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Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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):

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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).

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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).

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

 

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

 

consistent effect first observed at 0.75 ppm; results suggest that asthma patients engaged in moderate activity have transient bronchoconstriction after exercise in the presence of SO2, with consistent changes observed when concentrations reach 0.75 ppm

 

4 nonsmoking asthma patients (2 males, 2 females)

Inhalation

0.5

1, 3, 5 min

3-min exposure resulted in 173% increase in airway resistance; wheezing, chest tightness, dyspnea

Balmes et al. 1987

22 asthma patients (13 males, 9 females, aged 18–33)

Inhalation

All possible combinations of the following: 2 exposures (purified air and 0.6 ppm); 2 temperatures (21°C, 38°C); 20%, 80% RH.

~5 min during exercise

Symptom questionnaires and body plethysmographic measurements were completed before and after each exposure; exposure to 0.6 ppm in conjunction with low temperature and low humidity (21°C and 20% RH) tripled group mean specific airway resistance; however, exposure to 0.6 ppm and high humidity and high temperature (38°C, 80% RH) increased specific airway resistance by less than 40%

Linn et al. 1985

14 asthma patients (13 males, 9 females, aged 18–33)

Inhalation

0, 0.5, 1.0

10 min during light, medium, or heavy exercise

At 0.5 ppm during light exercise, mild to moderate respiratory effects were reported, at 1.0 and heavy exercise, effects were reported as moderate to severe; effects reported as shortness of breath, wheezing, and chest tightness; both FEV1 and SRaw showed significant

Gong et al. 1995

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Subject

Route

Concentration

(ppm)

Duration

Effect

Reference

 

exposure-related effects, but the authors comment that the exact magnitude is difficult to ascertain

28 male asthma patients aged 19– 34

Inhalation

0, 0.25, 0.50, 1

75 min (included 3 10-min periods of moderate treadmill exercise)

At 0.25 ppm there was no significant effect on SRaw; at 0.5 and 1.0 ppm, SRaw was increased two- and threefold above pre-exposure, respectively, increases were greatest after the first 10-min exercise period and less after the latter 2 10-min exercise periods; based on analysis of symptom questionnaires, only shortness of breath and chest discomfort were significantly increased after 10 min exposure to 1 ppm

Roger et al. 1985

14 asthma patients (10 males, 4 females, aged 20–55)

Inhalation

0, 0.5

30 min

Subjects exposed at rest.; no increase in SRaw observed; no exposure-related subjective symptoms noted

Jorres and Magnussen 1990

9 asthma patients (7 males, 2 females, aged 14– 18)

Inhalation

Filtered air, 1 ppm SO2 and 1 mg/m3 NaCl aerosol, or 1 mg/m3 NaCl aerosol alone

60 min (divided into 2 30-min periods with 5–7 min interruption when functional

Significant decreases in maximal flow at VMAX50 and VMAX75 observed after combined exposures; no significant changes observed during exposure to filtered air or NaCl droplet aerosol alone

Koenig et al. 1980

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

 

measurements were taken)

 

7 healthy subjects

Inhalation

4–6

10 min

Increased Raw as measured by body plethysmography

Nadel et al. 1965

Healthy subjects

Inhalation

1, 5

1 ppm (not reported); 5 ppm (10 min)

At 1 ppm SRaw increased after deep inhalation; at 5 ppm increased resistance during quiet mouth breathing

Lawther et al. 1975

Asthma patients

Inhalation

0.10, 0.25

10 min (individuals exercised during exposure)

Significant changes in Raw observed after 0.25 ppm exposure; most sensitive subjects exhibited some bronchoconstriction, as evidenced by a slight increase in SRaw following inhalation at 0.1 ppm

Sheppard et al. 1981

27 asthmatics

Inhalation

0, 0.25, 0.50, 1.00

10 min (individuals exercised during exposure)

Determined the SO2 concentration required to produce an increase in airway resistance 100% greater than the response to clean air (designated as PC(SO2)); substantial variability in PC(SO2), median PC(SO2) at 0.75 ppm, with 23 subjects had PC(SO2) from 0.28–1.90; 4 subjects had PC(SO2) above 2.0

Horstman et al. 1986

5 male paper mill workers

Inhalation, dermal

NR

 

2 workers accidentally exposed to SO2 under pressure; workers died within 5 min; 3 other workers exposed to lower concentrations experienced acute symptoms including ocular, nasal, and throat irritation and soreness, chest tightness, and intense dyspnea; severe

Charan et al. 1979

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Subject

Route

Concentration

(ppm)

Duration

Effect

Reference

 

conjunctivitis and superficial corneal burns; the pharyngeal mucosa hyperemic but free of ulcerations.

 

2 male pulp and paper mill workers

Inhalation

NR

15–20 min

1 worker survived, but exhibited delayed chronometric vital capacity, prolonged expiratory phase, and marked respiratory fatigue 4 mo after exposure; the other worker died 17 d after the accident, showing evidence of acute emphysematous changes, including peribronchiolar fibrosis and bronchiolotis obliterans

Galea 1964

3 healthy male cooper mineworkers

Inhalation, dermal

>40

3.5 h (for 2 survivors)

Copper iron sulfide dust explosion; 1 miner died within minutes. The other 2 experienced intense burning of eyes, nose, and throat; dyspnea; diffuse precordial and retro sternal chest pain; nausea, vomiting; urinary incontinence. 3 wk after the exposure, the workers had severe airway obstruction, hypoxemia, markedly decreased exercise tolerance, ventilation-perfusion mismatch, evidence of active inflammation (positive gallium scan)

Rabinovitch et al. 1989

9 healthy workers

Inhalation

NR (pyrite (FeS2) explosion in a

20–45 min

1 worker died; lung function of survivors was followed for 4 yr; the largest decreases in FVC; FEV1, and maximal

Harkonen et al. 1983

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

 

mine)

 

midexpiratory flow were seen at 1 wk, spirometry indicated obstructive findings in 6 workers, restrictive findings in 1 worker; at 3 mo, no further lung function decrement occurred; however, 4 y after the accident, reversible bronchiolar obstruction still present in 3 workers

 

Male aged 12

Inhalation, dermal

4.8 (concentration measured several days after exposure)

4 min

Accidental fall into a pit containing SO2; subject presented with acute irritation of eyes and mucous membranes of the upper airways, rhinopharyngitis, laryngitis, bonchitis, conjunctivitis, and corneal lesions; effects persisted for 5 d and then were followed by a symptom-free 3-d period. The following symptoms persisted for 12 mo: obstructing bronchitis; bonchiolitis; alveolitis; emphysema of the lung; mediastinum, and skin; bronchiectasis then developed and persisted for 12 mo. Lung emphysema and continuous partial respiratory insufficiency, accompanied by ventilatory obstruction persisted for 4 yr

Wunderlich et al. 1982

OCCUPATIONAL EXPOSURE

Copper smelter workers (exposed group) and mine repair

Inhalation

0.3–4 (exposed group)

Up to 20 yr

Exposed and control subjects were matched by age and smoking habits; FVC, FEV1, FEF50, and closing volume measurements from both groups were

Archer et al. 1979

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Subject

Route

Concentration

(ppm)

Duration

Effect

Reference

shop workers (control group); all workers were white males.

 

taken before and after the work shift. Mean FEV1 and FVC values were significantly decreased following a work shift in smelter workers in comparison to controls; more smelter workers had decreased FEV1 and FEF50 values during the day, more smelter workers complained of chest tightness

 

Workers in an electric refrigeration manufacturing plant; 100 workers exposed to sulfur dioxide; 100 were not exposed

Inhalation

20–30 ppm (average for exposed group)

3.82 yr (mean)

Exposed workers showed a significantly higher incidence of nasopharyngitis, of alteration in sense of smell and sense of taste, of increased sensitivity to other irritants; they also showed a significantly higher incidence of abnormal urinary acidity, of tendency to increased fatigue, of shortness of breath on exertion, and of abnormal reflexes; no demonstrable association between frequency or severity of initial symptoms and frequency of heavy exposure

Kehoe et al. 1932

Workers at a pulp mill; 54 workers were exposed to sulfur dioxide and another 54

Inhalation

2–36 ppm

NR

A significantly higher frequency of cough, expectoration, and dyspnoea on exertion was found in the exposed group; the maximal expiratory flow rate was significantly lower in the exposed group; there was no significant difference

Skalpe 1964

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

workers were not exposed

 

between exposed and nonexposed workers in vital capacity values

 

147 workers at a pulp mill who were exposed to sulfur dioxide and 124 worker at a paper mill who were not exposed; pulp mill workers were co-exposed to chlorine

Inhalation

1–33 ppm

16.3 yr (exposed group)

No significant differences in the prevalence of chronic non-specifc respiratory diseases between workers exposed to sulfur dioxide and those not exposed

Ferris et al. 1967

190 broom manufacturing workers (expose group) and 43 unexposed workers not exposed to SO2 (control group)

Inhalation

0–0.285 ppm SO2 (summer); 6.5– 56.8 ppm SO2 (winter). Dust concentrations 0– 21 mg/m3 (winter) and 3–27 mg/m3 (summer).

Compared exposure during winter months versus summer months

Exposed workers reported: coughing (94.2%), dyspnea (91.0%), burning of the nose, eyes and throat (74.7%), tearing (64.7%), and substernal pain (75.3%; sulfate concentration in the urine and methemoglobin and sulfhemoglobin concentrations in the blood of exposed workers significantly higher than in controls

Savic et al. 1987

COMMUNITY EXPOSURES

Population of London in 1950

Inhalation

1.3 (peak SO2 concentrations); particulate matter concentrations were reported to

5-d pollution episode

Total deaths 4,000, 3-fold higher than normal; excess deaths attributed to impaired respiratory function, including bronchitis and from cardiac effects; most deaths occurred in the elderly and in

WHO 1979

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Subject

Route

Concentration

(ppm)

Duration

Effect

Reference

 

be at least 4.5 mg/m3

 

individuals with preexisting cardiac or respiratory disease

 

Residents living near a pulp mill (exposed group); residents in nonpolluted community (referent group)

Inhalation

0.76–1.1 ppb (exposed community); 0.38 ppb (referent community)

March and April 1992

Increased incidence of cough, respiratory infections, headache in residents living near pulp mill as compared with referent community

Partti-Pellinen et al. 1996

Population of Athens, Greece (1984–1988)

Inhalation

0.014–0.027

1984–1988

Total mortality associated with SO2, smoke, and CO. SO2, and smoke independent predictors of mortality

Touloumi et al. 1994

Population of East Berlin

Inhalation

Mean=0.063

Winters of 1981–1989

After controlling for temperature and humidity, both SO2 and suspended particles were found to be contributors to excess mortality, the strongest association found for mortality lagged for 2 d

Rahlenbeck and Kahl 1996

2 English communities

Inhalation

0.04

 

Increase in lung cancer mortality in men and increases in mortality from bronchitis in men and women exposed long-term to SO2

Wicken and Buck (1964), as cited by Clayton (1978)

 

Inhalation

0.15–0.19 (with concomitant high soot concentrations)

 

Significant correlation observed between SO2 concentration and deaths or disease with 24-h mean SO2 concentrations

Joosting 1967, as cited by Clayton (1978)

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

1,000 men (aged 30–59)

Inhalation

0.16–0.21 (with accompanying smoke, 300–400 µg/m3)

 

Significant relationship between respiratory illness and SO2 and smoke observed.

Fletcher et al. 1968, as cited by Clayton (1978)

 

Inhalation

0.11–0.19

3–4 d

Excess mortality resulted when 24-h mean SO2 exceeded 0.19 ppm for a few days; hospital admissions and absenteeism increased when at 0.11–0.15 ppm for 3–4 consecutive days.

Brasser et al. 1967 as cited by Clayton (1978)

Abbreviations: FEF, forced expiratory flow; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; MEF, maximal expiratory flow; NR, not reported; BAL, bronchiolar alveolar lavage; RH, relative humidity; SRaw, specific airway resistance; VC, vital capacity; VMAX50, 50% of vital capacity.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

TABLE 9–3 Exposure of Healthy Subjects to Sulfur Dioxide

Concentration

Duration

Effect

Reference

3 ppm

7,200 min

Slight increase in small airway resistance

WHO 1979

5 ppm

10–360 min

Immediate exposures resulted in coughing and bronchoconstriction; moderate airflow resistance; threshold for minor ocular irritation

Sandstrom et al. 1989c; Andersen et al. 1974

10–16 ppm

10–30 min

Immediate exposure resulted in coughing; after acclimation, signs of irritation of pharynx, salivation, and airflow resistance

Frank et al. 1962, 1964

15 ppm

10 min

Pulmonary flow resistance of 3%

Frank 1964

25 ppm

360 min

Nearly intolerable upon initial exposure; following gradual acclimation, dryness and slight pain in nose, rhinorrhea, conjectival pain, decreased mucous flow and airflow resistance (reversible), irritation considered “never excessive”

Andersen et al. 1974

29 ppm

10 min

Pulmonary flow resistance of 18%

Frank 1964

Abbreviations: WHO, World Health Organization.

Occupational and Community Exposure Studies

Table 9–2 also presents data from occupational and epidemiologic studies that indicate that the respiratory system is the primary target for sulfur dioxide. There was variability in the study findings that probably resulted from a lack of adequate analytical measurements (use of area sampling rather than personnel monitoring); the multiplicity of confounding, concurrent exposures to other chemicals and participates; and the study indices investigated. However, some reasonable correlations between effects reported and exposure bounds can be determined.

Kehoe et al. (1932) reported no significant evidence of respiratory damage to workers reportedly exposed to sulfur dioxide concentrations of 20–30 ppm for a mean of 4 yr. The authors stated that even higher workplace airborne concentrations (80–100 ppm) occurred at the plant before the study began. There was no demonstrable association between frequency or severity of initial symptoms

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

(irritation, coughing, epistaxis, constriction of the chest, hemoptysis) and frequency of heavy exposure. A definite ability to acclimate to higher airborne concentrations was noted, although individual variability was found to be relatively high.

Skalpe (1964) investigated the effects of chronic sulfur dioxide exposure in Norwegian pulp mills. Individual Dräeger tubes recorded daily airborne concentrations of 2–36 ppm sulfur dioxide, although the author suggested that earlier exposures of the same individuals likely were “much higher.” A higher frequency of signs of irritation (cough, expectoration, dyspnea) was observed during exertion in sulfur-dioxide-exposed versus unexposed control populations. No significant differences in vital capacity were reported.

Ferris et al. (1967) reported no significant differences in the prevalence of chronic nonspecific respiratory disease between workers in the pulp industry and workers from a paper mill, all of whom were exposed to a broad range (1–33 ppm) of sulfur dioxide and had coexposure to chlorine. It is noteworthy that when both worker populations were compared with the local population, each exhibited a lower prevalence of chronic respiratory disease than did the general public.

Community exposure studies typically included concomitant exposures to particles, so the studies have limited utility in defining causation: sulfur dioxide was but one of several agents contributing to observed effects. The epidemiologic studies suggest that the respiratory effects of exposure to sulfur dioxide in combination with particles, are greater than are the effects caused by sulfur dioxide alone in healthy individuals–especially in the elderly and those with preexisting cardiac or respiratory disease (WHO 1979).

EXPERIMENTAL ANIMAL TOXICITY DATA

Acute Exposure

Acute inhalation exposure to sulfur dioxide produces lethal and nonlethal effects in laboratory animals. Data suggest that the sensitivity of animals to sulfur dioxide varies: Rats are most resistant and guinea pigs are most sensitive. Table 9–4 lists the concentrations that produce 50% mortality in exposed animals (LC50). Acute lethality at exposures greater than 100 ppm appears to be a function of concentration and duration of exposure. For example, LC50s were calculated in mice exposed to nominal concentrations of 150, 1,000, and 3,000 ppm sulfur dioxide for exposure durations of 847 h, 4 h, and 30 min, respectively (Hilado and Machado 1977; U.S. Department of Health Education and Welfare 1969, as cited in ACGIH 1994).

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

TABLE 9–4 LC50 for Exposure to Sulfur Dioxide

Species

Duration

LC50 (ppm)

Reference

Mouse

30min

3,000

Hilado and Machado 1977

Mouse

4 h

1,000

U.S. Department of Health, Education and Welfare 1969 (as cited in ACGIH 1994)

Mouse

847 h

150

U.S. Department of Health, Education and Welfare 1969 (as cited in ACGIH 1994)

Rat

4 h

1,057

Cohen et al. 1973

Guinea pig

20 h

1,000

U.S. Department of Health, Education and Welfare 1969 (as cited in ACGIH 1994)

Guinea pig

154 h

130

U.S. Department of Health, Education and Welfare 1969 (as cited in ACGIH 1994)

Abbreviation: LC50, median lethal concentration.

Table 9–5 presents data from various animal studies on the acute toxicity of sulfur dioxide. These studies support findings from the human studies, indicating that sulfur dioxide exerts its effect primarily on the respiratory system. Acute effects at relatively low concentrations (<20ppm) induced transient bronchoconstriction and increases in airway resistance. Higher concentrations produced more sustained biochemical, clinical, and histologic changes in the respiratory system. No material effects were noted in organs outside of the respiratory tract after acute exposure to sulfur dioxide.

No studies were found that examined effects in animals after dermal exposures to sulfur dioxide. However, data indicate that sulfur dioxide is a severe eye irritant, as sulfuric acid is formed when sulfur dioxide reacts with moist surfaces (ATSDR 1998).

Repeated Exposure

Repeated or continuous exposures to sulfur dioxide have been studied for several animal species. Data from some of these studies are summarized in Table

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

TABLE 9–5 Experimental Animal Toxicity Data, Exposure to Sulfur Dioxide

Species: No. per Group

Route

Concentration

(ppm)

Duration

Effect

NOAEL, LOAEL (ppm)

Reference

Rat (CD outbred): 8, male

Inhalation

224, 593, 965, 1168, 1319

4 h

Mortality was 0/8, 0/8, 3/8, 5/8, and 8/8 for 224, 593, 965, 1,168, and 1,319 ppm, respectively.

NOAEL: 593; LOAEL: 965 (resulting in death in 3 of 8 rats within 2 wk of exposure)

Cohen et al. 1973

Rat (Wistar), male

Inhalation

800

8 h

Loss of cilia and cell necrosis in trachea and main bronchus.

LOAEL: 800

Stratmann et al. 1991

Rat (Swiss Albino): 50, male

Inhalation

0, 0.87

24 h

Hematocrit and sulfhemoglobin statistically significantly increased in comparison to controls (hematocrit: 43.55±0.41% vs. 41.97±0.35%; sulfhemoglobin: 0.6±0.08% vs. 0.08±0.02%).

LOAEL: 0.87

Baskurt 1988

Rat, males

Inhalation

0, 30

5 d/wk, 12 wk

Inflammation of bronchial mucosa.

LOAEL: 30

Krasnowska et al. 1998

Rat

Inhalation

400

3 h/d; 5 d/wk, 2–42 d

Epithelial necrosis, loss of cilia, increased numbers and activity of goblet cells.

LOAEL: 400

Lamb and Reid 1968

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Species: No. per Group

Route

Concentration

(ppm)

Duration

Effect

NOAEL, LOAEL (ppm)

Reference

Rat: 6

Inhalation

10

1 h/d, 30 d

Eye irritation.

LOAEL: 10

Haider et al. 1982

Mouse (Swiss-albino): 4

Inhalation

1,100–14,286

1–8 min

Animals monitored for time to first sign of incapacitation, time to convulsion, and time to death. Time to first sign of incapacitation was under 3 min for 3,500 to 14,300 ppm and increased to 6 min as concentration decreased to 1,100 ppm. Average time to staggering increased from 1 to 6 min. Average time to convulsion increased from 2 to 8 min as concentration decreased from 14,300 to 3,500 ppm. Average time to death increased from 3 to 8 min as concentration decreased from 14,300 to 4,800 ppm. No deaths of animals exposed to 1,190 ppm for 30 min.

LOAEL: 1,100

Hilado and Machado 1977

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Mouse (ICR)

Inhalation

20

30, 60, 90, 120 min

Degenerative changes to the olfactory epithelium at 60 min

LOAEL: 20

Min et al. 1994

Guinea pig: 10–30

Inhalation

2.6, 20, 100, 200, 750

1 h

Increased airway resistance seen at all concentrations. Increase in SRaw was 20%, 25%, 70%, 140%, and 300% at concentrations of 2.6, 20, 100, 200, and 750 ppm, respectively.

LOAEL: 2.6

Amdur 1959

Guinea pig: males

Inhalation

1

1 h

Exposed animals challenged with acetylcholine showed a significant increase in pulmonary resistance.

NOAEL: 1

Chen et al. 1992

Guinea pigs: 6

Inhalation

24

3 h

Increased airway resistance increased from 20% at the end of the first h to 86% at the end of the third hr. 3 h after exposure, resistance had returned to control levels.

LOAEL: 24

Amdur 1959

Guinea pig: females

Inhalation

5

8 h/d, 5d

Severe destruction of ciliated epithelium and polymorphonuclear infiltrates.

LOAEL: 5

Riedel et al. 1992

Guinea pig: 12

Inhalation

10

1 h/d, 30 d

Eye irritation.

LOAEL: 10

Haider 1985

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Species: No. per Group

Route

Concentration

(ppm)

Duration

Effect

NOAEL, LOAEL (ppm)

Reference

Guinea pig

Inhalation

0.13, 1.01, 5.72

12 mo

Pulmonary function measurements indicated no adverse effects on lung mechanics.

NOAEL: 5.72

Alarie et al. 1970

Hamster

Inhalation

650

4 h/d; 5 d/wk; 19– 74 d

Dilated bronchi and alveolar ducts; small scattered areas of focal emphysema.

LOAEL: 650

Goldring et al. 1970

Rabbit: 21

Inhalation

0, 0.57

10 min

Respiratory flow slightly decreased and respiratory resistance slightly increased in exposed animals.

LOAEL: 0.57

Islam and Oberbarnscheidt 1994

Rabbit: females

Inhalation

200–300

10–20 min

Transient decrease in cough reflex and Hering-Breuer inflation reflex.

LOAEL: 200– 300

Hanacek et al. 1991

Rabbit: males

Inhalation

70–300

2 h/d; 6 d/wk; 5 wk

Decreased respiratory rate; rhinitis; tracheitis; bronchopneumonia; body weight gain 25% less than controls.

LOAEL 70–300

Miyata et al. 1990

Dog: 12

Inhalation

1.1–141

20–40 min

5% decreased compliance; increased resistance observed.

LOAEL: 1.1

Balchum et al. 1960b, as cited by ATSDR 1998

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Dog: 10

Inhalation

1.8–148

30–40 min

8.5% decreased compliance; 150–300% increased resistance.

LOAEL: 1.8

Balchum et al. 1960b as cited in ATSDR 1998

Dog: 3 or 7

Inhalation

0,500

1 h

Microscopic examination revealed tracheal epithelial damage in all exposed animals, but not in controls. At 1 h after exposure, injury was difficult to assess because the tracheal surfaces were covered with exfoliated cells or were in total disarray. At 6 h, lesions were well defined and large flattened cells covered the basement membranes where mucosal cells had exfoliated.

LOAEL: 500

Hulbert et al. 1989

Dog: 8 male or female

Inhalation

200

2 h

Exposure caused immediate increase in lung reactivity to histamine aerosol. Lungs most reactive immediately after exposure and lung reactivity had returned to control levels 2 h after exposure. Cells obtained from BAL increased after exposure; initially the increase was due to an increase in epithelial cells

LOAEL: 200

Jackson and Eady 1988

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

Species: No. per Group

Route

Concentration

(ppm)

Duration

Effect

NOAEL, LOAEL (ppm)

Reference

 

(0.25 and 1 h) and later by neutrophils (1, 2, 3, and 4 h). No changes observed in lymphocyte, macrophage, eosinophils, goblet cells or mast cells in fluid lavage.

 

Dog: 12

Inhalation

500

2 h/d, 5 d/wk, 21 wk

Exposure caused chronic bronchitis and conjunctivitis. Complete recovery occurred within 5 wk after exposure cessation.

LOAEL: 500

Greene et al. 1984

Monkey

Inhalation

0.14, 0.64, 1.28

24 h/d, 7 d/wk, 78 wk

No alteration in pulmonary function.

NOAEL: 1.28

Alarie et al. 1972

Monkey

Inhalation

5.1

23.3 h/d, 7 d/wk, 78 wk

No alteration in pulmonary function.

NOAEL: 5.1

Alarie et al. 1975

Abbreviations: BAL bronchiolar alveolar lavage; LOAEL, lowest observable adverse effect level; NOAEL, no observed adverse effect level; SRaw, specific airway resistance.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
×

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.

Suggested Citation:"9 Sulfur Dioxide." National Research Council. 2002. Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: The National Academies Press. doi: 10.17226/10242.
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Alarie, Y.C., A.A.Krumm, W.M.Busey, C.E.Urich, and R.J.Kantz. 1975. Long-term exposure to sulfur dioxide, sulfuric acid mist, fly ash, and their mixtures. Results of studies in monkeys and guinea pigs. Arch. Environ. Health 30(5):254–262.

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Next: 10 Conclusions and Recommendations »
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On-board fires can occur on submarines after events such as collision or explosion. These fires expose crew members to toxic concentrations of combustion products such as ammonia, carbon monoxide, hydrogen chloride, and hydrogen sulfide. Exposure to these substances at high concentrations may cause toxic effects to the respiratory and central nervous system; leading possible to death. T protect crew members on disabled submarines, scientists at the U.S. Navy Health Research Center's Toxicology Detachment have proposed two exposure levels, called submarine escape action level (SEAL) 1 and SEAL 2, for each substance. SEAL 1 is the maximum concentration of a gas in a disabled submarine below which healthy submariners can be exposed for up to 10 days without encountering irreversible health effects while SEAL 2 the maximum concentration of a gas in below which healthy submariners can be exposed for up to 24 hours without experiencing irreversible health effects. SEAL 1 and SEAL 2 will not impair the functions of the respiratory system and central nervous system to the extent of impairing the ability of crew members in a disabled submarine to escape, be rescued, or perform specific tasks.

Hoping to better protect the safety of submariners, the chief of the Bureau of Medicine and Surgery requested that the National Research Council (NRC) review the available toxicologic and epidemiologic data on eight gases that are likely to be produced in a disabled submarine and to evaluate independently the scientific validity of the Navy's proposed SEALs for those gases. The NRC assigned the task to the Committee on Toxicology's (COT's) Subcommittee on Submarine Escape Action Levels. The specific task of the subcommittee was to review the toxicologic, epidemiologic, and related data on ammonia, carbon monoxide, chlorine, hydrogen chloride, hydrogen cyanide, hydrogen sulfide, nitrogen dioxide, and sulfur dioxide in order to validate the Navy's proposed SEALs. The subcommittee also considered the implications of exposures at hyperbaric conditions and potential interactions between the eight gases.

Review of Submarine Escape Action Levels for Selected Chemicals presents the subcommittee's findings after evaluation human data from experimental, occupational, and epidemiologic studies; data from accident reports; and experimental-animal data. The evaluations focused primarily on high-concentration inhalation exposure studies. The subcommittee's recommended SEALs are based solely on scientific data relevant to health effects. The report includes the recommendations for each gas as determined by the subcommittee as well as the Navy's original instructions for these substances.

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