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Air Quality and Stationary Source Emission Control (1975)

Chapter: 3 Basic Biomedical Effects of Sulfur Oxides

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Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
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CHAPTER 3
BASIC BIOMEDICAL EFFECTS OF SULFUR OXIDES

BIOCHEMICAL MECHANISMS OF SULFUR OXIDE TOXICITY

Sulfur dioxide is a weak acid anhydride that is highly soluble in aqueous solutions, although its exact solubility at low concentrations has not been determined. At usual physiologic pH, sulfur dioxide in solution forms a mixture of sulfite, , and bisulfite, , ions. These ions are rapidly oxidized to sulfate, , by a widely distributed enzyme, sulfite oxidase. Accordingly, one can consider the biochemical mechanism of sulfur dioxide toxicity in terms of its weak acidity, of the action of sulfite-bisulfite ions, or of the effects of sulfate ions

The receptors for a number of neurochemical reflexes appear to be highly sensitive to changes in hydrogen ion concentration, and it is therefore conceivable that at major mechanism of sulfur dioxide toxicity is expressed through reflex bronchoconstrictive responses to a slight decrease in pH. Similarly, equivalent concentrations of the stronger sulfuric acid should be even more likely to produce a bronchoconstrictive response, and acid sulfate particles could activate the same pathways.

Relatively little is known about the distribution, metabolism, and eventual fate of sulfite and bisulfite ions in man. Experiments using radioactively labeled sulfur dioxide, 35SO2, have confirmed that the bulk of inhaled sulfur dioxide is absorbed and distributed throughout the body (Yokoyama et al. 1971, Balchum et al. 1960).

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
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However, the final chemical form of this sulfur is unknown; it is most likely to be sulfate, inasmuch as almost all the radioactivity is excreted as sulfate (Yokoyama et al. 1971). No information is available on the sites and rates of oxidation of sulfur dioxide to sulfate within the lungs or peripheral blood. The studies of Gunnison and his colleagues (Gunnison and Palmes 1974, Gunnison and Palmes 1973, Gunnison and Benton 1971) have demonstrated that rabbits exposed to sulfur dioxide develop measurable plasma concentrations of thiosulfonates that persist for days. Humans were found to have comparatively lower blood thiosulfonate concentrations after controlled exposure to sulfur dioxide at 0.3–6.0 ppm (Gunnison and Palmes 1974). Thiosulfonates are formed by the addition of sulfur dioxide across protein disulfide bonds. Although they have been identified thus far only in blood, the formation of lung thiosulfonates could be a mechanism of sulfur dioxide toxicity. The activity of enzymes containing integral disulfide bonds, such as ribonuclease, might be affected by this action of sulfur dioxide. The disruption of disulfide bonds is also believed to be the basis for in vitro potentiation of the red cell membrane effects of the indirect pathway of complement (DeSandre et al. 1970), the complement pathway reportedly responsible for the histamine release that is induced by allergen-reagin and results in asthma attacks (Malley et al. 1973). However, there is no direct evidence to link pulmonary or systemic thiosulfonates with sulfur dioxide toxicity. Furthermore, it should be noted that acetyclysteine, a common aerosol component used in the treatment of bronchitic disorders, is a sulfhydryl compound that is believed to act therapeutically by disrupting disulfide bonds in sputum.

Another potential biochemical mechanism of sulfite toxicity is the formation of free radicals. These reactive chemical species are presumably responsible for a number of the effects of sulfite observed during in vitro incubation with biologic compounds, including reduced pyridine nucleotides, tryptophan, methionine, indol-3-acetic acid, vitamin K, and thiamine (Shih and

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Petering 1973, Yang 1973, Yang and Saleh 1973, Yang 1970, Klebanoff 1961). Because only micromolar amounts of sulfite are required for many of these reactions, it is at least conceivable that some occur in the lungs. The exact free-radical species responsible for these effects are not known and may depend on the concentrations of trace metals and other interacting components. Superoxide anion (McCord and Fridovich 1969), hydroxyl, and sulfite radicals have been implicated in many disease processes, including cancer and aging. However, by analogy with similar processes, it is likely that the enzymatic oxidation of sulfite to sulfate by sulfite oxidase occurs in a tightly controlled milieu, thereby preventing the release of damaging free radicals. It is obviously important to obtain further information on the concentration of sulfite oxidase and on free-radical scavenging processes in the lungs.

Sulfite has also been shown to form adducts with flavin compounds and with folic acid, although in the latter case a large excess of sulfite is needed (Muller and Massey 1969, Vonderschmitt et al. 1967).

As will be discussed in more detail later, sulfite and bisulfite ions can react with deoxyribonucleic acid (DNA) to produce the deamination of cytosine. The ribonucleic acid (RNA) component uridine has also been shown to form an unstable intermediate on reaction with sulfite-bisulfite ions (Shapiro and Brauerman 1972). Neither reaction has been demonstrated in vivo; but the reaction with uridine occurs at lower concentrations and at normal pH, so it is more likely to be toxicologically significant. Modification of RNA would be expected to interfere with protein synthesis, and this has been demonstrated after incubation of bacteria with sulfite-bisulfite ions (Shapiro and Brauerman 1972). However, incubation of algae with bisulfite appears to interfere with DNA synthesis, rather than protein synthesis (Das and Runeckles 1974).

Other effects of sulfite-bisulfite ions observed at high concentrations in vitro include alterations of platelet function and interference

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

in the metabolic formation of red-cell 2,3-diphosphoglyceric acid, an important intermediate in the regulation of oxygen delivery to the tissues (Kikugawa and Hzuka 1972). However, free sulfite ions have not been detected in the blood of rabbits after exposure to sulfur dioxide at 25 ppm (Gunnison and Benton 1971).

There is little to suggest that sulfate ions formed as a result of sulfur dioxide inhalation play any role in toxicity. Sulfate is a normal body constituent in sufficient quantities so that ambient sulfur oxides would add little to total body concentrations. It is, of course, possible that a local increase in slulfate concentration within the lungs could be significant. This might alter sulfation rates of mucopolysaccharides, which are important extracellular lung components. In this respect, decreased concentrations of sulfated mucosubstances were observed by histochemical techniques in the bronchial surfaces of dogs chronically exposed to sulfur dioxide at 500–600 ppm (Spicer et al. 1974). Additional biochemical measurements revealed an increase in the activity of tracheobronchial glycotransferases. One of the few other studies to measure enzymatic changes after sulfur dioxide exposure (300 ppm, 6 hr/day for 10 days) reported increased activity of acid hydrolase, but not of other lysosmal enzymes, in alveolar macrophages (Barry and Mawdesley-Thomas 1970).

In summary, the biochemical mechanisms by which ambient concentrations of sulfur oxides produce effects in the lung are unknown. It it is accepted that the major physiologic consequence of sulfur oxide inhalation is bronchoconstriction, it is conceivable that effects are totally explainable by a decrease in pH. Hyperplasia of mucus-secreting cells, which may result from prolonged sulfur oxide exposure, might also be a response solely to acidity. However, this conservative approach to an explanation of sulfur oxide toxicity is most likely an oversimplification. Further studies using sensitive biochemical techniques and reasonable sulfur oxide exposures would be of value.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
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PHYSIOLOGIC AND ANATOMIC EFFECTS OF SULFUR OXIDES

The literature concerning animal respiratory physiologic response to the inhalation of sulfur oxides, particularly sulfur dioxide, is relatively voluminous. Much of the work has originated in the laboratory of Amdur, who has evaluated in depth the bronchoconstrictive response of guinea pigs to various ceoncentrations of sulfur dioxide, particles, and sulfuric acid, alone and in combination. Extensive studies of guinea pigs and other animals have also been done by others and this subject has been reviewed by Amdur (1971), Riley (1974), Alarie and Palmes (1974), and Dubois (1969).

The following discussion will concentrate on studies that have provided insight into the possible mechanisms of toxic action of the various sulfur oxides and that appear to be pertinent to an understanding of human response.

The major quantitated physiologic indicator of response to sulfur dioxide has been an increase in resistance to pulmonary flow, which has usually, but not always, (Davis et al, 1967) been related to bronchoconstriction. This has been observed in a number of animal species (Corn et al. 1972, Frank and Speizer 1965, Nadel et al. 1965, Swann et al. 1965, Salem and Aviado 1961, Balchum et al. 1960) and in man. In general, the acute response to sulfur dioxide in animals has been short-lived and has not persisted after cessation of exposure. In some instances, a return toward normal pulmonary flow resistance has been observed during continous sulfur dioxide exposure, indicating some degree of adaption. The apparent threshold for this acute response to sulfur dioxide is very high, relative to usual ambient concentrattions.

A number of ingenious pharmacologic and surgical techniques have been used to explore the mechanism by which increased respiratory flow resistance occurs, the site of the sulfur dioxide receptor, and the specific airway locale that is most affected. The major overall impression is that multiple potential receptors and effectors in various parts of the

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

respiratory tract can increase flow resistance (Frank and Speizer 1965) locally or reflexively in other parts of the airway. Inasmuch as sulfur dioxide inhaled in clean air is almost totally absorbed in the upper airways (Andersen et al. 1974, Frank et al. 1969, Vaughan et al. 1969, Frank et al. 1967, Frank and Speizer 1965, Dalhamn and Strandberg 1961), its effects on bronchi lower in the respiratory tract must be mediated by some indirect pathway. The studies of Widdicombe, Nadel, and their co-workers have demonstrated a number of receptors in the upper respiratory tract that, when stimulated, result in cough, local airway narrowing, or constriction of other respiratory tract areas (Nadel et al. 1965, Nadel and Widdicombe 1962, Widdicombe et al. (1962). Although airway narrowing due to sulfur dioxide generally appears to result from reflexes mediated through the vagus nerve, humeral pathways acting on smooth muscle may also be operative (Nadel et al. 1965, Salem and Aviado 1961). It is also possible that sulfur dioxide absorbed in the upper respiratory tract may be carried in the pulmonary circulation to the lower airways, thereby providing another possible mechanism of bronchoconstriction (Frank et al. 1967).

Another important point that is obvious from animal experiments is the substantial and consistently observed variability in the response of different animals of the same species. Laboratory animals of the same species tend to have more homegeneous genetic and environmental backgrounds than does man, so an even greater variability in human response would be expected.

An interesting study was presented by Islam et al. (1972), in which dogs were exposed sequentially and repetitively to an aerosol of the bronchoconstrictive agent acetylcholine and then to sulfur dioxide for 1 hr. After sulfur dioxide exposure, marked potentiation of the bronchoconstrictive response to acetylcholine was observed; it appeared to be linear in response to sulfur dioxide at 1–5 ppm, but declined somewhat at 10 ppm. The pertinence of this study is its suggestion that sulfur dioxide may potentiate the response to

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

neuropharmacologic agents that normally act to produce bronchoconstriction after vagus nerve stimulation.

The studies of the acute response to sulfur dioxide alone have provided important information, but more pertinent data have been obtained from experiments in which animals were exposed to combinations of sulfur dioxide and particles or to other sulfur oxides. Amdur originally demonstrated a synergistic effect of sulfur dioxide aerosols of respirable size (Andur 1957). However, a synergistic interaction of sodium chloride particles and sulfur dioxide could not be confirmed in casts (Corn et al. 1972) or man. The recent work of McJilton et al. (1973) has provided additional insight into this process by demonstrating the importance of relative humidity: A synergistic response in the pulmonary flow resistance of guinea pigs exposed to a submicrometer aerosol of sodium chloride (900–1,000 ug/m3) and sulfur dioxide (1.1 ppm) was observed only at a relative humidity of greater than 80 percent; no effect on pulmonary flow resistance was observed when the relative humidity was less than 40 percent, nor when the animals were exposed to sulfur dioxide or the aerosol alone. The authors hypothesize that the deliquescense of sodium chloride, which occurs at about 70 percent relative humidity, leads to an increased loading of sulfur dioxide onto the aerosol and therefore to a greater delivery of sulfur dioxide to the lower part of the lungs. With high relative humidity, the pH of the aerosol is low, owing presumably to the formation of bisulfite ions (no sulfate was detected).

Two points should be made. First, the relative humidity of the respiratory tract is close to 100 percent, so deliquescence of inhaled dry sodium chloride will occur in any event; however, the authors suggest that the bulk of sulfur dioxide will be removed within the guinea pig nose and that there is insufficient time for both the deliquescence of dry sodium chloride within the nose and the absorption of sulfur dioxide onto the aerosol before the sulfur dioxide is scrubbed out by the nasal mucosa. Second, the studies of Amdur

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

demonstrating synergism in this same nosebreathing animal were performed at about 50 percent relative humidity, which is below the deliquescence point of sodium chloride; this might be explainable by the fact that sulfur dioxide can still be absorbed onto dry particles, although to a lesser extent. Inasmuch as Amdur generally used higher aerosol concentrations, absorption onto the dry particles may have been sufficient to account for the findings of synergism.

Other studies by Amdur and her colleagues in the gunea pig, evaluating a series of different inert aerosols inhaled in conjuction with sulfur dioxide, have indicated that particle size is of great importance (the smaller the particle, the greater the effect); that potentiation is observed only with soluble aerosols (the greater the solubility, the greater the effect); that soluble metallic aerosols produce a greater effect than inert aerosols, presumably because of the catalytic formation of sulfuric acid; and that the effect of aerosol-sulfur dioxide mixtures tends to persist, whereas that of sulfur dioxide alone disappears rapidly (Amdur and Underhill 1968, Amdur 1959, 1957).

This guinea pig model has also been used to study the effects of other sulfur oxides. Aerosols of sulfuric acid are far more potent than sulfur dioxide in increasing pulmonary flow resistance, and the response is more rapid and prolonged (Amdur 1971, 1969, 1959, 1958). Sulfuric acid is also more potent than the combined effects of sulfur dioxide and sodium chloride aerosol, particularly at low concentrations. The aerosol size of sulfuric acid influenced the degree of the increase in pulmonary flow resistance, the course of the response, and the extent of airway obstruction. Synergism between sulfur dioxide and sulfuric acid aerosol on pulmonary flow resistance in guinea pigs has also been reported (Amdur 1957).

Short-term inhalation of aerosols of various particulate sulfates were found to increase pulmonary flow resistance at concentrations at which inert aerosols have no effect (Amdur and Corn 1963). Zinc ammonium sulfate was more potent than either zinc sulfate or ammonium

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

sulfate; this suggests that the acidity of the aerosol may be important. However, ammonium sulfate had a smaller effect than zinc sulfate. Again, toxicity was inversely related to particle size. A 20 percent increase in airway resistance was noted during exposure to zinc ammonium sulfate at 200 ug/m3 (particle size, 0.3 um). The rationale for the study of these compounds was the retrospective observation of Hemeon (1955) that zinc ammonium sulfate and zinc sulfate were present in substantial concentrations during the 1948 Donora air pollution disaster. Ferric sulfate inhaled alone was found to increase pulmonary flow resistance, but ferrous sulfate had no effect (Amdur and Underhill 1968).

A recent study by Alarie et al. (1973) evaluated mice exposed to sodium sulfite and sodium metabisulfite. Only the latter compound produced sensory irritation, with effects similar to those of sulfur dioxide. The authors hypothesize that the formation of bisulfite in the slightly alkaline nasal mucosa is a central mechanism of effect.

Amdur has summarized her studies in guinea pigs and prepared dose-response curves comparing the effects of the various sulfur oxides (Amdur 1971). The data clearly indicate that sulfur dioxide is far less irritating than equivalent concentrations of sulfuric acid and zinc ammonium sulfate. The relative toxicity of the latter two compounds depends on particle size. In some cases, zinc ammonium sulfate appears to be more potent than sulfuric acid. These findings emphasize the need for accurate determination of the composition and size of particles in polluted air. In general, the data indicate that atmospheric oxidation of a relatively small fraction of sulfur dioxide will produce particulate aerosols more toxic than the parent gas. Furthermore, the effects of sulfur dioxide and its products are probably additive and perhaps synergistic.

Man has been the subject of a number of controlled experimental studies of the acute effects of sulfur dioxide. Increased airway resistance, due presumably to bronchoconstriction, is the major feature of the

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

response to sulfur dioxide (Melville 1970, Nadel et al. 1965, Frank et al. 1964, 1962). Recent studies by Andersen et al. demonstrating that sulfur dioxide concentrations resulting in an increased forced expiratory volume do not affect airway closing volume indicate that only the relatively larger parts of the bronchi are affected (Andersen et al. 1974). Increased airway flow resistance is also observed as a consequence of exposure to very high concentrations of particles (Dubois and Dautrebande 1958). Only healthy subjects have been used in these experiments, and, although marked variability has been observed, responses to sulfur dioxide concentrations as low as 0.75 ppm have only rarely been reported (Bates and Hazucha 1973). This effect of sulfur dioxide is rapidly reversible and, as in animals, appears to be mediated through vagus nerve relfex arcs (Nadel et al. 1965a, 1965b). Sulfur dioxide at 1–5 ppm also may produce an increase in pulse rates and respiration, as well as a decreased tidal volume, although this is not consistently observed (Amdur et al. 1953). Inhalation through the nose appears to produce a smaller response than inhalation by mouth, but again there is some variability in results. In some subjects, the response to sulfur dioxide appears to decrease on prolonged or later exposure.

An interesting series of studies have been presented by Weir and Bromberg (1973, 1972). Normal subjects had an increased airway resistance during exposure to sulfur dioxide at 3 ppm for 5 days, which persisted for less than 2 days after removal from the chamber. Exposure of patients with preexisting respiratory disease to 0.3–3.0 ppm for a week resulted in highly variable responses, but produced no consistent effect.

Attempts to demonstrate a synergistic effect of sulfur dioxide and sodium chloride aerosol in man have been unsuccessful (Burton et al. 1969, Frank 1964, Frank et al. 1964). However, Snell and Luchsinger (1969) observed synergism of 0.5-ppm sulfur dioxide and a submicrometer distilled water aerosol on maximal expiratory flow rate in one experiment. An additive effect of combined exposure to sulfur dioxide (5 ppm) and nitrogen

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

dioxide (5 ppm) has also been reported (Abe 1967).

Of great interest is a recent study by Bates and Hazucha (1973) which demonstrated a synergistic effect of sulfur dioxide and ozone in healthy men. No changes in pulmonary function were observed in volunteers who breathed 0.37-ppm sulfur dioxide alone for 2 hr. However, inhalation of 0.37-ppm ozone and 0.37-ppm sulfur dioxide produced a definite decrement in maximal midepiratory flow rate. Ozone alone at this concentration had a much smaller effect. It is of further interest that the volunteers underwent intermittent exercise in the exposure chamber and that sulfur dioxide alone at 0.75 ppm had a small but significant effect. Because this is the lowest concentration of sulfur dioxide reported to have an effect in man, the results suggest that exercise potentiates the action of sulfur dioxide, perhaps by increasing mouth-breathing and inspiratory flow rates.

There are a number of possible explanations for the observed synergism between ozone and sulfur dioxide. A likely one is that sulfuric acid was formed by the reaction of these two agents in the presence of water vapor or mucous in the respiratory tract. It is also possible that, by decreasing the pH of the mucous lining, sulfur dioxide increases the solubility of ozone and thereby potentiates an ozone effect. Further studies of this important observation are needed, particularly to rule out the possibility that sulfuric acid aerosol was formed in the chamber.

Pattle and his colleagues (Sim and Pattle 1957, Pattle and Cullumbine 1956) have exposed healthy volunteers to sulfuric acid. At the high concentrations used in their experiments (5–10 ppm, 20–40 mg/m3), a marked increase in airway resistance was observed, as were chest discomfort, rales, cough, and lacrimation. Two subjects who were repetitively exposed developed bronchitits symptoms. The presence of water vapor potentiated the observed responses, but addition of ammonia vapor decreased the effect. The latter finding suggests that ammonium sulfate is not as toxic as sulfuric acid.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

A number of investigators have studied the effects of short-term exposure to sulfur dioxide on various aspects of mucociliary transport. Decreased ciliary activity has been reported in the tracheas of rabbits after inhalation (100–200 ppm) or direct tracheal exposure (10 ppm) (Dalhamn and Strandberg 1961, Calley 1942). This effect was not potentiated when carbon particles capable of absorbing sulfur dioxide were inhaled with it (Dalhamn and Strandberg 1963). The clearance of particles from the lower respiratory tract has been evaluated in donkeys, in which inhibitory effects were observed at 300 ppm (Spiegelman et al. 1968), and in rats, in which sulfur dioxide had a slight stimulatory effect at 0.1 ppm, but resulted in a decrease in clearance at 1 ppm for 170 hr. (Ferin and Leach 1973). In the latter study, short term high-dose exposures had a smaller effect than long-term low-dose exposures. Andersen et al. (1974) recently reported a study in which healthy human volunteers were shown to have a decrease in nasal mucous flow rate during 6 hr of exposure to sulfur dioxide at 1.5 and 25 ppm, although the findings at 1 ppm were not statistically significant. Subjects who initially had the lowest nasal flow rates were most affected by sulfur dioxide. The decrease in flow rate was most prominent in the anterior part of the nose, which absorbed the bulk of the sulfur dioxide. Increased nasal flow resistance was also observed in all subjects. This had previously been reported as an inconstant effect by Speizer and Frank (1966).

Studies of the long-term effects of sulfur dioxide in animals have generally demonstrated no deleterious effects at concentrations within the range of usual ambient conditions. Chronic inhalation of concentrations greater than 100 ppm has resulted in hyperplasia of mucus-secreting cells and metaplasia of the bronchial epithelium similar to that observed in chronic bronchitits in man (Spicer et al. 1974, Asmundsson et al. 1973, Goldring et al. 1970, Lamb and Reid 1968, Pattle and Cullumbine 1956). However, in a study of cynomolgus monkeys, Alarie et al. (1972) observed no changes in

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

sensitive pulmonary-function tests, lung histology, or blood chemistry during 78 weeks of uninterrupted exposure to sulfur dioxide at 0.14 or 1.28 ppm. Other studies by the same group demonstrated no effect of sulfur dioxide on guinea pigs exposed for a year to similar concentrations (Alarie et al. 1970). In addition, no adverse effects were observed in guinea pigs and monkeys exposed to fly ash (obtained from the effluent of coal-burning plants and having a mass median diameter of 2.6–3.4 um) inhaled with sulfur dioxide in the same concentrations and durations as in the above experiments (Alarie et al. 1973). Inhalation of sulfur dioxide (35 ppm) and corn starch and corn dust particles (particle size, >2 um) has been reported to have effects on pigs similar to that of sulfur dioxide alone (Martin and Willoughby 1972). Rabbits inhaling sulfur dioxide at 10 ppm for 16 hr/day initially had an increased rate of clearance of inhaled particles (3–6 um), but this diminished after 6 weeks of exposure (Holma 1967).

These studies were performed in healthy animals and might not mimic the long-term effects of sulfur dioxide on people with chronic lung disease. However, production of lung disease by treatment of hamsters with papain or exposure of dogs to nitrogen dioxide has not been found to potentiate the response to later exposure to sulfur dioxide at very high concentrations (Lewis et al. 1973, Goldring et al. 1970). In addition, animals chronically exposed to Los Angeles air responded similarly to clean air controls when acutely exposed to sulfur dioxide (Emik et al. 1971).

Fewer studies of long-term exposure to sulfuric acid have been performed. Thomas et al. (1958) reported that exposure of guinea pigs to 2,000 ug/m3 for 3 months produced little effect. At higher concentrations, the pathologic findings depended on particle size. Alarie et al. (1973) observed no effects on lung function or histology of guinea pigs exposed for a year to sulfuric acid at 80 ug/m3 (particle size, 0.84 um) or 100 ug/m3 (particle size, 2.8 um). However, adverse effects were observed in cynomolgus monkeys exposed to various concentra-

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

tions of sulfuric acid for 78 weeks. The changes were slight but detectable at 380 ug/m3 (particle size, 2.2 um) and 480 ug/m3 (particle size, 0.5 um) and were more prominent at higher concentrations. Major observations included alterations in the distribution of ventilation (as measured by nitrogen washout), hyperplasia of the bronchial epithelium, and thickening of the bronchiolar walls. Particle size appeared to have little relation to eventual damage, although there was a tendency toward less adverse effects with particles in the smaller (submicrometer) range.

Lewis and his colleagues (Lewis et al. 1974, 1973, Bloch et al. 1972, Lewis et al. 1969, Vaughan et al. 1969) have performed a series of studies in beagles that included individual or combined exposure to sulfur dioxide and sulfuric acid for up to 5 years. A mixture of sulfur dioxide (13.4 mg/m3, 5 ppm) and sulfuric acid (900 ug/m3) resulted in physiologic changes that suggested both lung parenchymal disease and airway obstruction. Sulfuric acid alone produced a decrease in lung diffusing capacity; sulfur dioxide alone resulted in increased airway resistance and alterations of lung compliance similar to those reported in other animals. In one study, beagles that had previously been chronically exposed to nitrogen dioxide tended to have a somewhat smaller response to sulfur oxides; this suggests that the preexisting lung alterations were protective. Additional studies by this group have provided suggestive, but not conclusive, evidence that inhalation of sulfur dioxide-sulfuric acid mixtures potentiates the pulmonary hyperinflation produced by chronic inhalation of raw auto exhaust and may lead to some cardiac abnormalities. One technical problem concerning sulfuric acid explosures is that ammonia produced by animal excreta might buffer the sulfuric acid and produce ammonium sulfate aerosol.

Among the most important results of the animal and controlled human exposure experiements cited above is the insight into potential mechanisms of sulfur oxide toxicity at ambient concentrations. Sulfur dioxide acting

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

alone is unlikely to be physiologically important, except during periods of severe inversion coupled with grossly inadequate emission control. However, sulfur oxide concentrations that are within the range of ambient concentrations not infrequently experienced in polluted areas of the United States may produce effects by one or more of the following mechanisms:

  1. A direct effect of ambient sulfuric acid.

  2. A direct effect of ambient suspended particulate sulfates.

  3. An effect of sulfur dioxide potentiated by adsorption onto inert particles of respirable size.

  4. An effect of sulfur dioxide potentiated by metallic particles that catalyze its oxidation in the airway.

  5. An effect of sulfur dioxide potentiated by simultaneous inhalation of ozone.

Inasmuch as the various sulfur oxides tend to be present together in polluted air, the effects described above may well occur simultaneously in an additive, or perhaps synergistic, manner.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

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Alarie, Y., W.M.Busey, A.A.Krumm, and C.E.Ulrich (1973). Long-term continuous exposure to sulfuric acid mist in cynomolgus monkeys and guinea pigs. Arch. Envrion. Health 27:16–24.

Alarie, Y., R.J.Kants, II, C.E.Ulrich, A.A.Krumm, and W.M.Busey (1973). Long-term continous exposure to sulfur dioxide and fly ash mixtures in cynomolgus monkeys and guinea pigs. Arch. Environ. Health 27:251–253.

Alarie, Y., I.Wakisaka, and S.Oka (1973). Sensory irritation by sulfite aerosols. Environ. Physiol. Biochem. 3:182–184.

Alarie, Y., and E.D.Palmes (1974). Animal experiments, pp. 474–478. In National Academy of Sciences-National Academy of Engineering. Health Effects of Air Pollutants, Vol 2. A report by the Coordinating Committee on Air Quality Studies, prepared for the U.S. Senate Committee on Public Works. Washington, D.C.: U.S. Government Printing Office.

Alarie, Y., C.E.Ulrich, W.M.Busey, A.A.Krumm, and H.N.MacFarland (1972). Long-term continous exposure to sulfur dioxide in cynomolgus monkeys. Arch. Environ. Health 24:115–128.

Alarie, Y., C.E.Ulrich, W.M.Busey, H.E.Swann, Jr., and H.N.MacFarland (1970). Long-term continous exposure of guinea pigs to sulfur dioxide. Arch. Environ. Health 21:769–777.

Amdur, M.O. (1957). The influence of aerosols upon the respiratory response of guinea pigs to sulfur dioxide. Amer. Ind. Hyg. Assoc. 18:149–155.

Amdur, M.O. (1958). The respiratory response of guinea pigs to sulfuric acid mist. Arch. Ind. Health 18:407–414.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Amdur, M.O. (1959). The physiological response of guinea pigs to atmospheric pollutants. Int. J. Air Pollut. 1:170–183.

Amdur, M.O. (1969). Toxicologic appraisal of particulate matter, oxides of sulfur, and sulfuric acid. J. Air Pollut. Control Assoc. 19:638–644.

Amdur, M.O. (1971). Aerosols formed by oxidation of sulfur dioxide. Review of their toxicology. Arch. Environ. Health 23:459–468.

Amdur, M.O., and M.Corn (1963). The irritant potency of zinc ammonium sulfate of different particle sizes. Amer. Ind. Hyg. Assoc. J. 24:326–333.

Amdur, M.O., W.W.Melvin, and P.Drinker (1953). Effects of inhalation of sulphur dioxide by man. Lancet 2:758–759.

Amdur, M.O., and D.Underhill (1968). The effect of various aerosols on the response of guinea pigs to sulfur dioxide. Arch. Environ. Health 16:460–468.

Andersen, Ib., G.R.Lundqvist, P.L.Jensen, and D.F.Proctor (1974). Human response to controlled levels of suflur dioxide. Arch. Environ. Health 28:31–39.

Asmudsson, T., K.H.Kilburn, and W.N.McKenzie (1973). Injury and metaplasia of airway cells due to sulfur dioxide. Lab. Invest. 29:41–53.


Balchum, O.J., J.Dybicki, and G.R.Meneely (1960). Pulmonary resistance and compliance with concurrent radioactive sulfur distribution in dogs breathing S35O2. J. Appl. Physiol. 15:62–66.

Barry, D.H., and L.E.Mawdesley-Thomas (1970). Effect of sulphur dioxide on the enzyme activity of the alveolar macrophage of rats. Thorax 25:612–614.

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Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Bloch, W.N. Jr., T.R.Lewis, K.A.Busch, J.G.Orhoefer, and J.F.Stara (1972). Cardiovascular status of female beagles exposed to air pollutants. Arch. Environ. Health 24:342–353.

Burton, G.G., M.Corn, J.B.L.Gee, C.Vasallo, and A.P.Thomas (1969). Response of healthy men to inhaled low concentrations of gas-aerosol mixtures. Arch. Environ. Health 18:681–692.


Corn, M., N.Kotsko, D.Stanton, W.Bell and A.P.Thomas (1972). Response of cats to inhaled mixtures of sulfur dioxide and SO2-NaC1 aerosol in air. Arch. Environ. Health 24:248–256.

Cralley, L.V. (1942). The effect of irritant gases upon the rate of ciliary activity. J. Ind. Hyg. Toxicol. 24:193–198.


Dalhamn, T., and L.Strandberg (1961). Acute effect of sulphur dioxide on the rate of ciliary beat in the trachea of rabbit, in vivo and in vitro, with studies on the absorptional capacity of the nasal cavity. Int. J. Air Water Pollut. 4:154–167.

Dalhamn, T., and L.Strandberg (1963). Synergism between sulphur dioxide and carbon particles. Studies on adsorption and on ciliary movements in the rabbit trachea in vivo. Int. J. Air Wat. Pollut. 7:517–529.

Das, G., and V.C.Runeckles (1974). Effects of bisulfite on metabolic development in synchronous Chlorella pyrenoidosa. Environ. Res. 7:353–362.

Davis, T.R.A., S.P.Battista, and C.J.Kensler (1967). Mechanism of respiratory effects during exposure of guinea pigs to irritants. Arch. Environ. Health 15:412–419.

De Sandre, G., S.Cortesi, R.Corrocher, G.Falezza, and G.Perona (1970). On the mechanism of the in vitro production of Ham-positive red cells by sulphydryl compounds: Role of pH and free -SH groups. Brit. J. Haemat. 18:551–556.

Dubois, A.B. (1969). Mechanism of bronchial response to inhalants. Environ. Res. 2:397–403.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Dubois, A.B., and L.Dautrebande (1958). Acute effects of breathing inert dust particles and of carbachol aerosol on the mechanical characteristics of the lungs in man. Changes in response after inhaling sympathomimetic aerosols. J. Clin. Invest. 37:1746–1755.


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Ferin, J., and L.J.Leach (1973). The effect of sulfur dioxide on lung clearance of TiO2 particles in rats. Amer. Ind. Hyg. Assoc. J. 34:260–263.

Frank, N.R. (1964). Studies on the effects of acute exposure to sulphur dioxide in human subjects. Proc. Roy. Soc. Med. 57:1029–1033.

Frank, N.R., M.O.Amdur, and J.L.Whittenberger (1964). A comparison of the acute effects of sulfur dioxide administered alone or in combination with NaC1 particles on the respiratory mechanics of healthy adults. Int. J. Air Wat. Pollut. 8:125–133.

Frank, N.R., M.O.Amdur, J.Worcester, and J.L.Whittenberger (1962). Effects of acute controlled exposure to sulfur dioxide on respiratory mechanics in healthy male adults. J. Appl. Physiol. 17:252–258.

Frank, N.R., and F.E.Speizer (1965). Sulfur dioxide effects on the respiratory system in dogs. Arch. Environ. Health 11:624–634.

Frank, N.R., R.E.Yoder, J.D.Brain, and E.Yokoyama (1969). Sulfur dioxide (35S labeled) absorption by the nose and mouth under conditions of varying concentration and flow. Arch. Environ. Health 18:315–322.

Frank, N.R., R.E.Yoder, E.Yokoyama, and F.E.Speizer (1967). The diffusion of 35Sulfur dioxide from tissue fluids into the lungs following exposure of dogs to 35sulfur dioxide. Health Phys. 13:31–38.


Goldring, I.P., S.Greenburg, S-S.Park, and I.M.Ratner (1970). Pulmonary effects of sulfur dioxide exposure in the Syrian hamster. II. Combined with emphysema. Arch. Environ. Health 21:32–37.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Gunnison, A.F., and A.W.Benton (1971). Sulfur dioxide: Sulfite. Interaction with mammalian serum and plasma. Arch. Envrion. Health 22:381–388.

Gunnison, A.F., and E.D.Palmes (1973). Persistence of plasma S-sulfonates following exposure of rabbits to sulfite and sulfur dioxide. Toxicol. Appl. Pharmacol. 24:266–278.

Gunnison, A.F., and E.D.Palmes (1974). S-sulfonates in human plasma following inhalation of sulfur dioxide. Amer. Indust. Hyg. Assoc. J. 3:288–291.


Hemeon, W.C.L. (1955). The estimation of health hazards from air pollution. Arch. Ind. Health 11:397–407.

Holma, B. (1967). Lung clearance of mono- and di-disperse aerosols determined by profile scanning and whole-body counting. A study on normal and sulfur dioxide exposed rabbits. Acta Med. Scand. Supplementum 473. pp. 1–102.


Islam, M.S., E.Vastag, and W.T.Ulmer (1972). Sulphur-dioxide induced bronchial hyperreactivity against acetylcholine. Int. Arch. Arbeitsmed. 29:221–232.


Kikugawa, K., and K.Hzuka (1972). Inhibition of platelet aggregation by bisulfite-sulfite. J. Pharmaceut. Sci. 61:1904–1907.

Klebanoff, S.J. (1961). The sulfite-activated oxidation of reduced pyridine nucleotides by peroxidase. Biochim. Biophys. Acta 48:93–103.


Lamb, D., and L.Reid (1968). Mitotic rates, goblet cell increase and histochemical changes in mucus in rat bronchial epithelium during expsosure dioxide. J. Pathol. Bacteriol 96:97–111.

Lewis, T.R., K.I.Campbell, and T.R.Vaughan, Jr. (1969). Effects on canine NO2 impairment, particulate interaction, and subsequent SOx. Arch. Environ. Health 18:596–601.

Lewis, T.R., W.J.Moorman, W.F.Ludmann, and K.I.Campbell (1973). Toxicity of long-term exposure to oxides of sulfur. Arch. Environ. Health 26:16–21.

Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Lewis, T.R., W.J.Moorman, Y-y.Yang, and J.Stara (1974). Long-term exposure to auto exhaust and other pollutant mixtures. Effects on pulmonary function in the beagle. Arch. Environ. Health 29:102–106.


Malley, A., L.Baecher, G.Crossley, and D.Burger (1973). Allergen-reaginmediated histamine release reactions. I. Role of the alternate complement pathway. Int. Arch. Allergy 44:122–139.

Martin, S.W., and R.A.Willoughby (1972). Organic dusts, sulfur dioxide, and the respiratory tract of swine. Arch. Environ. Health 25:158–165.

McCord, J.M., and I.Fridovich (1969). The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide and oxygen. J. Biol. Chem. 244:6056–6063.

McJilton, C., R.Frank, and R.Charlson (1973). Role of relative humidity in the synergistic effect of a sulfur dioxide-aerosol mixture on the lung. Science 182:503–504.

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Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

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Suggested Citation:"3 Basic Biomedical Effects of Sulfur Oxides." National Research Council. 1975. Air Quality and Stationary Source Emission Control. Washington, DC: The National Academies Press. doi: 10.17226/10840.
×

Vaughan, T.R., Jr., L.F.Jennelle, and T.R.Lewis (1969). Long-term exposure to low levels of air pollutants. Effects on pulmonary function in the beagle. Arch. Environ. Helath 19:45–50.

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