Air Quality Criteria for Particulate Matter and Sulfur Oxides (EPA 1982); and Supplement to the Second Addendum (1986) to Air Quality Criteria for Particulate Matter and Sulfur Oxides (1982) (EPA 1994a,b). Experimental Studies Table 9–2 summarizes exposure studies that used controlled exposures to sulfur dioxide. Mild irritation, bronchoconstriction, and decreased lung function, as assessed by measurements of specific airway resistance or decreases in forced expiratory volume or expiratory flow, are produced after exposure of healthy individuals to low concentrations of sulfur dioxide. People with asthma are more susceptible. Exercise, cold air, and airborne participates appear to exacerbate the toxic effects (Gong et al. 1995; Roger et al. 1985; Schachter et al. 1984; Stacy et al. 1981). Concentration seems to be more important than duration as a determinant of health effects. Initial atmospheric exposure to sulfur dioxide can result in immediate discomfort, irritation, and coughing that abate after gradual acclimation to increasing concentrations (Andersen et al. 1974). Health effects reported by healthy volunteers are summarized in Table 9–3. Accidental Exposures Several case reports detail accidental exposures to sulfur dioxide (Table 9–2). Those events involved inhalation and ocular exposures to unquantified concentrations, so dose-response determinations were not possible. Accidents have resulted in death, primarily from respiratory arrest (Charan et al. 1979; Galea 1964; Harkonen et al. 1983; Rabinovitch et al. 1989). Signs of intoxication preceding or found antecedent to death included bronchoconstriction, lung pathology, decreases in lung function; and ocular, nasal, and throat irritation (Charan et al. 1979; Galea 1964; Harkonen et al. 1983; Rabinovitch et al. 1989; Wunderlich et al. 1982). Survivors suffered bronchitis, bronchiolitis, bronchopneumonia, alveolitis, and emphysema (Galea 1964; Wunderlich et al. 1982).

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 9–2 Human Toxicity Data, Exposure to Sulfur Dioxide Subject Route Concentration (ppm) Duration Effect Reference EXPERIMENTAL STUDIES 14 healthy males Inhalation 1–8 10 min (through face mask) At 5 ppm, subjects complained of dryness in throat and upper respiratory passages; 1–8 ppm, decreased respiratory volume and increased respiratory rate were noted Amdur et al. 1953 31 non-smoking males, aged 18– 40 (individuals exercised on a treadmill 45 min after entering exposure chamber) Inhalation and intradermal tests for 16 allergens, including sulfur dioxide 16 Individuals, 0.75±0.04 ppm; 15 were exposed to air 2 h Airflow resistance increased 2–55% in 14 of 16 subjects following the first hour of exposure. Average increase in exposed subjects was 14.6%; average 10.3% decrease in control subjects; 8 exposed subjects with 1 or more positive allergen skin tests appeared to be significantly more reactive than subjects who tested negative in skin tests Stacy et al. 1981 8 healthy, nonsmoking individuals, 21– 29 years (subjects exercised for the last 15 minutes of exposure) Inhalation 0, 0.4, 2, or 4 20 min At 4 ppm, 5 of 8 subjects reported nasal irritation; throat irritation was more common (p<0.05) during than before exposure to 2 ppm; it was reported more frequently during and at the end of exposure to 4 ppm than before exposure (p<0.02) and more commonly (p<0.05) at the end of exposure to 4 ppm than at the end of 0.4 ppm exposure Sandstrom et al. 1988 14 healthy subjects, aged Inhalation 4 (10 subjects) or 8 (4 subjects) 20 min BAL parameters were measured. At 4 and 8 ppm, an increase in alveolar Sandstrom et al. 1989a

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Review of Submarine Escape Action Levels for Selected Chemicals 22–33 (individuals exercised during exposure)   macrophage activity (as measured by lysozyme positive macrophages) observed 24 h after exposure; at 8 ppm, an increase in total number of macrophages and lymphocytes; at 72 h, BAL fluid of 8 ppm exposure group returned to baseline.   22 healthy males, aged 22–27 (individuals exercised during exposure) Inhalation 8 20 min BAL observed 2 wk before exposure, and 4, 8, 24, and 72 h after exposure in 8 subjects; at 4 h, increased numbers of lysozyme-positive macrophages, lymphocytes, and mast cells observed; lymphocytes, lysozyme-positive macrophages, total alveolar macrophage counts, and total cell numbers reached a peak at 24 h post-exposure and returned to pre-exposure levels by 72 h Sandstrom et al. 1989b 22 healthy males, aged 22–37 Inhalation 4, 5, 8, or 11 20 min BAL observed 2 wk before exposure, and 4, 8, 24, and 72 h after exposure in 8 subjects; at 4, 5, 8, and 11 ppm, mast cells, lymphocytes, lysozyme-positive macrophages, and total number of macrophages increased in BAL fluid 24-h post-exposure, with the effects being concentration-dependent at 4, 5, and 8 ppm Sandstrom et al. 1989c 20 healthy, nonsmoking adults (10 females, 10 Inhalation 1 or filtered air 4 h 4 exposed subjects reported upper respiratory irritation and 1 reported ocular irritation; 7 exposed subjects perceived either due to odor and/or taste. Kulle et al. 1984

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Review of Submarine Escape Action Levels for Selected Chemicals Subject Route Concentration (ppm) Duration Effect Reference males), aged 20– 35 (each subject served as his/her own control and exercised for 15 min both 1 and 3 h into the exposure period)   11 healthy adult males Inhalation (mouth breathing) 0, 1, 5, or 13 10–30 min At 13 and 5 ppm, pulmonary flow resistance was increased an average of 72% and 39% above that of controls; at 5 ppm, cough, irritation, and increased salivation also observed; 1 ppm, no treatment-related effects; authors concluded that peak response occurred after 5–10 min of exposure Frank et al. 1962 6 healthy nonsmoking adult males Inhalation (mouth breathing) SO2 at 1–2, 4–6, or 14–17 ppm, alone or in conjunction with NaCl aerosol (18 mg/m3) 30 min At 4–6 and 14–17 ppm SO2 with or without NaCl, a concentration-dependent increase in pulmonary flow resistance was observed; at 1–2 ppm, no significant effects observed Frank et al. 1964 11 healthy adult males Inhalation (compari- 15, 29 10 min At 15 and 29 ppm, pulmonary flow resistance increased 20% and 65% for Frank 1964

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Review of Submarine Escape Action Levels for Selected Chemicals   son was made between oral and nasal SO2 administration)   mouth breathers and 3% and 18% for nose breathers   11 healthy subjects Inhalation 0.55 10 min No nasal or ocular irritation reported Dautrebrande and Capps 1950 Healthy subjects (number not specified) Inhalation, dermal (subjects exposed wearing close-fitting goggles) 0, 1, 5 Ocular exposure: 15 s; inhalation subjects inhaled 10 breaths of 1 L at given concentration 5 ppm threshold for ocular irritation; 1 ppm threshold for broncho-constriction. Douglas and Coe 1987 15 healthy males, aged 20–28 Inhalation 0, 1, 5, 25 6 h At 25 and 5 ppm, dose-dependent decrease in nasal mucous flow, an increase in nasal flow resistance and a decrease in FEV1; at 1 ppm no observed effect; after exposure all but 1 of the 25 ppm subjects complained of irritative effects but none considered irritation “excessive”; 5 subjects exposed to 5 ppm complained of effects Andersen et al. 1974

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Review of Submarine Escape Action Levels for Selected Chemicals Subject Route Concentration (ppm) Duration Effect Reference 10 healthy men, aged 55–73 Inhalation 0.1 ppm of SO2 and 1 mg/m3 NaCl aerosol, 1 ppm SO2 and 1 mg/m3 NaCl aerosol, or 1 mg/m3 NaCl aerosol alone 20 min at rest and 10 min during moderate exercise Significant decreases in FEV1 2–3 min after exposure in all groups; decrease observed after 1 ppm SO2 and NaCl was significantly greater than after exposure to NaCl alone Rondinelli et al. 1987 10 asthma patients subjects (4 males, 6 females, median age 27) and 10 healthy subjects (5 males, 5 females, median age 26 yr) Inhalation 0, 0.25, 0.50, 0.75, 1 40 min (subjects exercised for first 10 min); on separate days subjects were exposed to 0 or 1 ppm in the absence of exercise No significant effects observed in healthy individuals on any day, or in asthma patients at rest; in exercising asthma patients, exposure to 1 ppm resulted in significant changes from baseline in airway resistance, FEV1, MEF at 60% of VC below total lung capacity on the partial flow volume curve [MEF40% (P)], and reductions in flows at (VMAX50%); no significant changes in these parameters observed at lower concentrations, with the exception of small decreases in VMAX50% at 0.25 and 0.5 ppm; for exercising asthma patients, a dose-dependent relationship was observed: Average changes in airway resistance, FEV1, MEF40%, (P), and VMAX50% increasing with SO2 concentrations, with a Schachter et al. 1984

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Review of Submarine Escape Action Levels for Selected Chemicals 9–5. Rats exposed to sulfur dioxide up to 400 ppm for less than 90 d showed a thickening of the mucous layer in the trachea and an increase in goblet cells and mucous glands that is similar to human chronic bronchitis (Krasnowska et al. 1998; Lamb and Reid 1968). Animal studies at exposure concentrations below 10 ppm demonstrated reversible functional abnormalities. Chronic exposures (>90 d) at 500 ppm resulted in bronchitis and conjunctivitis in dogs (Greene et al. 1984), but exposure at 650 ppm for up to 74 d produced intense sensory irritation and histologic changes in the lungs and bronchi of hamsters (Goldring et al. 1970). Guinea pigs exposed at nearly 6 ppm for 12 mo and monkeys at 1.3 ppm for 20 mo exhibited no adverse respiratory effects (Alarie et al. 1970). At 5 ppm, dogs showed an increase in pulmonary upper airway resistance and decreased lung compliance (Balchum et al. 1959). Irritation effects seen in these animal studies diminished with repeat exposures, suggesting an adaptive response, an occurrence also shown in humans (Dept. of Labor 1975, as cited in ATSDR 1998). Substantive repeated dosing effects of sulfur dioxide exposure was limited to effects on the respiratory system. MECHANISM OF ACTION Sulfur dioxide induces airway resistance as a result of reflex bronchoconstriction (Frank et al. 1962; Nadel et al. 1965) and respiratory inhibition that is mediated through vagal reflexes by cholinergic and noncholinergic mechanisms. Noncholinergic components include but are not limited to tachykinins, leukotrienes, and prostaglandins. The extent to which cholinergic or noncholinergic mechanisms contribute to sulfur dioxide-induced effects is not known and could vary between people with and without asthma and among animal species. Early study of bronchoconstricitive mechanisms of sulfur dioxide with ventilated, tracheostomized cats indicated that pulmonary resistance increased during the first breath but reversed rapidly (Nadel et al. 1965). Intravenous injection of atropine (a parasympathetic receptor blocker) or cooling of the cervical vagosympathetic nerves abolishes bronchoconstriction; rewarming the nerve reestablishes the response. The rapidity of the response and its reversal emphasize the parasympathetically mediated tonal change in smooth muscle. Studies with human subjects have confirmed the predominance of parasympathetic mediation, but histamine from inflammatory cells could play a secondary role in the bronchoconstrictive responses of people with asthma (Sheppard et al. 1981). Sheppard (1988) examined the chemical mechanisms that underlie the bronchoconstrictive effect of sulfur dioxide. Sulfur dioxide dissolves in water to form bisulfite ion, sulfite ion, and hydrogen ion. The bisulfite ion is a nucleophile that can disrupt disulfite bonds. It has been postulated that bisulfite

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Review of Submarine Escape Action Levels for Selected Chemicals formed at the airway surface during inhalation of sulfur dioxide initiates bronchoconstriction by disrupting disulfide bonds in tissue proteins. NAVY’S RECOMMENDED SEALS The Navy proposes a SEAL 1 of 3 ppm. The SEAL 1 of 3 ppm appears to be based on the study by Weir et al. (1972). In this study 12 healthy, adult males exposed continuously to less than 1 ppm for 120 h experienced no adverse effects; however, at 3 ppm, the subjects experienced slightly increased airway resistance. That information was only included in an abstract and no data was presented. Thus, no definitive dose-response information could be derived. The Navy’s proposed SEAL 2 for exposure to sulfur dioxide is 6 ppm. The Navy did not describe how it derived this SEAL, although it could have been derived from a study by Andersen et al. (1974), who exposed 15 males at 1, 5, and 25 ppm for 6 h, and observed a significant decrease in nasal mucous flow rate and an increase in nasal airflow resistance in subjects exposed at 5 and 25 ppm for 6 h. A decrease in forced expiratory volume at 1 s and in forced expiratory flow during the middle half of expired flow volume was observed in the subjects exposed at all concentrations. ADDITIONAL RECOMMENDATIONS FROM THE NRC AND OTHER ORGANIZATIONS The recommended exposure limits of other organizations are presented in Table 9–6. The 24-h emergency exposure guidance level (EEGL) is the most relevant guidance level to compare to the SEALs (NRC 1984). EEGLs were developed for healthy military personnel for emergency situations. An important difference between EEGLs and SEALs is that EEGLs allow mild, reversible health effects, whereas SEALs allow moderate, reversible health effects. That is, SEALs allow effects that are somewhat more intense or potent than those for EEGLs. Therefore, the SEALs are higher than the corresponding EEGLs. SUBCOMMITTEE ANALYSIS AND RECOMMENDATIONS The toxic effect of particular concern associated with sulfur dioxide exposure is irritation of the upper respiratory tract, and it is considered to be of a localized nature. There is no evidence of systemic toxicity or organ system effects; hence, irritation appears the sole effect of concern.

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 9–6 Recommendations from Other Organizations for Sulfur Dioxide Organization Type of Exposure Level Recommended Exposure Level (ppm) Reference ACGIH TLV 2 ACGIH (1994)   STEL 5   AIHA ERPG-1 ERPG-2 ERPG-3 0.3 3 15 AIHA 2001 ATSDR Acute MRL 0.01 ATSDR (1998) DFG MAK (8 h/d during 40-h workweek) 2 DFG 1997   Peak limit (5 min maximum duration, 8 times per shift) 4   EPA NAAQS (24 h) 0.14 (365 mg/m3) EPA (1998)a   NAAQS (annual arithmetic mean) 0.03 (80 mg/m3)   NIOSH REL 2 NIOSH (2000)   STEL 5     IDLH 100   NRC EEGL (10 min) 30 NRC (1984)   EEGL (30 min) 20     EEGL (1 h) 10     EEGL (24 h) 5     CEGL (90 d) 1   OSHA PEL-TWA (8 h) 2 OSHA (1998) aNational Primary Ambient Air Quality Standards for Sulfur Oxides (Sulfur Dioxide). 40 CFR 50.4. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AIHA, American Industrial Hygiene Association; ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, community exposure guidance level; DFG, Deutsche Forschungsgemeinshaft; EEGL, emergency exposure guidance level; EPA, Environmental Protection Agency, IDLH, immediately dangerous to life and health; MAK, maximum concentration values in the workplace; MRL, minimal risk level; NAAQS, National Ambient Air Quality Standard; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL-TWA, permissible exposure limit-time-weighted average; REL, recommended exposure limit; STEL, short-term exposure limit; TLV, Threshold Limit Value.

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Review of Submarine Escape Action Levels for Selected Chemicals Many of the biologic responses seen at lower concentrations are judged to pose a lesser degree of concern than would be associated with the risks attendant to emergency evacuation from a disabled submarine. Hence, a considerable tolerance to development of such responses is considered acceptable. The effects generally noted—including lung airflow, bronchoconstriction, and mucous secretion—are reversible after exposure cessation and are not considered to significantly affect long-term health of survivors. They also are considered insufficient to adversely affect escape. It is recognized that respiratory irritation caused by sulfur dioxide exposure becomes objectionable immediately when the gas is encountered at relatively low concentrations; relatively rapid acclimation, however, occurs with continued exposure, and gradual increases result in tolerance of concentrations that would be intolerable if encountered directly (Andersen et al. 1974). Considerable weight has been given to occupational exposure information, which used longer term, substantively higher sulfur dioxide exposures than were used in many of the controlled human exposure studies. The occupational data are considered particularly valuable in providing practical information about the relationships of concentration and time course, tolerance, and acclimation to irritant effects caused by sulfur dioxide exposures in a healthy human population—as would be more closely representative of the population found in a submarine. Submarine Escape Action Level 1 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 1 of 3 ppm for sulfur dioxide is too conservative. The subcommittee recommends a SEAL 1 of 20 ppm. The subcommittee’s recommendation is supported by several occupational studies that show tolerance to irritant effects from repeated exposures at 20 ppm (Ferris et al. 1967; Kehoe et al. 1932; Skalpe 1964). It is also supported by a study in which volunteers showed tolerance to a 6-h exposure at 25 ppm (Andersen et al. 1974) and minimal pulmonary flow resistance to a 10-min nose-only exposure at 15 or 29 ppm (Frank 1964). Effects on mucus flow and airflow resistance are to be expected at exposure concentrations of 20 ppm (Frank et al. 1964), however, they should not impair the submariners’ ability to escape. Healthy submariners should be able to tolerate irritative effects associated with exposures to less than 20 ppm for up to 10 d.

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Review of Submarine Escape Action Levels for Selected Chemicals Submarine Escape Action Level 2 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 6 ppm for sulfur dioxide is too conservative. The subcommittee recommends a SEAL 2 of 30 ppm. The subcommittee’s recommended SEAL 2 is based on an occupational study in which workers exposed to 30 ppm for several years tolerated the irritative effects of sulfur dioxide (Kehoe et al. 1932). The crew of a disabled submarine should be able to tolerate the irritative effects from exposure to sulfur dioxide at concentrations below 30 ppm for up to 24 h. DATA GAPS AND RESEARCH NEEDS Little information is available to substantiate respiratory irritation effects above 30 ppm or that thoroughly investigate the interaction of sulfur dioxide and airborne particulates. Some evidence suggests that interactive effects are possible, but there is insufficient information to differentiate between sensory, functional, or physiologic effects and exposure concentration. Because the effects of concern are primarily upper respiratory rather than systemic or involving the deep lung, additional research on systemic and lower respiratory-tract effects is not expected to add materially to these recommendations. Data from animal studies suggest that a lack of prior exposure to sulfur dioxide may intensify its irritative effects from a modest exposure and therefore, the Navy should conduct research examining the adaptive effects of sulfur dioxide exposure. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1994. Threshold Limit Value for Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 2001. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook Fairfax, VA: American Industrial Hygiene Association. Alarie, Y., C.E.Ulrich, W.M.Busey, H.E.Swann Jr, and H.N.MacFarland. 1970. Long-term continuous exposure of guinea pigs to sulfur dioxide. Arch. Environ. Health 21(6):769–777. Alarie, Y., C.E.Ulrick, W.M.Busey, A.A.Krumm, and H.N.MacFarland. 1972. Long-term continuous exposure to sulfur dioxide in cynomolgus monkeys. Arch. Environ. Health 24(2):115–127.

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