INTRODUCTION

Hydrogen sulfide and sulfur dioxide are two sulfur-based gases that exhibit entirely different toxicological characteristics. Litigation issues involving these two gases are as different as are their disparate toxic effects in humans.

HYDROGEN SULFIDE

Toxicology

Hydrogen sulfide is a highly toxic gas that has caused many fatalities. It exerts its significant toxic effects primarily in two ways: 1. As a central nervous system toxin (neurotoxin), and 2. As a local irritant. Although not considered a toxic effect, very low concentrations of hydrogen sulfide in the air can create a very significant odor nuisance. More than 1000 cases of acute hydrogen sulfide poisoning have been reported over the past five decades. Case fatality rates approximate 5% (Aves, 1929; Ahlborg, 1951; Kleinfeld, et al., 1964; Burnett, et al., 1977; Arnold, et al. 1984; Gregorakos, et al., 1995). Inhaled hydrogen sulfide is very rapidly destroyed by normal detoxification mechanisms and does not accumulate in the body (Haggard, 1921; Evans, 1967).

1. Central nervous system toxicity
When inhaled, hydrogen sulfide is quickly and effectively absorbed into the blood through the lung and immediately transported to the brain where it acts as an inhibitor of a critical respiratory enzyme, cytochrome oxidase (Smith and Gosselin, 1979). This enzyme is necessary for cellular respiration, and when it is inhibited, the brain is deprived of molecular oxygen required for its normal functioning. Cerebral hypoxia is the result.

At air concentrations of about 750 ppm, inhalation of hydrogen sulfide gas can cause immediate collapse and unconsciousness. If exposure is very brief, for example, transitory envelopment by a passing gas cloud, the victim may awaken promptly and experience no adverse effects at all (Beauchamp, et al., 1984; Guidotti, 1994). In industries where hydrogen sulfide exposure is commonplace, for example oil field work, employees often refer to this phenomenon as "knockdown" (Guidotti, 1994). These early, rapid central nervous system effects are probably a result of direct neurotoxicicity (Milby & Baselt, 1999a,b). If exposure is prolonged, or air concentrations are high (above 1000-1500 ppm), the unconscious victim may cease breathing (apnea), and will die unless promptly moved to fresh air and given immediate artificial respiration (Haggard and Henderson, 1922). Overall, however, most victims of hydrogen sulfide-induced collapse recover completely (Milby and Baselt, 1999a; Beauchamp, et al., 1984). In a small percentage of victims, primarily those who are very severely poisoned or who are not promptly rescued, prolonged apnea can lead to hypoxic encephalopathy with sequelae ranging from mild neurological deficits to hypoxia-related dementias or death (Freireich, 1946; Hurwitz and Taylor, 1954; Larson, 1964; Kemper, 1966; Matuso, et al., 1979; Adelson and Sunshine, 1986; Deng and Chang, 1987; Tvedt, et al., 1991).

The preponderance of scientific evidence suggests that permanent central nervous system sequelae result from hypoxia secondary to respiratory insufficiency (Beauchamp, et al., 1984; Milby & Baselt, 1999a; Riffenstein, et al., 1992). Understanding this mechanism of action is important to both the treating physician and the forensic toxicologist. To the clinician, the critical need for prompt treatment aimed at re-oxygenating the brain becomes undisputable. The forensic toxicologist should be aware that there is no reliable evidence that poisoning by this gas leads to neurotoxic sequelae such as memory loss, concentration problems, ataxia, headaches, or other chronic effects in the absence of clinically significant cerebral hypoxia occurring as a direct consequence of one or more of the following events: unambiguous unconsciousness with apnea, respiratory insufficiency induced by pulmonary edema, or significant airway obstruction (Milby, 1962; Beauchamp, et al., 1984; Milby and Baselt, 1999b).

2. Local irritation
     A. Eye Iritation
After several hours of exposure to hydrogen sulfide gas in concentrations of about 50 ppm, or after only a few minutes at higher, neurotoxic air levels, conjunctivitis and keratoconjunctivitis may become clinically apparent (Milby, 1962; Beauchamp, et al.1984). In older literature, this was called "gas eye" (Yant, 1930). The current OSHA PEL of 20 ppm was established to protect against eye irritation in most workers.

     B. Pulmonary edema
Hydrogen sulfide, unlike sulfur dioxide, is not very soluble in water. For this reason, it is not efficiently removed from the inhaled air by the moist mucous membranes of the upper respiratory tract and is free to penetrate deeply into the lungs. Here it encounters the most sensitive tissues of the lung causing irritation, which may give way to pulmonary edema (Burnett, et al., 1977; Arnold, et al., 1985, Tanaka, et al., 1999). On a practical basis, the more dramatic, life-threatening neurotoxic effects associate with hydrogen sulfide toxicity often overshadow its irritative effects, although in some cases, pulmonary edema can cause serious complications, even death (Kleinfeld, et al., 1964). In consideration of the potential danger for developing pulmonary edema, a person significantly exposed to hydrogen sulfide gas should be under medical observation, preferably under hospital conditions, for at least 24 hours after exposure (Milby, 1962).

3. Odor nuisance
Most people can detect the characteristic rotten-egg smell of hydrogen sulfide gas at very low air concentrations, usually well under 0.1 ppm (Beauchamp, et al., 1984). Short-lived exposures to air levels of this magnitude do not cause physical injury, nor is there any reliable evidence that such exposures induce sensitivity to the gas or to other chemicals. However, under some conditions, especially if exposure is intense or prolonged, the pervasive, foul, rotten-egg odor of hydrogen sulfide can cause transitory headache and sleep disturbances at air concentrations at low as 0.250 -0.300 ppm (Milby and Baselt, 1999a; Haahtela, et al., 1992; PHS, 1964). However, these nuisance symptoms may well represent nothing more than a non-specific response to a foul odor.

Litigation Issues

Hydrogen sulfide as an odor nuisance

Easily detectable levels of this gas are commonly found in the vicinity of waste lagoons, geothermal facilities, special waste disposal sites, petrochemical installations, volcanic activity, and the like. In the experience of the author, industrial emissions of hydrogen sulfide gas that initiate litigation rarely reach as high as 0.100 ppm and are usually much lower. At air concentrations of 0.250-0.300 ppm, the odor of hydrogen sulfide, especially if frequent or persistent, can create a nuisance problem of legitimate concern. Accordingly, under some conditions, complaints of headache and sleep disturbances attributed to hydrogen sulfide emissions may be well founded. It is important to emphasize that there is no reliable evidence that intermittent exposure to air levels less than a few ppm does causes physical illness, long-term health effects, or hypersensitivity to other chemical substances.

Hydrogen sulfide exposure with symptoms

Mild, transitory symptoms of exposure such as headache, dizziness, and incoordination can appear within seconds to minutes following exposure to several hundred ppm of hydrogen sulfide gas. These symptoms resolve quickly and completely upon cessation of exposure. At higher levels, symptoms can include abrupt collapse with or without apnea.

For the purposes of clarification, acute hydrogen sulfide neurotoxicity characterized by sudden collapse and loss of consciousness can be considered in three increasingly severe stages (Milby and Baselt, 1999b):

Stage One: Sudden collapse followed by prompt and complete recovery. The victim continues to breathe and the heart continues to beat. There are no lasting effects. The phenomenon referred to in the medical literature as "knockdown" is included in this category. Stage One appears to be the most common form of hydrogen sulfide-induced collapse.

Stage Two: Sudden collapse with delayed recovery. Spontaneous breathing continues. Most victims recover completely, but a few develop sequelae ranging from minor neurological deficits to major, debilitating dementias.

Stage Three: Sudden collapse and prolonged unconsciousness with respiratory paralysis and apnea leading to hypoxic encephalopathy. Only a few cases of acute hydrogen sulfide intoxication can be considered Stage Three. Delayed rescue or exposure to concentrations of hydrogen sulfide gas exceeding 1500 ppm are factors that can contribute to Stage Three collapse and possible persistent neurological effects or death.

To be exposed to hydrogen sulfide is not necessarily to be damaged by it. Hydrogen sulfide, when inhaled, is very rapidly destroyed by the blood and does not accumulate in the body. Accordingly, although repeated exposures to small concentrations of this gas may be considered a nuisance, such exposures are of no toxicological significance. Recovery from hydrogen sulfide poisoning is nearly always complete if apnea, pulmonary edema-induced respiratory insufficiency, or clinically significant airway obstruction do not enter the picture. After recovery, there is no relapse.

SULFUR DIOXIDE

The characteristic "burning match" odor of sulfur dioxide is detectable by most persons at air concentrations of about 0.5 ppm. At levels of 10-20 ppm, nose, throat, and upper respiratory tract irritation are likely to become prominent complaints. Eye irritation is not an early symptom, usually not becoming apparent until air concentrations reach 20 to 50 ppm (PHS, 1998). Accidental exposure to 100 ppm for a few minutes has caused serious bronchitis (Skalpe, 1964).

Because of its irritating characteristics, persons exposed to sulfur dioxide at air concentrations of more than a few ppm will make every effort to "flee the scene". Accordingly, as a practical matter, only persons who cannot promptly evacuate an area contaminated by sulfur dioxide are at significant risk of incurring non-trivial injury to the eyes or respiratory tract.

Sulfur dioxide fumes do not penetrate the skin. The toxic effects of sulfur dioxide are derived wholly from its ability to directly irritate the eyes, the moist mucous membranes of the upper respiratory tract, and the lung. Acute impairment of lung function associated with toxicologically significant exposure to sulfur dioxide is obstructive in nature due, at least in part, to irritant-induced bronchoconstriction.

Controlled studies in humans have documented that acute inhalation of sulfur dioxide can cause bronchoconstriction, particularly in asthmatics. As a group, exercising asthmatics are probably the persons most susceptible to sulfur dioxide inhalation, often responding adversely to levels of 0.1 ppm (PHS, 1998). Among healthy volunteers, the threshold for respiratory function changes is about 1.0 ppm over a period of several hours. These acute functional changes, reflex-mediated bronchoconstriction, tend to disappear during exposure or shortly thereafter (Merchant, 1986). It is not clear whether adaptation to these low concentrations takes place with repeated exposure, although workers exposed to sulfur dioxide on a daily basis appear to develop some tolerance to its irritating effects (Keogh, et al., 1932; Romanoff, 1939; Greenwald, 1954).

A 10-year follow-up study of workers exposed to sulfur dioxide air concentrations ranging from 4 to 33 ppm did not reveal an increase of chronic respiratory disease or deterioration of pulmonary function as compared to a control group (Ellenhorn and Barceloux, 1988).

A biphasic response to exposure to very high concentrations of sulfur dioxide has been described (Weiss, 1994; Woodford, et al, 1979; Rabinovitch, et al., 1989; Charen, et al., 1979; Galea, 1964). The first phase consists of immediate symptoms of eye, nose, and throat irritation with chest tightness and non-productive cough. The second phase, appearing several weeks later, is characterized by respiratory failure due to fibrosis of the terminal bronchioles (bronchiolitis obliterans).

Sulfur dioxide exposure and reactive airway dysfunction syndrome (RADS)

In 1985, Brooks and his colleagues described an asthma-like illness in men who had undergone a single inhalation exposure to high levels of an irritating vapor, fume, or smoke (Brooks, et al., 1985). The investigators termed this illness "reactive airway dysfunction syndrome (RADS)". None of the affected individuals had preexisting respiratory disease and, following exposure, all showed evidence of hyperreactive airways.

Demonstration of hyperreactive airways is necessary for a diagnosis of RADS. This can be done in two ways: a positive methacholine challenge test and/or significant response to a bronchodilator during pulmonary function testing. A negative methacholine test does not necessarily exclude a diagnosis of RADS, but it has been the author's experience that in the legal arena, a positive methacholine test is of great help in reaching a diagnostic opinion acceptable at the level of "more likely than not".

High-level exposure to sulfur dioxide has been reported to cause airway hyperreactivity consistent with RADS (Harkonen, et al., 1983; Alford, et al., 1988; Pilirili, et al., 1996).

Litigation Issues

In the author's experience, brief exposure to about 5-ppm sulfur dioxide can precipitate an acute asthma attack in a person with preexisting asthma. The author is not aware of any reliable scientific evidence that low level exposure to sulfur dioxide, whether single or repeated, can cause asthma in a previously non-asthmatic individual.

In the author's experience, the term RADS is often used imprecisely to describe a host of pulmonary problems that bear little or no relationship, either clinically or etiologically, to the syndrome describe by Brooks and his colleagues. In the author's experience, the most common deviations from the Brooks criteria includes delayed onset of initial symptoms for days or weeks after exposure and undisclosed or undiscovered presence of preexisting asthma.

An issue receiving increasing attention is whether RADS can be induced by repeated, low-level exposures to one or more irritants in contradistinction to a single high-level exposure (Kipen, et al.; Bessette, et al., 1993). At the time of this writing, this issue is unresolved.

For a more complete discussion of the diagnosis and prognosis of RADS, the reader is invited to go to: http://toxicology.leadingexperts.com//rads.html. For a complete list of references, please contact Dr. Thomas Milby