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9
Sulfur Dioxide1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2 and AEGL-3—are developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-
1
This document was prepared by the AEGL Development Team composed of Cheryl B. Bast (Oak Ridge National Laboratory) and Chemical Managers Loren Koller and George Woodall (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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sensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, longlasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
Sulfur dioxide is a colorless gas at ambient temperature and pressure. It can be detected by taste at concentrations of 0.35-1.05 ppm and has a pungent, irritating odor with an odor threshold of 0.67-4.75 ppm. Sulfur dioxide is used in the production of sodium sulfite, sulfuric acid, sulfuryl chloride, thionyl chloride, organic sulfonates, disinfectants, fumigants, glass, wine, industrial and edible protein, and vapor pressure thermometers. It is also used during the bleaching of beet sugar, flour, fruit, gelatin, glue, grain, oil, straw, textiles, wood pulp, and wood. Sulfur dioxide is also used in leather tanning, brewing and preserving, and in the refrigeration industry. It is a by-product of ore smelting coal, and fuel-oil combustion, paper manufacturing, and petroleum refining (WHO 1984).
Sulfur dioxide is an irritant of the upper respiratory tract and eyes. Conjunctivitis, corneal burns, and corneal opacity may occur from direct contact with high concentrations of sulfur dioxide. Death from respiratory arrest may occur from acute over-exposure, while survivors may develop bronchitis, bronchopneumonia, and fibrosing obliterative bronchiolitis. Bronchoconstriction accompanied by increased pulmonary resistance may be asymptomatic or may occur with high-pitched rales. Moderate exposure may result in a prolonged expiratory phase. Respirable particles, cold air, dry air, exercise, and
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mouth-breathing may increase the severity of adverse effects caused by sulfur dioxide (WHO 1984).
AEGL-1 values were based on the weight-of-evidence from human asthmatic data suggesting that 0.20 ppm may be a NOEL for bronchoconstriction in exercising asthmatics. No treatment-related effects were noted in asthmatics exposed to 0.2 ppm for 5 min (Linn et al. 1983b), 0.25 ppm for 10-40 min (Schacter et al. 1984), 0.25 ppm for 75 min (Roger et al. 1985), 0.5 ppm for 10-40 min (Schacter et al. 1984), or 0.5 ppm for 30 min (Jorres and Magnussen 1990). However, an increase in airway resistance (SRaw) of 134-139% was observed in exercising asthmatics exposed to 0.25 ppm for 5 min (Bethel et al. 1985); the increase in SRaw in this study, but not in the other studies, may be attributed to the lower relative humidity (36%) in the Bethel et al. (1985) study compared to the other studies (70-85%). No uncertainty factors were applied because the weight of evidence approach utilized studies from a sensitive human population, exercising asthmatics. The role of exposure duration to the magnitude of SO2-induced bronchoconstriction in asthmatics appears to decrease with extended exposure. For example, asthmatics exposed to 0.75 ppm SO2 for 3-h exhibited increases in SRaw of 322% 10-min into exposure, 233% 20-min into the exposure, 26% 1-hr into the exposure, 5% 2-h into the exposure, and a decrease of 12% at the end of the 3-h exposure period. These data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-1 values for SO2 were held constant across all time points. Exposure to concentrations at the level of derived AEGL-1 values is expected to have no effect in healthy individuals, but the concentrations are consistent with the definition of AEGL-1 for asthmatic individuals.
AEGL-2 values were based on the weight-of-evidence from human asthmatic data suggesting that 0.75 ppm induces moderate respiratory response in exercising asthmatics for exposure durations of 10-min to 3-h (Hackney et al. 1984; Schacter et al. 1984). No uncertainty factors were applied because the weight of evidence approach utilized studies from a sensitive human population, exercising asthmatics. The role of exposure duration to the magnitude of SO2-induced bronchoconstriction in asthmatics appears to decrease with extended exposure. For example, asthmatics exposed to 0.75 ppm SO2 for 3-h exhibited increases in SRaw of 322% 10 min into exposure, 233% 20 min into the exposure, 26% 1-hr into the exposure, 5% 2 h into the exposure, and a decrease of 12% at the end of the 3 h exposure period. These data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-2 values for SO2 were held constant across all time points. Exposure to concentrations at the level of derived AEGL-2 values is expected to have no effect in healthy individuals, but the concentrations are consistent with the definition of AEGL-2 for asthmatic individuals.
The AEGL-3 values were based on a calculated BMLC05 in rats exposed to SO2 for 4-h (573 ppm) (Cohen et al. 1973). An uncertainty factor of 10 was
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applied for intraspecies extrapolation due to the wide variability in response to SO2 exposure between healthy and asthmatic humans. An uncertainty factor of 3 was applied for interspecies variability; this factor of 3 was considered sufficient because no deaths were reported in guinea pigs exposed to 750 ppm SO2 for 1 h (Amdur 1959), in dogs exposed to 400 ppm SO2 for 2 h (Jackson and Eady 1988), or in rats exposed to 593 ppm for 4-h (Cohen et al. 1973). Furthermore, a median lethal exposure time (Lt50) of 200 min was reported for mice exposed to 900 ppm SO2 (Bitron and Aharonson 1978) and three of eight rats died when exposed to 965 ppm for 240 min (Cohen et al. 1973), suggesting limited interspecies variability. Data are not sufficient to ascertain whether a maximal response to SO2 for a lethal end point is obtained within 10 min. Therefore, time scaling will be utilized in the derivation of AEGL-3 values. It has been shown that the concentration-exposure time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data were unavailable for an empirical derivation of n for sulfur dioxide. Therefore, an n of 3 was applied to extrapolate to the 1-h time period, and n of 1 was used for extrapolation to the 8-h time period to provide AEGL values that would be protective of human health (NRC 2001). The 1-h AEGL-3 value was also adopted as 10-min and 30-min values because asthmatic humans are highly sensitive to sulfur dioxide at short time periods.
The calculated values are listed in Table 9-1.
1.
INTRODUCTION
Sulfur dioxide is a colorless gas at ambient temperature and pressure. It can be detected by taste at concentrations of 0.35-1.05 ppm and has a pungent, irritating odor with an odor threshold of 0.67-4.75 ppm. It is soluble in water and forms sulfurous acid which is slowly oxidized to sulfuric acid by dissolved oxygen. In the gaseous state, sulfur dioxide may react with oxygen to form sulfur trioxide which then reacts with moisture to form sulfuric acid. Sulfuric acid may also be associated with airborne particles and react with the particles to form other sulfur compounds (WHO 1984).
Sulfur dioxide is produced by burning sulfur or iron pyrites in air and is used in the production of sodium sulfite, sulfuric acid, sulfuryl chloride, thionyl chloride, organic sulfonates, disinfectants, fumigants, glass, wine, industrial and edible protein, and vapor pressure thermo-meters. It is also used during the bleaching of beet sugar, flour, fruit, gelatin, glue, grain, oil, straw, textiles, wood pulp, and wood. Sulfur dioxide is also used in leather tanning, brewing and preserving, and the refrigeration industry. It is a by-product of ore smelting, coal and fuel-oil combustion, paper manufacturing, and petroleum refining (WHO 1984).
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TABLE 9-1 Summary of AEGL Values for Sulfur Dioxide
10-min
30-min
1-h
4-h
8-h
End Point (Reference)
AEGL-1 (Nondisabling)
0.20 ppm (0.52 mg/m3)
0.20 ppm (0.52 mg/m3)
0.20 ppm (0.52 mg/m3)
0.20 ppm (0.52 mg/m3)
0.20 ppm (0.52 mg/m3)
NOEL for bronchoconstriction in exercising asthmatics (Linn et al. 1983b; Schacter et al. 1984; Bethel et al. 1985; Roger et al. 1985; Jorres and Magnussen 1990)
AEGL-2 (Disabling)
0.75 ppm (1.95 mg/m3)
0.75 ppm (1.95 mg/m3)
0.75 ppm (1.95 mg/m3)
0.75 ppm (1.95 mg/m3)
0.75 ppm (1.95 mg/m3)
Moderate bronchoconstriction in exercising asthmatics (Hackney et al. 1984; Schacter et al. 1984)
AEGL-3 (Lethality)
30 ppm (78 mg/m3)
30 ppm (78 mg/m3)
30 ppm (78 mg/m3)
19 ppm (49 mg/m3)
9.6 ppm (25 mg/m3)
Calculated BMCLC05 in the rat after a 4-h exposure (Cohen et al. 1973)
Sulfur dioxide is an irritant of the upper respiratory tract and eyes. Conjunctivitis, corneal burns, and corneal opacity may occur from direct contact with high concentrations of sulfur dioxide. Death from respiratory arrest may occur from acute over-exposure, while survivors may develop bronchitis, bronchopneumonia, and fibrosing obliterative bronchiolitis. Bronchoconstriction accompanied by increased pulmonary resistance may be asymptomatic or may occur with high-pitched rales. Moderate exposure may result in a prolonged expiratory phase of the respiratory cycle. Co-exposure to respirable particles may increase the severity of adverse effects caused by sulfur dioxide (WHO 1984).
The chemical structure is depicted below, and the physicochemical properties of sulfur dioxide are presented in Table 9-2.
2.
HUMAN TOXICITY DATA
2.1.
Case Reports
2.1.1.
Acute Lethality
Charan et al. (1979) described an industrial accident in a paper mill resulting in the deaths of two of five exposed workers. Two maintenance workers (ages 56 and 59 years, nonsmokers) were repairing a digester partially filled with wooden chips. The digester was in a large shed where the tempera-
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ture was 70 F. The valve of a line containing SO2 and steam was accidentally opened by another worker and the digester was immediately filled with concentrated SO2 under pressure. Both workers climbed out using a rope ladder suspended in the digester. Both workers died of respiratory arrest within 5 min of escape from the digester. Post-mortem examination revealed a “coagulated appearance” of the pharynx and larynx, frequent denudation of superficial columnar epithelium accompanied by retention of basal cells, and pink edema fluid in the airways. Histologic examination of the lungs showed extensive sloughing of the mucosa of the large and small airways and hemorrhagic alveolar edema. Three additional workers, presumably exposed to lower concentrations of SO2, survived the accident; these include a worker who helped the trapped workers escape, an individual wearing a dual-cartridge mask ascending to the top of the digester by an open elevator, and a fireman who responded to the accident. The acute symptoms in the 3 survivors included ocular, nasal, and throat irritation and soreness, chest tightness, and intense dyspnea. The eyes had severe conjunctivitis and superficial corneal burns and the pharyngeal mucosa was hyperemic but free of ulcerations. Pulmonary function tests performed at regular intervals showed that one survivor was asymptomatic, one survivor developed asymptomatic mild obstructive and restrictive disease, and the third survivor developed symptomatic severe airway obstruction unresponsive to bronchodialators. No SO2 exposure concentrations were provided.
TABLE 9-2 Physical and Chemical Data for Sulfur Dioxide
Parameter
Data
Reference
Chemical Name
Sulfur dioxide
ATSDR 1998
Synonyms
Sulfurous anhydride, sulfur oxide, sulfurous oxide, sulfurous acid anhydride
O’Neil et al. 2001
CAS Registry No.
7446-09-5
ATSDR 1998
Chemical Formula
SO2
O’Neil et al. 2001
Molecular Weight
64.06
O’Neil et al. 2001
Physical State
Gas (or liquid)
ATSDR 1998
Odor
Pungent, irritating
ATSDR 1998
Melting/Boiling/Flash Point
−72°C/−10°C/no data
O’Neil et al. 2001
Density
2.927 g/L (gas)
ATSDR 1998
Solubility
Soluble in water and organic solvents
O’Neil et al. 2001
Vapor Pressure
3000 mm Hg at 20°C
ATSDR 1998
Conversion factors in air
1 ppm = 2.6 mg/m3
1 mg/m3 = 0.38 ppm
NRC 1984
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In another report, Galea (1964) describes an accident in a pulp and paper mill where two men were exposed to an undetermined concentration of SO2 for 15 to 20 min. One worker was a 45-year-old man who was a heavy smoker. He survived the accident but exhibited a delayed chronometric vital capacity, prolonged expiratory phase, and marked respiratory fatigue four months after the accident. The second worker was a 35-year-old man who was a non-smoker. He presented with slight ocular irritation and pain on deep breathing. He was released from the hospital a few days after the accident since his clinical condition had improved. Ten days later, he was readmitted complaining of a dry, irritable cough, dyspnea, and mucous. He had rales at both lung bases and required a tracheotomy on the seventh day of his readmission. He died the following day, seventeen days after the date of the accident. Extensive peribronchiolar fibrosis and bronchiolotis obliterans was assumed to be responsible for the acute emphysematous changes consistent with the immediate cause of death.
Rabinovitch et al. (1989) described an accident in an underground copper mine where three healthy male workers were exposed to high concentrations of SO2 as the result of a copper iron sulfide dust explosion. One miner died within mins. The other two survived by covering their heads with rubber pants and using compressed air to provide adequate ventilation. They were rescued 3.5 h after the explosion at which time the measured SO2 concentration was greater than 40 ppm. No other toxic gases were identified and particles of copper and iron were at background levels for the mine. The survivors presented with intense burning of the eyes, nose, and throat, dyspnea, diffuse precordial and retro sternal chest pain, nausea, vomiting, and urinary incontinence. One of the workers had skin irritation resulting in first degree burns. Two weeks after the accident, all of their symptoms except the dyspnea had resolved. Within three weeks of the accident, both workers had severe airway obstruction, hypoxemia, markedly decreased exercise tolerance, ventilation-perfusion mismatch, and evidence of active inflammation (positive gallium scan). Progressive improvement was observed over the next year; however, ventilation-perfusion scans remained abnormal.
In another mining accident, nine workers were descending into a mine in a cage of a hoist at which time a pyrite (FeS2) explosion occurred (Harkonen et al. 1983). The workers were exposed to gases, primarily an undetermined concentration of SO2, for 20 to 45 min. At the mining level, the workers tried to rescue themselves by breathing from compressed air vents. One of the workers died and the others were injured. The lung function of the survivors was followed for 4 years. The largest decreases in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and maximal midexpiratory flow were observed 1 week after the accident. Pyrometer indicated obstructive findings in 6 workers and restrictive findings in 1 worker. After three months, no further lung function decrement occurred; however, four years after the accident, bronchiolar obstruction was still present in three workers.
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2.1.2.
Nonlethal Toxicity
Wunderlich et al. (1982) described an accident where a 12-year-old boy fell into a pit (4 m deep; 2.45 × 1.45 m area) containing SO2 on the grounds of a chemical manufacturing plant. He was not able to free himself and remained in the pit for approximately 4 h until he was found and rescued. Several days later, the measured concentration of SO2 in the pit was 4.8 ppm; thus, it is possible that the concentration was higher at the time of the accident. He presented with acute irritation of the eyes and mucous membranes of the upper airways, rhinopharyngitis, laryngitis, bronchitis, conjunctivitis, and corneal lesions. These effects persisted for five days and were followed by a symptom-free period of three days. Bronchitis, bronchiolitis, alveolitis, emphysema of the lung, and bronchiectasis then developed and persisted for 12 months in spite of aggressive therapy. Thereafter, lung emphysema and continuous partial respiratory insufficiency, accompanied by ventilatory obstruction were observed for 4 years. No follow-up beyond four years was reported.
Charan et al. (1979), Galea (1964), Rabinovitch et al. (1989), and Harkonen et al. (1983) describe cases where both non-lethal and lethal effects were observed. These case-reports are described in Section 2.1.1.
2.2.
Epidemiologic Studies
2.2.1.
Occupational Exposure
Lung function and sputum cytology were compared between copper smelter workers chronically exposed to 0.3 to 4 ppm SO2 and a control group of mine repair shop workers (Archer et al. 1979). All subjects were white males and exposed and control subjects were paired by age and smoking habits. Measurements of FVC, FEV1, FEF50, and closing volume were made both before and after the work shift for both exposed and control workers. Sputum samples for cytological analysis were also collected from both groups of workers. Mean FEV1 and FVC values were significantly (p<0.05) decreased after a work shift in the smelter compared to controls and significantly more smelter workers had decreased FEV1 and FEF50 values during the day when compared to controls. Also, more smelter workers complained of chest tightness compared to the control workers. Smelter workers had a higher percentage of sputum samples with moderate and marked atypical than controls; however, the cytological effects did not reach statistical significance.
Sulfur dioxide is used as a bleaching agent in the production of brooms. In another workplace monitoring study, Savic et al. (1987) compared a group of 190 workers from a broom manufacturing factory with a group of 43 workers not exposed to SO2 in the workplace (no other information concerning the
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control groups was provided). Sulfur dioxide concentrations in the broom factory ranged from 0 to 0.285 ppm during the summer (windows were open) and from 6.5 to 56.8 ppm in the winter. Dust concentrations were similar in both summer (0-21 mg/m3) and winter (3-27 mg/m3). The most common subjective symptoms reported by exposed workers included 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 concentration in the blood of exposed workers was significantly increased (p<0.01) compared to controls. No difference was found in sulfhemoglobin concentrations.
2.2.2.
Community Exposure: Ambient Air Pollution
Many studies concerning the relationship between SO2 exposure in polluted air and human health have been conducted; however, these studies are confounded by the presence of particulate matter and other air pollutants. Perhaps the most notable example of increased mortality from SO2 and particulate matter exposure occurred in London in the 1950’s (IPCS 1979). The London episode lasted 5 days. The number of deaths was approximately 4000 more (a three-fold increase) than would have been expected under normal circumstances. Most deaths occurred in the elderly and in people with preexisting cardiac or respiratory disease. Peak SO2 concentrations were 1.3 ppm while particulate matter concentrations were too high to be monitored (4.5 mg/m3 was provided as a conservative estimate). The excess deaths were attributed to bronchitis or to other impairments of the respiratory tract. Increased mortality from cardiac effects was also observed. The effects observed from this incident are attributed to the combination of SO2 and extremely high concentration of particulate matter. Direct attribution of effects to SO2 is toxicologically questionable because of the exceptionally high concentrations of particulate matter (see Section 4.4).
More recently, Touloumi et al. (1994) examined the effects of air pollution on mortality in Athens, Greece from 1984-1988. Mean SO2 levels (averaged over 2 recording stations) for the 5-year period ranged from 0.014 to 0.027 ppm. Total mortality was associated with SO2, smoke, and CO, with both SO2 and smoke being independent predictors of daily mortality. The strongest association was found for mortality lagged for 1 day. However, this study is of limited use due to the confounding pollutants and long exposure period (up to 5 years). In another study, Rahlenbeck and Kahl (1996) examined the relationship between mortality and air pollution in East Berlin for the winters of 1981-1989. When 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 days. The mean SO2 concentration over the 9-year period was 0.063 ppm.
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Rao et al. (1973), Castellsague et al. (1995), and Goldstein and Weinstein (1986) found no relationship between air pollution sulfur dioxide peaks and asthma attack rates in children. In another study, Partti-Pellinen et al. (1996) found increased incidences of cough, respiratory infections, and headache in residents living near a pulp mill compared with a reference community. The average SO2 concentrations were 0.00038 ppm in the reference community and 0.00076-0.0011 ppm in the exposed community. However, in view of the existing experimental database, it is likely that confounding pollutants, and not solely SO2, contributed to the observed effects.
Many other reports have shown an association between sulfur dioxide exposure and respiratory symptoms such as decreased lung function, coughing, chest tightness, and increased incidences of respiratory infections (Stebbings and Hayes 1976; Saric et al. 1981; Vedal et al. 1987; Hoek and Brunekreef 1993; Braback et al. 1994; Schwartz et al. 1994; Higgins et al. 1995; Soyseth et al. 1995; Braun-Fahrlander et al. 1997; Peters et al. 1997). However, these epidemiological studies are of limited usefulness to define a precise cause-effect relationship since other air pollutants, especially particulate matter, ozone, and nitrogen oxides, are also present.
2.3.
Experimental Studies
Many controlled human studies examining the effects of SO2 are available and indicate that the respiratory system is the principal target after acute exposure. Data show that asthmatics are particularly sensitive to the effects of SO2 and that effects are enhanced (in both healthy individuals and asthmatics) by exercise. Since it would not be feasible to include all available human SO2 data, the studies summarized below are considered sufficient to be quantitatively representative of data describing effects from acute exposure to SO2. Selected data from controlled exposures to SO2 in non-asthmatic individuals are presented in Table 9-3 and data from asthmatic individuals are presented in Table 9-4.
2.3.1.
Nonasthmatic Subjects
Amdur et al. (1953) exposed 14 healthy males (ages 28-58 years) to varying concentrations of SO2 through a face mask for 10 min. At 5 ppm most subjects complained of dryness in the throat and upper respiratory passages. Decreased respiratory volume and increased respiratory rate were noted at 1-8 ppm SO2.
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TABLE 9-3 Selected Data from Exposure of Nonasthmatic Humans to SO2
Concentration
Duration
Subjects
Exposure Parameters
Effect
Reference
1-8 ppm
10 min
14
Exposure through facemask
1-8 ppm:
↓Respiratory volume
↑respiratory rate
5 ppm: dry throat
Amdur et al. 1953
0.75 ppm
2 h
16
21 °C, 60% RH, Treadmill exercise 45 min. after entering chamber
SRaw: ↑2-55% (14.6% avg)
Stacy et al. 1981
0.4 ppm
20 min
8
20 °C, 50% RH, exercise
No effects on respiratory function parameters.
Sandstrom et al. 1988
2.0 ppm
75 W, last 15 min of exposure
4.0 ppm
Nasal irritation: 4 ppm (5/8) Throat irritation: concentration-dependent at 0.4, 2, and 4 ppm
4.0 ppm
20 min
10
20 °C, 50% RH, exercise
Transient concentration-related ↑ alveolar macrphage activity
Sandstrom et al. 1989a
8.0 ppm
4
75 W
8.0 ppm
20 min
22
20 °C, 50% RH, exercise
Transient concentration-related ↑ alveolar macrophage activity
Sandstrom et al. 1989b
75 W
4.0 ppm
20 min
22
20 °C, 50% RH, at rest
Transient ↑ in alveolar macrophage activity. Concentration-related up to 8 ppm, no further increase at 1 ppm
Sandstrom et al. 1989c
5.0 ppm
8.0 ppm
11.0 ppm
1.0 ppm
4 h
20
22.2 °C, 60% RH, exercise
No effects on lung function parameters.
Kulle et al. 1984
100 W
Upper respiratory irritation (4/20)
Ocular irritation (1/20)
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Touloumi, G., S.J. Pocock, K. Katsouyanni, and D. Trichopoulos. 1994. Short-term effects of air pollution on daily mortality in Athens: A time-series analysis. Int. J. Epidemiol. 23(5):957-967.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309.
Vedal, S., M.B. Schenker, A. Munoz, J.M. Samet, S. Batterman, and F.E. Speizer. 1987. Daily air pollution effects on children’s respiratory symptoms and peak expiratory flow. Am. J. Public Health 77(6):694-698.
WHO (World Health Organization). 1984. Sulfur dioxide. Pp. 115-150 in Recommended Health-based Occupational Exposure Limits for Respiratory Irritants.
WHO Technical Report Series 707. Geneva: World Health Organization.
Wunderlich, V.P., W. Leupold, W. Mittenzwey, and E. Rupprecht. 1982. Severe lung damage by inhalation of sulfur dioxide [in German]. Deut. Gesundheitswes. 37(11):519-524.
Yadav, J.S., and V.K. Kaushik. 1996. Effect of sulfur dioxide exposure on human chromosomes. Mutat. Res. 359(1):25-29.
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APPENDIX A
Time-Scaling Calculations for Sulfur Dioxide
Derivation of AEGL-1
Key Study:
Weight-of -evidence approach suggests 0.20 ppm is NOEL for bronchoconstriction in exercising asthmatics (see table below)
Concentration
Duration
Subjects
Exposure Parameters
Effect
Reference
0.2 ppm
5 min
8
23 °C, 85% RH, exercise 48 L/min
None
Linn et al. 1983b
0.25 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
None
Schacter et al. 1984
0.25 ppm
5 min
19
9
23 °C, 36% RH, exercise 60 L/min
SRaw ↑134%
Bethel et al. 1985
23 °C, 36% RH, exercise 80-90 L/min
SRaw ↑139%
0.25 ppm
75 min
28
26 °C, 70% RH, exercise 42 L/min intermittent
None
Roger et al. 1985
0.4 ppm
5 min
23
23 °C, 85% RH, exercise 48 L/min
SRaw ↑69%
Vmax25-75 ↑10%
Linn et al. 1983b
0.5 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
None
Schacter et al. 1984
Toxicity end point:
NOEL for bronchoconstriction in exercising asthmatics
Scaling:
Data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-1 values for SO2 will be held constant across all time points.
Uncertainty factors:
None: subjects were exercising asthmatics 10-min, 30-min, 1-h, 4-h, and 8-h AEGL-1 = 0.20 ppm
Derivation of AEGL-2
Key study:
Weight-of -evidence approach suggests 0.75 ppm induces moderate respiratory response in exercising asthmatics for exposure durations of 10-min to 3-h ppm (see table below)
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Toxicity end point:
Moderate, but reversible, respiratory effects in exercising asthmatics
Scaling:
Data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-2 values for SO2 were held constant across all time points.
Uncertainty factors:
None: subjects were exercising asthmatics
10-min, 30-min, 1-h., 4-h, and 8-h AEGL-2 = 0.75 ppm
0.75 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
SRaw ↑150%
FEF ↓22%
FEV1 ↓8%
Schacter et al. 1984
0.75 ppm
3 h
17
22 °C, 85% RH, exercise 45 L/min (first 10-min of exposure)
SRaw ↑:
322% (at 10-min)
233% (at 20-min)
26% (at 1-hr)
5% (at 2-hr)
FEV1 : ↓20% (at 15-min)
Hackney et al. 1984
1.0 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
SRaw ↑470%
FEF ↓27%
FEV1 ↓14%
Schacter et al. 1984
1.0 ppm
75 min
28
26 °C, 70% RH, exercise 42 L/min, intermittent
SRaw ↑300%
Roger et al. 1985
1.0 ppm
30 min
10
26 °C, 70% RH, exercise 41 L/min (3-10 min periods separated by rests of 15 min)
SRaw ↑172%
SRaw ↑137%
SRaw 106%
Kehrl et al. 1987
1.0 ppm
30 min
10
26 °C, 70% RH, continuous exercise 41 L/min
SRaw ↑233%
Kehrl et al. 1987
1.0 ppm
1 min
8
22 °C, 75% RH, exercise 60 L/min
SRaw ↑93%
Balmes et al. 1987
3 min
SRaw ↑395%
5 min
SRaw ↑580%
1.0 ppm
0.5 min
12
20 °C, 40% RH, exercise 40 L/min
No SRaw effect
Horstman et al. 1988
1.0 min
No SRaw effect
2.0 min
SRaw ↑121%
5.0 min
SRaw ↑307%
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
Derivation of AEGL-3
Key study:
Cohen et al. 1973
BMCL05 in rats exposed for 4 h (573 ppm)
Scaling:
C3 × t = k
(573 ppm)3 × 4 h = 752530068 ppm·h
C1 × t = k
(573 ppm)1 × 4 hr = 2292 ppm·h
Uncertainty factors:
10 for intraspecies variability
3 for interspecies variability
10-min AEGL-3
1-h AEGL-3 value adopted as 10-min value because asthmatic humans are highly sensitive to sulfur dioxide at short time periods
30-min AEGL-3
1-h AEGL-3 value adopted as 30-min value because asthmatic humans are highly sensitive to sulfur dioxide at short time periods
1-h AEGL-3
C3 × 1 h = 752530068 ppm·h
C3 = 752530068 ppm
C = 909
1-h AEGL-3 = 909 ppm/30 = 30 ppm
4-h AEGL-3
4-h AEGL-3 = 573 ppm/30 = 19 ppm
8-h AEGL-3
C1 × 8 hr = 2292 ppm·hr
C1 = 287 ppm
C = 287
8-h AEGL-3 = 287 ppm/30 = 9.6 ppm
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APPENDIX B
Derivation Summary of AEGLs for Sulfur Dioxide
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
0.20 ppm
0.20 ppm
0.20 ppm
0.20 ppm
0.20 ppm
Weight-of -evidence approach suggests 0.20 ppm is NOEL for bronchoconstriction in exercising asthmatics
Time Scaling: Data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-1 values for SO2 will be held constant across all time points.
Data adequacy: Robust data base of controlled studies in both healthy and asthmatic humans.
Weight of Evidence for AEGL-1
Concentration
Duration
Subjects
Exposure Parameters
Effect
Reference
0.2 ppm
5 min
8
23 °C, 85% RH, exercise 48 L/min
None
Linn et al. 1983b
0.25 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
None
Schacter et al. 1984
0.25 ppm
5 min
19
9
23 °C, 36% RH, exercise 60 L/min
SRaw ↑134%
Bethel et al. 1985
23 °C, 36% RH, exercise 80-90 L/min
SRaw ↑139%
0.25 ppm
75 min
28
26 °C, 70% RH, exercise 42 L/min intermittent
None
Roger et al. 1985
0.4 ppm
5 min
23
23 °C, 85% RH, exercise 48 L/min
SRaw ↑69%
Vmax25-75 ↓10%
Linn et al. 1983b
0.5 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
None
Schacter et al. 1984
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
0.75 ppm
0.75 ppm
0.75 ppm
0.75 ppm
0.75 ppm
Weight-of -evidence approach suggests 0.75 ppm induced moderate bronchoconstriction in exercising asthmatics.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
0.75 ppm
0.75 ppm
0.75 ppm
0.75 ppm
0.75 ppm
Time Scaling: The role of exposure duration to the magnitude of SO2-induced bronchoconstriction in asthmatics appears to decrease with extended exposure. Data suggest that a major portion of the SO2-induced bronchoconstriction occurs within 10-min and increases minimally or resolves beyond 10-min of exposure. Therefore, AEGL-2 values for SO2 were held constant across all time points.
Data adequacy: Robust data base of controlled studies in both healthy and asthmatic humans.
Weight of Evidence for AEGL-2
0.75 ppm
3 h
17
22 °C, 85% RH, exercise 45 L/min (first 10-min of exposure)
SRaw ↑:
322% (at 10-min)
233% (at 20-min)
26% (at 1-hr)
5% (at 2-hr)
FEV1 : ↓20% (at 15-min)
Hackney et al. 1984
0.75 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
SRaw ↑150%
FEF ↓22%
FEV1 ↓8%
Schacter et al. 1984
1.0 ppm
10-40 min
10
23 °C, 70% RH, exercise 35 L/min
SRaw ↑470%
FEF ↓27%
FEV1 ↓14%
Schacter et al. 1984
1.0 ppm
75 min
28
26 °C, 70% RH, exercise 42 L/min, intermittent
SRaw ↑300%
Roger et al. 1985
1.0 ppm
30 min
10
26 °C, 70% RH, exercise 41 L/min (3- 10 min periods separated by rests of 15 min)
SRaw ↑172%
SRaw ↑137%
SRaw 106%
Kehrl et al. 1987
1.0 ppm
30 min
10
26 °C, 70% RH, continuous exercise 41 L/min
SRaw ↑233%
Kehrl et al. 1987
1.0 ppm
1 min
8
22 °C, 75% RH, exercise 60 L/min
SRaw ↑93%
Balmes et al. 1987
3 min
SRaw ↑395%
5 min
SRaw ↑580%
1.0 ppm
0.5 min
12
20 °C, 40% RH, exercise 40 L/min
No SRaw effect
Horstman et al. 1988
1.0 min
No SRaw effect
2.0 min
SRaw ↑121%
5.0 min
SRaw ↑307%
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
30 ppm
30 ppm
30 ppm
19 ppm
9.6 ppm
Reference: Cohen, H.J., R.T. Drew, J.L. Johnson, and K.V. Rajagopalan. 1973.
Molecular basis of the biological function of molybdenum: The relationship between sulfite oxidase and the acute toxicity of bisulfite and SO2. Proc. Natl. Acad. Sci. USA 70(12):3655-3659.
Test Species/Strain/Sex/Number: CD outbred rats/8 males/concentration.
Exposure Route/Concentrations/Durations: Rats/Inhalation: 224, 593, 965, 1168, or 1319 ppm/4 h (BMCL05 of 573 ppm, was determinant for AEGL-3).
End Point/Concentration/Rationale: BMCL05/ 573 ppm/ threshold for death for 4 h exposure in rats.
Effects: Concentration: Mortality
224 ppm
0/8
593 ppm
0/8
965 ppm
3/8
1168 ppm
5/8
1319 ppm
8/8
Uncertainty Factors/Rationale:
Total uncertainty factor: 30
Intraspecies = 10: due to the wide variability in response to SO2 exposure between healthy and asthmatic humans.
Interspecies = 3: considered sufficient because no deaths were reported in guinea pigs exposed to 750 ppm SO2 for 1 h (Amdur 1959), in dogs exposed to 400 ppm SO2 for 2 h (Jackson and Eady 1988), or in rats exposed to 593 ppm for 4-h (Cohen et al. 1973).
Furthermore, a median lethal exposure time (Lt50) of 200 min was reported for mice exposed to 900 ppm SO2 (Bitron and Aharonson 1978) and three of eight rats died when exposed to 965 ppm for 240 min (Cohen et al. 1973), suggesting limited interspecies variability.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Insufficient data.
Time Scaling: Data are not sufficient to ascertain whether a maximal response to SO2 for a lethal end point is obtained within 10 min. Therefore, time scaling was utilized in the derivation of AEGL-3 values. An n of 3 was applied to extrapolate to the 1-h time period, and n of 1 was used for extrapolation to the 8-h time period to provide AEGL values that would be protective of human health (NRC 2001). The 1-h AEGL-3 value was also adopted as 10-min and 30-min values because asthmatic humans are highly sensitive to sulfur dioxide at short time periods.
Data adequacy: Well-conducted study with appropriate end point for AEGL-3.
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APPENDIX C
Category Plots for Sulfur Dioxide
FIGURE C-1 Category plots for sulfur dioxide for asthmatic humans.
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FIGURE C-2 Category plots for sulfur dioxide for healthy humans.
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FIGURE C-3 Category plots for sulfur dioxide for animals.
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