Handbook of Clinical Neurology, Vol. 131 (3rd series) Occupational Neurology M. Lotti and M.L. Bleecker, Editors © 2015 Elsevier B.V. All rights reserved
Chapter 8
Hydrogen sulfide intoxication TEE L. GUIDOTTI* Medical Advisory Services, Rockville, MD, USA
Hydrogen sulfide is a relatively common inhalation hazard for its high level of toxicity, encountered in settings as diverse as sewers, the oil and gas industry, fishing and storage, aquaculture, and (mostly successful) suicides (Agency for Toxic Substances and Disease Registry, 2006). Occupational exposure to hydrogen sulfide was described by Ramazzini, elegantly and accurately, in 1700. The clinical picture of acute toxicity from hydrogen sulfide has intrigued numerous investigators because of the unusual suddenness of its most characteristic feature, immediate loss of consciousness. It has been written of hydrogen sulfide that “death may come on like a stroke of lightning” (Oesterhelweg and Puschel, 2008). Toxicity from this gas ranges from mild and quickly reversible, in the cases of sudden loss of consciousness called “knockdown,” to instantly lethal (Woodall et al., 2005). A more complete understanding of the toxicology of hydrogen sulfide has been impeded by confusion in the literature, which often and unfortunately perpetuates demonstrably incorrect information. One of them is that hydrogen sulfide exerts its major effects by the same mechanism of action as cyanide, which is clearly not the case. As with most uncommon problems in clinical toxicology, much of the literature on hydrogen sulfide toxicity consists of case reports of occupational exposure, both individual and multiple (Stine et al., 1976; Peters, 1981; Hoidal et al., 1986; Mack, 1987; Knight and Presnell, 2005; Ago et al., 2008; Oesterhelweg and Puschel, 2008; Lee et al., 2009; Poli et al., 2010; Fujita et al., 2011; Nogue et al., 2011; Lancia et al., 2013), and, even more tragically, case series from typically multiple casualities arising from the same incident where a rescue has been attempted, with tragic results (Demaret and Fialaire, 1974; Gunn and Wong, 2001; Gallay et al., 2002; US Chemical Safety and Hazard Investigation
Board, 2003; Kage et al., 2004; Poli et al., 2010; Bassindale and Hosking, 2011; Nogue et al., 2011; Zaba et al., 2011). Fortunately, there have been very few pediatric cases (Claudet et al., 2012; Sastre et al., 2013). However, this may change with the growing popularity of the form of suicide involving its use. Acute hydrogen sulfide toxicity cases are sporadic, unpredictable, and relatively uncommon in absolute terms. However, they do occur more often in the oil and gas sector where there is an opportunity for such cases to be observed and documented. When clinical information must come from individual case reports, it is inevitable that exposure cannot be quantified, that some outcome measures will not be available in a timely fashion, and that the baseline preexposure state will not be documented, especially neurobehavioral function. Confounding factors are often not mentioned in case reports, although it is important to exclude them, such as head trauma, prolonged hypoxemia due to hypoventilation, and the possibility of already oxygen-deficient atmospheres in a confined space. Even so, case reports from many dissimilar situations are remarkably consistent. The emphasis in this chapter is on clinical neurology and the pathophysiology of neurologicmanifestations of toxicity. Reproductive, developmental, and carcinogenicity issues are not considered in this review, because of limited relevance to human exposure. Pulmonary toxicity is discussed in some detail, both because it is an important practical issue in management and because hypoxemia may complicate the picture of neurotoxicity.
CONTEXT AND INTRODUCTION Hydrogen sulfide is the second most common cause of fatal gas inhalation exposures in the workplace (at 7.7%, second to carbon monoxide at 36%) and has unique
*Correspondence to: Tee L. Guidotti, Medical Advisory Services, P.O. Box 7479, Gaithersburg MD 20898-7479 USA. E-mail: [email protected]
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features that make hydrogen sulfide cases toxicologically unusual and stereotypical. Due to the situations in which it occurs, acute hydrogen sulfide toxicity is reported almost exclusively among fit, previously healthy working-age men. As in most such incidents, casualties usually occur in multiples as would-be rescuers rush to save their co-workers and, in their heroic but misguided haste, neglect to protect themselves with self-contained breathing apparatus. Intensive training and ready availability of personal protective equipment are required to prevent such situations (Mattarano 1999). Largely because of recent accelerated development that is now settling into maintenance and behavior-dependent routine operations, there have been a disproportionate number of cases reported recently from industries in China, particularly in the oil and gas sector (Jianwen et al., 2014). However, sporadic cases can occur anywhere because of the disseminated nature of sewer and agricultural operations. Chronic, low-concentration exposure on a communitywide basis may occur where there is a common or point source, such as an industrial facility or a geologic source, but is sometimes alleged to occur from persistent sewer or drain malfunction with resulting gas exposure. Misunderstandings, and sometimes misrepresentations, of the subacute and chronic toxicity of hydrogen sulfide have led to improbable accusations and even false claims. This has led to litigation and often contentious community issues. The problem of sorting out true toxicity from the symptoms of apprehension is complicated by the odor of the gas, which even at very low concentrations may arouse awareness, concern, and anxiety when it is perceived as a threat.
spaces. In the field, they often occur in depressions in the land or pits, where the gas settles because it is heavier than air. Unpublished information on hydrogen sulfiderelated knockdowns exists in the form of incident reports in the oil and gas industry but this is difficult or impossible for outsiders to access, although efforts have been made to establish a registry (Guidotti, 1996a). (Privileged opportunities granted to the author to review some of these unpublished reports have revealed no deviations from what is reported in the literature.) Sour gas, natural gas containing hydrogen sulfide, contains more than hydrocarbons and hydrogen sulfide, including some small amounts of carbon disulfide, carbonyl sulfide, methyl mercaptans, and trace metals, but these other components are toxicologically insignificant in practice and can be ignored. The hazard is managed mainly by monitoring technology, which has a reputation for “false” alarms, although some of these undoubtedly reflect transient passage of higher concentrations of the gas through the area. In the past, sour gas was often flared (ignited) in order to oxidize hydrogen sulfide to less acutely toxic but irritating sulfur dioxide; this is still done as an emergency measure (Fig. 8.1). Occasionally there is confusion over the odor of processed natural gas, for example, arising from gas leaks or suicide attempts in houses. Mercaptans are added to natural gas as a safety measure to ensure detection of leaks. They have a sweeter odor than hydrogen sulfide and are essentially nontoxic at the levels used. Very rarely, liquid hydrogen sulfide is encountered as a special-use reagent or chemical feedstock. (There is only one producer in the USA.) The principles of
Exposure scenarios and sources Hydrogen sulfide toxicity is generated wherever sulfurcontaining compounds decompose under reducing conditions, either chemical or by microbial action. The substrate may be petroleum and natural gas (which are formed from long-decomposed archaic biologic material (petroleum), sewage, animal waste, rotting animal matter, pulp and paper mill effluent, tanneries, asphalt, sulfide ore smelting operations, or geologic sources of sulfur such as volcanoes. In industry, the agent is probably most recognized as a hazard in the oil and gas industry, where it is a major hazard in upstream “sour” (high-sulfur-containing) crude oil and natural gas production, in pumping stations and gas plants, and in refineries (where sulfur is scrubbed from the gas stream in sulfur recovery units and may be concentrated). In industrial settings such as refineries, incidents typically occur in confined
Fig. 8.1. A sour-gas plant in the foothills of the Rocky Mountains, in Alberta. This plant receives from many wells in the vicinity a stream of natural gas rich in hydrogen sulfide, which it removes by absorption in a concentrated amine solution and which is eventually converted to sulfur. It also strips out small-molecular-weight “natural-gas liquids” for separate sale and dries the natural gas stream for entry into a pipeline. Note that there is no visible flare for venting and oxidizing hydrogen sulfide, which used to be a common sight. The industry has succeeded in reducing flaring to a minimum by better control over gas flow and desulfurization.
HYDROGEN SULFIDE INTOXICATION management are the same as for incidents involving the gas, except that clothing on the victim may have to be removed for the protection of first responders and the person decontaminated before transport. Wastewater treatment plants present a hazard, even in the open, away from confined spaces (Nogue et al., 2011). Sewer gas is a combination of hydrogen sulfide and methane but the latter has very low toxicity and so contributes nothing to the clinical presentation, although it is often remarked upon as if it did. Outgassing from sewage can, and occasionally does, generate lethal exposures, particularly when a stagnant pool is disturbed. This is a known hazard in workers who maintain sewerage, and clean out septic tanks and cesspools. Similarly, concentrations of animal waste also produce hydrogen sulfide in agriculture. Sporadic lethal exposures occur most often in swine confinement or liquid manure operations. Such events do not always occur in confined spaces (Costigan, 2003; Knubben-Schweizer et al., 2011). Lethal exposures occur most often when a worker is mucking or pumping manure, because the disturbance releases the gas. Decomposition during storage of organic material in the holds of fishing boats or in failed refrigeration units may yield significant concentrations of hydrogen sulfide in confined spaces (Tvedt et al., 1991; Gerasimon et al., 2007). Most recently, aquaculture has been associated with a growing number of fatalities worldwide (Myers, 2010). Volcanic activity releases enormous quantities of hydrogen sulfide to the atmosphere, potentially causing local deaths, and has been implicated by some geoscientists as a possible cause of the Permian extinction, which followed the eruption of several volcano chains (Lamarque and Orlando, 2007). Likewise, hydrogen sulfide seeps from vents in the deep ocean, which are fortunately beyond human exposure, and sustains life evolved to sulfur metabolism in the anaerobic deep ocean. As a practical matter, geologic sources are a hazard in tapping geothermal wells for energy. A small number of cases in the broader community occur from exposure associated with natural water sources, principally geysers, natural hot springs, and pools (Daldal et al., 2010). The geothermal hot pools of Rotorua, New Zealand, have sadly had a disproportionate share of these incidents, sometimes involving tourists (Bassindale and Hosking, 2011). Hydrogen sulfide recently became an instrument of choice for suicide among the younger generation in Japan, peaking in 2008 as a result of social media communicating the means to generate the gas from common household chemicals. As a means of suicide, it was very effective, with a fatality rate of 95% (Morii et al., 2010; Fujita et al., 2011). The method unfortunately works well
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to achieve fatally toxic concentrations in confined spaces and so is most often used in locked cars. Often the suicidant is wearing tight-fitting goggles to avoid painful eye irritation. However tragic for the individual involved, this method of suicide also presents grave risks to others, with the potential for multiple secondary casualties to the community, especially would-be rescuers, first responders, family members, friends arriving at the scene, and even, when performed in closets and apartments, entire neighborhoods (Truscott, 2008; Ishikawa, 2010). Knowing this, suicidants often leave signs visible through the car window warning first responders and others of hazardous materials and toxic gas. This method of suicide has been reported rarely but increasingly in the USA, Australia, and Canada (Lamarque and Orlando, 2007; Goode, 2011; Chemical Suicides, 2012; Bott and Dodd, 2013; Sams et al., 2013).
Physiologic role Sulfide is produced endogenously and also by commensal bacterial in the gut (giving odor to flatus, which is mostly methane) and mouth (contributing to halitosis). Sulfide is present normally in tissues of the body, especially the gut. Given the toxicity of the gas, the exceptionally high normal concentrations in brain tissue puzzled investigators until the physiologic role of the gas was discovered (Reiffenstein et al., 1992). The physiologic role of hydrogen sulfide, as opposed to its toxicologic role, is only now emerging (Wang, 2012; Wang et al., 2014). A detailed review of the physiologic role of hydrogen sulfide is premature and beyond the scope of this chapter, except to indicate that this knowledge is likely to change and refine toxicologic models in the future. There are early indications that hydrogen sulfide has a role in the response to stroke, brain and spinal cord injury, and dementia, but the fragmentary evidence is too early to be coherent. There is a close similarity and interaction among the gas transmitters hydrogen sulfide, carbon monoxide, and nitric oxide (which is much less toxic). Perturbation in their physiologic role is likely to have consequences in both exacerbating and limiting injury, but was undiscovered and therefore completely outside the thinking of toxicology until very recently. Hydrogen sulfide is a paracrine mediator, a diffusible vasorelaxing agent, immune modulator, and neuromodulator (Popov, 2013). It may have a role in insulin sensitivity and glucose metabolism (Zhang et al., 2013). Hydrogen sulfide may act following acute injury (for example, by stroke or trauma) to maintain perfusion, preserve the integrity of the microcirculation, dampen glutamate-mediated excitotoxicity, preventing overexuberant apoptosis, and to quench oxidative stress.
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On the other hand, it may aggravate the situation by elevating calcium influx and so contributing to calcium overload in secondary neuronal injury (Olson, 2011; Wang et al., 2014). Toxic exposure that interferes with these functions may involve direct effects on the nervous system, perhaps mediating cell responses in stroke (Qu et al., 2006) as well as in other organ systems. The state of “suspended animation” induced during knockdown shows promise as a therapeutic intervention (Olson, 2011; Li et al., 2012).
PROPERTIES Hydrogen sulfide (H2S, molecular weight 34.08) is a flammable, colorless gas that is offensively odorous (smell of rotten eggs or cabbage), soluble in lipid, and poorly soluble in water (vapor pressure in water 18.75 102 kPa), and heavier than air (density 1.19). In aqueous media it dissociates readily into hydrosulfide, but not to sulfide as follows. Undissociated hydrogen sulfide and the hydrosulfide ion are predominant at a 1:2 ratio at pH 7.4 (Reiffenstein et al., 1992; Agency for Toxic Substances and Disease Registry, 2006):
H2 S $ H + + HS $ 2H + + S2 pKa1 ¼ 7:04: pKa2 ¼ 11:96 Biologic sources of hydrogen sulfide tend to release intermittent peaks or pulses of the gas, usually together with methane (which is for all practical purposes nontoxic). Once released, the dense gas may persist until displaced by wind or ventilation in low-lying ground, depressions such as trenches or pits, or in confined spaces. Hydrogen sulfide in water, for example in sewage, swamps, and the deep ocean, tends to accumulate to saturation and then is released spontaneously or with perturbation, such as heating or physical disturbance. This results in “burping” of the gas and a bolus effect, which can then be trapped in confined spaces or pits (Nogue et al., 2011). Sustained release tends to be more common from geologic sources, as in the “oilpatch.” Even there, volcanic activity, tapped pockets of gas, and the vagaries of oil and gas extraction may result in a variable exposure profile over short periods.
CLINICAL TOXIDROME A “toxidrome” in toxicology is a syndrome of symptoms and signs characteristic of the effects of a toxic agent. Hydrogen sulfide is unique in its toxidrome for acute and subacute exposure. Whether a toxic effect exists at low exposure levels remains controversial.
Acute Acute hydrogen sulfide toxicity is one of the most unusual and reliable toxidromes in medical toxicology, and features several bizarre signs that allow clinical differentiation to be made from other toxic gases (Yant, 1930; Burnett and King, 1978; Smith and Gosselin, 1979; Beauchamp et al., 1984; Arnold et al., 1985; Wang, 1989; Reiffenstein et al., 1992; Milby and Baselt, 1999; Woodall et al., 2005; Guidotti, 2010). These will be discussed in order of clinical significance in surviving victims. The toxidrome of hydrogen sulfide includes the following progressive symptoms at increasing exposure levels, such that individual cases, unless occurring suddenly, typically include all the effects that precede them: 1. 2. 3. 4. 5. 6.
odor perception conjunctivitis olfactory paralysis, not to be confused with olfactory fatigue “knockdown” (acute central neurotoxicity, reversible) pulmonary edema (uncommon) apnea (not observed).
Cases of toxicity from hydrogen sulfide always show these features, singly or in combination, almost always in the sequence numbered, regardless of the susceptibility or characteristics of the victim or subject. Atypical presentations are so uncommon as to call the diagnosis into question, even in highly unusual cases. When they are not reported, the history is often incomplete or the victim was overcome too quickly for the progression to be observed or to develop fully. Apnea, immediate paralysis of breathing, is a lethal risk at very high concentrations, and may be the cause of death in victims who are already unconscious from knockdown. Clinically it is not observed separately because the victim invariably is already dead. Apnea is an important effect used in animal studies, however, because it is reproducible of neurotoxicity in the rat, which is more susceptible than human beings. Approximate thresholds for each cardinal effect are given in Table 8.1. The stereotypical toxidrome assumes, of course, that there has not been trauma to the head from falling or a period of anoxia or hypoperfusion, as might occur with near-lethal exposures. It also assumes that there is no premorbid condition or susceptibility state that would substantially modify the presentation; to date, none has been demonstrated.
Knockdown In the oilpatch, “knockdown” specifically means sudden loss of consciousness due to hydrogen sulfide exposure. (The term has other meanings in other industries and
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Table 8.1 Health effects of hydrogen sulfide at various approximate exposure levels (Guidotti, 1994, 1996b, 2007, 2010) Concentration (ppm) 0.01–0.3 1–5 5 10 15 20 20–50 100 150–200 250–500 500 1000
Effects Odor threshold (highly variable) Moderate offensive odor, may be associated with nausea, tearing of the eyes, headaches, or loss of sleep with prolonged exposure; healthy young male subjects experience no decline in maximal physical work capacity Aerobic metabolism inhibited in skeletal muscle (lowest observed effect level, probably close to threshold), no observable signs or symptoms; 8-hour occupational exposure limit in Alberta Ceiling level (15 minutes) in Alberta; OSHA PEL 8-hour time-weighted average; anaerobic metabolism threshold inhibited during exercise; eye irritation 15-minute occupational exposure limit in Alberta; short-term exposure limit OSHA PEL Evacuation level in Alberta; ceiling (15-minute time-weighted average) exposure limit OSHA, odor very strong; conjunctivitis may occur Conjunctivitis (eye irritation) and lung irritation. Possible eye damage after several days of exposure; may cause digestive upset and loss of appetite; 50 ppm is the peak (never to be exceeded) OSHA PEL “Gas eye” and lung irritation; olfactory paralysis, sensation of odor disappears Olfactory paralysis; severe eye and lung irritation Pulmonary edema may occur, especially if exposure is prolonged Serious damage to eyes within 30 minutes; severe lung irritation; “knockdown” (sudden unconsciousness) and death (especially if exposure prolonged by hours); amnesia for period of exposure Breathing may stop within one or two breaths (apnea); immediate collapse
OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit.
working life, and the phenomenon does not have a special name in other industries where it occurs.) Hydrogen sulfide-induced acute central neurotoxicity leads to abrupt and reversible loss of consciousness and collapse, often described by those who witness it as like turning off a switch. A knockdown may easily be fatal if exposure at high concentration (roughly 500–1000 ppm) is prolonged, but if exposure is transient, as it often is in an oilfield due to air movement, it may also be quickly reversible. The victim typically falls down as if letting the strings loose on a marionette. If exposure is transient, as usually happens in the oilpatch, recovery may be equally rapid and apparently complete in functional terms. Survivors have even reported to the author that the experience is not unpleasant and may be mildly euphoric, assuming they have not injured themselves in the fall. Given long experience in the “oilpatch” (areas where oil and gas production are prevalent), the author has interviewed many oil and gas workers who have had near-misses or actual knockdowns associated with hydrogen sulfide, and has been involved in fatality investigations. The histories given by patients or observers told after the fact are remarkably consistent with each other and with the relevant literature (Burnett and King, 1978). Observers who witness a knockdown consistently describe it as immediate and complete collapse, often using the metaphor that it is as if a switch had been turned off or a puppeteer had dropped the strings on a
marionette. Recovery from a knockdown is described as being as quick, almost instantaneous, with the person suddenly realizing that he or she is lying on the ground but experiencing no confusion or postictal effects. Oilfield workers, at least above a certain age, usually immediately recognize what happened and get up easily. In the past it was quite common for them to return to work without reporting the incident. Those who observe recovery from a knockdown often describe it using the metaphor of someone turning a switch back on. Those who actually experience a knockdown and recover from it have sometimes said to the author that it was not an unpleasant sensation and that they woke up immediately without mental confusion.
Pulmonary edema and irritant toxicity The significance of pulmonary edema or apnea (another acute, high-level effect) to clinical neurology is obvious: prolonged hypoxemia resulting in anoxic brain damage. However, this appears to be uncommon. Pulmonary edema is associated with prolonged exposure while the victim is unconscious (Richardson, 1995; Tanaka et al., 1999; Daldal et al., 2010). Hydrogen sulfide is irritating to mucous membranes. This effect mostly involves the deep lung and, as discussed in the next subsection, the epithelium (outer lining) of the eye. Because gaseous hydrogen sulfide is poorly soluble in water, it tends to be carried deeply into the lung, where
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diffuse alveolar damage may occur, resulting in toxic inhalation and a risk of pulmonary edema (Guidotti, 2001, 2006). Older studies suggest that 20% of cases of hydrogen sulfide toxicity reaching the emergency department in a setting where most cases came from the oil and gas sector showed at least some evidence of pulmonary edema (Roth et al., 1997). Although this seems implausibly high, it may reflect the residual cases between those who did not seek care (oil companies now demand it) and early fatalities. Compared to other toxic gases, death by pulmonary edema seems to be quite unusual in hydrogen sulfide toxicity. In one series of 152 cases from China, an overall mortality of only 5% was reported, far below the 50% usually cited for mortality from noncardiogenic pulmonary edema (Wang, 1989). First, concentrations high enough to induce pulmonary edema would in most cases already have induced central effects (at levels well above the threshold for knockdown) that would already be lethal, before progression to alveolar edema. The modulatory effect of hydrogen sulfide on inflammation may also spare the lung from early injury and protect against acute endothelial disruption and diffuse alveolar damage. Also, hydrogen sulfide may be much less toxic to lung than other tissues and may even have profound protective effects. For example, it has a potent effect in reducing experimentally induced oxidative injury in the lung (Cao et al., 2014). Experimental studies have shown that hydrogen sulfide is only moderately cytotoxic for pulmonary cells, it does not initiate severe irreversible changes despite extensive pulmonary edema, and does not seem to disrupt the basement membrane of the alveolar endothelium (Lopez et al., 1988; Cao et al., 2014). Thus, the ultimate prognosis for recovery and lung remodeling is likely to be good if the patient can be supported through the acute episode. There are several possible reasons for this. This may be why there are very few reports of chronic lung disease, either airways or interstitial (Duong et al., 2001) associated with recovery from hydrogen sulfide inhalation, and those in the literature more often suggest relatively mild obstructive rather than restrictive effects (Richardson, 1995).
Gas eye (irritative conjunctivitis) “Gas eye” is a superficial inflammation of the cornea and conjunctiva due to the irritant effect of hydrogen sulfide (Tansy et al., 1981; Lambert et al., 2006). It is often recurrent in workers who are exposed for prolonged periods to relatively low occupational concentrations, 20 ppm and possibly lower. Some workers have said to the author that they relied on eye irritation as a
second warning sign of exposure over the permissible occupational exposure limit, because it occurs at a lower level than loss of olfaction. (This is a dangerous practice.) Gas eye is characterized by microvacuolization and edema in the corneal epithelium, leading to mild refractory and chromatic distortion in the form of a colored halo surrounding objects and other visual changes. Blepharospasm, an acute spasm of the orbicularis oculi muscle, may result in tearing, periorbital pain, and photophobia (Tansy et al., 1981; Guidotti, 1994; Milby and Baselt, 1999; Lambert et al., 2006). This form of blepharospasm is acute and not to be confused with eyelid fasciculation. In Rotorua, New Zealand, there was a statistically significant doubling of risk for admission to hospital due to eye disorders, including conjunctivitis, which is an uncommon reason for hospitalization. Given ambient levels, this is a plausible effect of exposure (Bates et al., 1997).
Olfactory effects The odor threshold and olfactory effects of hydrogen sulfide are critical in occupational health because odor provides the primary warning signal to workers that the gas is present. Hydrogen sulfide is very odorous, with a low olfactory threshold, from less than 0.01 to 0.3 ppm depending on individual sensitivity. By 1–5 ppm, the odor is very offensive, aptly described as rotten eggs. Thus, at lower levels the gas has excellent warning properties. However, at high exposure levels the warning properties disappear because at relatively high concentrations (about 100 ppm) hydrogen sulfide paralyzes the olfactory mechanism, preventing perception of any smell. This effect removes the primary warning sign of hydrogen sulfide exposure and the principal warning to, say, oilfield workers suddenly caught in a plume (Turner and Fairhurst, 1990; Smith and Gosselin, 1979; Milby and Baselt, 1999; Guidotti, 2010). Two distinct mechanisms are involved in loss of olfactory acuity to hydrogen sulfide. As with most strong odors, workers may experience olfactory fatigue at lower levels of exposure and may become accustomed to them in the short term. Olfactory fatigue is common to the sensory processing of many strong odors and leads to behavioral tolerance of the odor. There is also a mechanism specific and almost unique to hydrogen sulfide, known as olfactory paralysis. Olfactory fatigue is a sensory adaptation. Olfactory paralysis is neurotoxicity of the olfactory nerve and bulb. Unfortunately, the two phenomena are frequently confused in the literature.
HYDROGEN SULFIDE INTOXICATION Olfactory paralysis due to both neurotoxicity affecting the olfactory bulb and fibers may be followed by hyposmia or anosmia, a permanent loss of the ability to perceive odor. This pattern of toxicity was demonstrated experimentally to be attributable to selective toxicity to olfactory mucosa in the nasal passages and to olfactory neuron loss after subchronic inhalation (Turner and Fairhurst, 1990; Brenneman et al., 2000; Roberts et al., 2006). Hyposmia has been found to be present in most men who recovered from severe, potentially lethal hydrogen sulfide toxicity (Hirsch, 2002). Human subjects exposed to transient high levels of hydrogen sulfide have been reported to show deficits on standardized tests of smell and taste years later (Hirsch, 2002). This is not invariable, however, because tolerance can be induced in the short term and the olfactory mucosa can recover if exposure does not persist too long (Roberts et al., 2006).
SECONDARY SYMPTOMS AND SIGNS As with all toxic conditions, there are secondary symptoms and signs of hydrogen sulfide toxicity that vary and in some cases are secondary rather than direct effects, and sometimes side effects of treatment (such as hypotension from excessive nitrite). The literature documenting the prevalence and profile of these secondary effects is much weaker than that reporting the cardinal effects, not surprisingly.
Acute respiratory effects Bronchospasm occurs in many, but not all, cases but, remarkably, is not reported to result in bronchitis, chronic irritant-induced asthma, or reactive airways dysfunction syndrome (Shivanthan et al., 2013). This may be an example of the lung-sparing effect of hydrogen sulfide as a physiologic modulator of inflammation. Shortness of breath is to be expected for a respiratory irritant and may be a sign of the onset of pulmonary edema. However, in at least one case, dyspnea and cough were relieved during hyperbaric oxygen treatment following hydrogen sulfide exposure, suggesting that shortness of breath may reflect hypoxia (Gallay et al., 2002). Exposure in the short term at 10 ppm does not appear to be associated with reduced lung function or increased airways reactivity (Bhambhani et al., 1996a). However, other studies have suggested that an isolated reduction in residual volume, occurring in 23% of cases exposed in an industrial setting, in the absence of any radiologic or clinical signs, constitutes a subclinical effect to acute exposure (Buick et al., 2000). If confirmed, this unusual effect may be related to inhibitory effects on pulmonary receptors and reflex activity, rather than an effect on
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lung mechanics, as assumed by the author of the study (Klentz and Fedde, 1978; Almeida and Guidotti, 1999). Further emphasizing the possible significance of a modulatory effect of hydrogen sulfide on the lung is the observation that there is an apparent exposure-related reduction in asthma risk (incidence and prevalence) in Rotorua, where ambient levels of hydrogen sulfide are high.
Acute cardiac effects Given the purported mechanism of sudden cytochrome inhibition and disruption in energetic metabolically active cells, one would expect the heart to be a frequent target organ with a toxic cardiomyopathy resulting on recovery. However, there have been surprisingly few validated reports of cardiotoxicity (Christia-Lotter et al., 2007; Amino et al., 2009). Two case reports suggest myocardial ischemia resulting in the absence of any sign of coronary artery disease in otherwise healthy young male workers. One in Korea initially went into acute heart failure with left ventricular dilation but responded well to the usual treatment of acute congestive failure. After recovery, he was significantly impaired with symptoms of dyspnea on exertion and showed a reduced ejection fraction and reduced ventricular chamber size. He showed no neurologic sequelae (Lee et al., 2009). The other, in Japan, was the second victim in a stereotypical unsuccessful rescue attempt and showed evidence of skeletal rhabdomyolysis but delayed myocardial injury, from which he eventually recovered completely (Hirakawa et al., 2013).
Nonspecific symptoms and signs Unfortunately, the secondary literature usually does not distinguish among secondary symptoms that occur in exposed persons who do not experience knockdown or conjunctivitis (two benchmark clinical symptoms that establish exposure levels) and those that do, and almost never is there an exposure assessment refined enough to establish an exposure–response relationship. Headache and short-term cognitive changes, such as short-term memory loss, are common but very nonspecific, as they may occur in many other situations and as a response to distraction and posttraumatic stress. Headache occurred in about a third of hydrogen sulfide exposures but was a transient phenomenon lasting a day or so (Audeau et al., 1985; Sjaasted and Bakketeig, 2006). One exception involved recovery from a prolonged knockdown and cardiac arrest in which chronic headache followed treatment by heroic measures (Asif and Exline, 2012). Seizure disorders are only reported for 2% of cases, historically, but most such cases have probably been associated with anoxic brain damage in near-lethal cases
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(Arnold et al., 1985). In a case series involving a release in an oil refinery in Sri Lanka, about which exposure details were unavailable, a worker with neurofibromatosis (confirmed after the incident) was found unconscious and cyanotic, and developed decerebrate posturing with repeated generalized tonic-clonic seizures while unconscious. After initially responding to ventilation with 100% oxygen and benzodiazepines, the patient went back into status epilepticus after being started on sodium nitrite (hypotension not reported). Astonishingly, he recovered with initial neurologic, predominantly cerebellar, signs that improved and was left with only residual dysarthria and mild ataxia (Shivanthan et al., 2013). In at least one case in which a detailed clinical description is available, an apparently new-onset seizure occurred during a knockdown and resolved without evolving into a chronic seizure disorder (Audeau et al., 1985). One may speculate that the nerve tissue-sparing effect of hydrogen sulfide may play a role in the favorable outcomes. Gastrointestinal symptoms (including jaundice and diarrhea) were reported in the older literature but not in more recent, systematic case series (Arnold et al., 1985). Nausea and vomiting are to be expected given the malodorous exposure, which most people find disgusting (Guidotti, 2010).
CHRONIC EFFECTS There are many unanswered questions about neurotoxicity from hydrogen sulfide.
Neurotoxicity A central issue in studying neurotoxicity associated with hydrogen sulfide has been to differentiate between the primary effects of toxicity in the vicinity of 500 ppm, which cause knockdown as a neurologic event, and the effects of anoxia which can occur as a result or because the atmosphere was low in oxygen to begin with (as in confined spaces and sewers). Hydrogen sulfide toxicity may be the result of several effects, including interference with oxygen uptake and metabolism and also hypoxia from oxygen deprivation due to apnea or respiratory insufficiency. These mechanisms would produce the constellation of findings identified in anoxic brain injury. There may also be other, direct mechanisms of neurotoxicity. Occupational exposure to hydrogen sulfide in four workers did result in loss of consciousness during a release, associated with abnormal evoked response potentials (assessing cortical function) and subclinical neuropsychiatric clinical findings without overt disease. The subjects had cardinal symptoms (eye irritation), confirming that exposure had occurred, possibly repeatedly,
at exposure levels that must have exceeded 50 ppm much of the time and may have reached 243 ppm, as noted in other incidents at this refinery. The pattern of symptoms and impairment was not uniform among subjects. However, these same subjects also had evidence of posttraumatic stress disorder, which can influence neurobehavioral testing, and were not representative of the exposed population, having been selected precisely because they demonstrated abnormalities (Hirsch, 2002). It is now accepted that neurologic sequelae can follow knockdown in the context of acute high-level exposure. Evidence remains weak for effects associated with chronic, low-level exposure, discussed below. It would be expected that, if these effects occur, they would be observed first and most consistently at higher exposures. However, in the case of hydrogen sulfide, exposures that result in knockdown may easily be confounded by head trauma during falls, which is common (Arnold et al., 1985; Wang, 1989; Gabbay and Perrone, 2001), and hypoxemia from apnea or seizure activity (Wang, 1989; Tvedt et al., 1991; Snyder et al., 1995; Tanaka et al., 1999). Even so, in the past, when these events were far more common, oilfield workers often went back to work after a knockdown.
Peripheral neuropathy Despite the observation that demyelination can occur in experimental models (Solnyshkova, 2003), peripheral neuropathy is not often or consistently reported in cases of hydrogen sulfide toxicity. Some well-documented cases describe a tingling paresthesia which does not appear to be associated with chronic neuropathy (Wasch et al., 1989). The finding does not necessarily imply selective neurotoxicity because a paresthesia of this type could also be central or mediated by vascular changes.
Chronic respiratory effects following recovery It is not clear whether prolonged or repeated hydrogen sulfide exposure is associated with chronic respiratory impairment. A single case report has suggested that interstitial fibrosis followed exposure to hydrogen sulfide, but the case has many other unusual features and may not be representative (Duong et al., 2001). Cross-sectional studies of sewer workers, who are exposed to hydrogen sulfide but also have other risk factors, such as exposure to bioaerosols and endotoxin, suggest that lung function is significantly reduced after accounting for smoking and may show an accelerated rate of decline with age. The relationship between age and lung function was skewed in this sample, however,
HYDROGEN SULFIDE INTOXICATION and showed an exposure–response relationship only at the extremes, and did not take outmigration from the reference group (which may have been exposed to chlorine) into consideration (Richardson, 1995). Longitudinal studies required to confirm this finding are not available. Another cross-sectional study of oilfield workers did not find such an effect. Subjects who had experienced a knockdown did not show a difference from those who had not in this population. However, this study had profound methodologic issues, not least of which was that respiratory symptoms were part of the exclusion criteria for their selection (Hessel et al., 1997). (The subjects had been recruited to be a reference group for another study, a point which was not made clear in the article.) It is a paradox of the hydrogen sulfide literature that exposure is not known to induce airways reactivity or the condition known as “reactive airways dysfunction syndrome,” although this might be expected based on the gas’s known irritant effect. One may speculate that this could be a direct consequence of the physiologic anti-inflammatory role of hydrogen sulfide.
CHRONIC EFFECTS OF LOWER-LEVEL EXPOSURE (
Chapter 8
Hydrogen sulfide intoxication TEE L. GUIDOTTI* Medical Advisory Services, Rockville, MD, USA
Hydrogen sulfide is a relatively common inhalation hazard for its high level of toxicity, encountered in settings as diverse as sewers, the oil and gas industry, fishing and storage, aquaculture, and (mostly successful) suicides (Agency for Toxic Substances and Disease Registry, 2006). Occupational exposure to hydrogen sulfide was described by Ramazzini, elegantly and accurately, in 1700. The clinical picture of acute toxicity from hydrogen sulfide has intrigued numerous investigators because of the unusual suddenness of its most characteristic feature, immediate loss of consciousness. It has been written of hydrogen sulfide that “death may come on like a stroke of lightning” (Oesterhelweg and Puschel, 2008). Toxicity from this gas ranges from mild and quickly reversible, in the cases of sudden loss of consciousness called “knockdown,” to instantly lethal (Woodall et al., 2005). A more complete understanding of the toxicology of hydrogen sulfide has been impeded by confusion in the literature, which often and unfortunately perpetuates demonstrably incorrect information. One of them is that hydrogen sulfide exerts its major effects by the same mechanism of action as cyanide, which is clearly not the case. As with most uncommon problems in clinical toxicology, much of the literature on hydrogen sulfide toxicity consists of case reports of occupational exposure, both individual and multiple (Stine et al., 1976; Peters, 1981; Hoidal et al., 1986; Mack, 1987; Knight and Presnell, 2005; Ago et al., 2008; Oesterhelweg and Puschel, 2008; Lee et al., 2009; Poli et al., 2010; Fujita et al., 2011; Nogue et al., 2011; Lancia et al., 2013), and, even more tragically, case series from typically multiple casualities arising from the same incident where a rescue has been attempted, with tragic results (Demaret and Fialaire, 1974; Gunn and Wong, 2001; Gallay et al., 2002; US Chemical Safety and Hazard Investigation
Board, 2003; Kage et al., 2004; Poli et al., 2010; Bassindale and Hosking, 2011; Nogue et al., 2011; Zaba et al., 2011). Fortunately, there have been very few pediatric cases (Claudet et al., 2012; Sastre et al., 2013). However, this may change with the growing popularity of the form of suicide involving its use. Acute hydrogen sulfide toxicity cases are sporadic, unpredictable, and relatively uncommon in absolute terms. However, they do occur more often in the oil and gas sector where there is an opportunity for such cases to be observed and documented. When clinical information must come from individual case reports, it is inevitable that exposure cannot be quantified, that some outcome measures will not be available in a timely fashion, and that the baseline preexposure state will not be documented, especially neurobehavioral function. Confounding factors are often not mentioned in case reports, although it is important to exclude them, such as head trauma, prolonged hypoxemia due to hypoventilation, and the possibility of already oxygen-deficient atmospheres in a confined space. Even so, case reports from many dissimilar situations are remarkably consistent. The emphasis in this chapter is on clinical neurology and the pathophysiology of neurologicmanifestations of toxicity. Reproductive, developmental, and carcinogenicity issues are not considered in this review, because of limited relevance to human exposure. Pulmonary toxicity is discussed in some detail, both because it is an important practical issue in management and because hypoxemia may complicate the picture of neurotoxicity.
CONTEXT AND INTRODUCTION Hydrogen sulfide is the second most common cause of fatal gas inhalation exposures in the workplace (at 7.7%, second to carbon monoxide at 36%) and has unique
*Correspondence to: Tee L. Guidotti, Medical Advisory Services, P.O. Box 7479, Gaithersburg MD 20898-7479 USA. E-mail: [email protected]
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features that make hydrogen sulfide cases toxicologically unusual and stereotypical. Due to the situations in which it occurs, acute hydrogen sulfide toxicity is reported almost exclusively among fit, previously healthy working-age men. As in most such incidents, casualties usually occur in multiples as would-be rescuers rush to save their co-workers and, in their heroic but misguided haste, neglect to protect themselves with self-contained breathing apparatus. Intensive training and ready availability of personal protective equipment are required to prevent such situations (Mattarano 1999). Largely because of recent accelerated development that is now settling into maintenance and behavior-dependent routine operations, there have been a disproportionate number of cases reported recently from industries in China, particularly in the oil and gas sector (Jianwen et al., 2014). However, sporadic cases can occur anywhere because of the disseminated nature of sewer and agricultural operations. Chronic, low-concentration exposure on a communitywide basis may occur where there is a common or point source, such as an industrial facility or a geologic source, but is sometimes alleged to occur from persistent sewer or drain malfunction with resulting gas exposure. Misunderstandings, and sometimes misrepresentations, of the subacute and chronic toxicity of hydrogen sulfide have led to improbable accusations and even false claims. This has led to litigation and often contentious community issues. The problem of sorting out true toxicity from the symptoms of apprehension is complicated by the odor of the gas, which even at very low concentrations may arouse awareness, concern, and anxiety when it is perceived as a threat.
spaces. In the field, they often occur in depressions in the land or pits, where the gas settles because it is heavier than air. Unpublished information on hydrogen sulfiderelated knockdowns exists in the form of incident reports in the oil and gas industry but this is difficult or impossible for outsiders to access, although efforts have been made to establish a registry (Guidotti, 1996a). (Privileged opportunities granted to the author to review some of these unpublished reports have revealed no deviations from what is reported in the literature.) Sour gas, natural gas containing hydrogen sulfide, contains more than hydrocarbons and hydrogen sulfide, including some small amounts of carbon disulfide, carbonyl sulfide, methyl mercaptans, and trace metals, but these other components are toxicologically insignificant in practice and can be ignored. The hazard is managed mainly by monitoring technology, which has a reputation for “false” alarms, although some of these undoubtedly reflect transient passage of higher concentrations of the gas through the area. In the past, sour gas was often flared (ignited) in order to oxidize hydrogen sulfide to less acutely toxic but irritating sulfur dioxide; this is still done as an emergency measure (Fig. 8.1). Occasionally there is confusion over the odor of processed natural gas, for example, arising from gas leaks or suicide attempts in houses. Mercaptans are added to natural gas as a safety measure to ensure detection of leaks. They have a sweeter odor than hydrogen sulfide and are essentially nontoxic at the levels used. Very rarely, liquid hydrogen sulfide is encountered as a special-use reagent or chemical feedstock. (There is only one producer in the USA.) The principles of
Exposure scenarios and sources Hydrogen sulfide toxicity is generated wherever sulfurcontaining compounds decompose under reducing conditions, either chemical or by microbial action. The substrate may be petroleum and natural gas (which are formed from long-decomposed archaic biologic material (petroleum), sewage, animal waste, rotting animal matter, pulp and paper mill effluent, tanneries, asphalt, sulfide ore smelting operations, or geologic sources of sulfur such as volcanoes. In industry, the agent is probably most recognized as a hazard in the oil and gas industry, where it is a major hazard in upstream “sour” (high-sulfur-containing) crude oil and natural gas production, in pumping stations and gas plants, and in refineries (where sulfur is scrubbed from the gas stream in sulfur recovery units and may be concentrated). In industrial settings such as refineries, incidents typically occur in confined
Fig. 8.1. A sour-gas plant in the foothills of the Rocky Mountains, in Alberta. This plant receives from many wells in the vicinity a stream of natural gas rich in hydrogen sulfide, which it removes by absorption in a concentrated amine solution and which is eventually converted to sulfur. It also strips out small-molecular-weight “natural-gas liquids” for separate sale and dries the natural gas stream for entry into a pipeline. Note that there is no visible flare for venting and oxidizing hydrogen sulfide, which used to be a common sight. The industry has succeeded in reducing flaring to a minimum by better control over gas flow and desulfurization.
HYDROGEN SULFIDE INTOXICATION management are the same as for incidents involving the gas, except that clothing on the victim may have to be removed for the protection of first responders and the person decontaminated before transport. Wastewater treatment plants present a hazard, even in the open, away from confined spaces (Nogue et al., 2011). Sewer gas is a combination of hydrogen sulfide and methane but the latter has very low toxicity and so contributes nothing to the clinical presentation, although it is often remarked upon as if it did. Outgassing from sewage can, and occasionally does, generate lethal exposures, particularly when a stagnant pool is disturbed. This is a known hazard in workers who maintain sewerage, and clean out septic tanks and cesspools. Similarly, concentrations of animal waste also produce hydrogen sulfide in agriculture. Sporadic lethal exposures occur most often in swine confinement or liquid manure operations. Such events do not always occur in confined spaces (Costigan, 2003; Knubben-Schweizer et al., 2011). Lethal exposures occur most often when a worker is mucking or pumping manure, because the disturbance releases the gas. Decomposition during storage of organic material in the holds of fishing boats or in failed refrigeration units may yield significant concentrations of hydrogen sulfide in confined spaces (Tvedt et al., 1991; Gerasimon et al., 2007). Most recently, aquaculture has been associated with a growing number of fatalities worldwide (Myers, 2010). Volcanic activity releases enormous quantities of hydrogen sulfide to the atmosphere, potentially causing local deaths, and has been implicated by some geoscientists as a possible cause of the Permian extinction, which followed the eruption of several volcano chains (Lamarque and Orlando, 2007). Likewise, hydrogen sulfide seeps from vents in the deep ocean, which are fortunately beyond human exposure, and sustains life evolved to sulfur metabolism in the anaerobic deep ocean. As a practical matter, geologic sources are a hazard in tapping geothermal wells for energy. A small number of cases in the broader community occur from exposure associated with natural water sources, principally geysers, natural hot springs, and pools (Daldal et al., 2010). The geothermal hot pools of Rotorua, New Zealand, have sadly had a disproportionate share of these incidents, sometimes involving tourists (Bassindale and Hosking, 2011). Hydrogen sulfide recently became an instrument of choice for suicide among the younger generation in Japan, peaking in 2008 as a result of social media communicating the means to generate the gas from common household chemicals. As a means of suicide, it was very effective, with a fatality rate of 95% (Morii et al., 2010; Fujita et al., 2011). The method unfortunately works well
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to achieve fatally toxic concentrations in confined spaces and so is most often used in locked cars. Often the suicidant is wearing tight-fitting goggles to avoid painful eye irritation. However tragic for the individual involved, this method of suicide also presents grave risks to others, with the potential for multiple secondary casualties to the community, especially would-be rescuers, first responders, family members, friends arriving at the scene, and even, when performed in closets and apartments, entire neighborhoods (Truscott, 2008; Ishikawa, 2010). Knowing this, suicidants often leave signs visible through the car window warning first responders and others of hazardous materials and toxic gas. This method of suicide has been reported rarely but increasingly in the USA, Australia, and Canada (Lamarque and Orlando, 2007; Goode, 2011; Chemical Suicides, 2012; Bott and Dodd, 2013; Sams et al., 2013).
Physiologic role Sulfide is produced endogenously and also by commensal bacterial in the gut (giving odor to flatus, which is mostly methane) and mouth (contributing to halitosis). Sulfide is present normally in tissues of the body, especially the gut. Given the toxicity of the gas, the exceptionally high normal concentrations in brain tissue puzzled investigators until the physiologic role of the gas was discovered (Reiffenstein et al., 1992). The physiologic role of hydrogen sulfide, as opposed to its toxicologic role, is only now emerging (Wang, 2012; Wang et al., 2014). A detailed review of the physiologic role of hydrogen sulfide is premature and beyond the scope of this chapter, except to indicate that this knowledge is likely to change and refine toxicologic models in the future. There are early indications that hydrogen sulfide has a role in the response to stroke, brain and spinal cord injury, and dementia, but the fragmentary evidence is too early to be coherent. There is a close similarity and interaction among the gas transmitters hydrogen sulfide, carbon monoxide, and nitric oxide (which is much less toxic). Perturbation in their physiologic role is likely to have consequences in both exacerbating and limiting injury, but was undiscovered and therefore completely outside the thinking of toxicology until very recently. Hydrogen sulfide is a paracrine mediator, a diffusible vasorelaxing agent, immune modulator, and neuromodulator (Popov, 2013). It may have a role in insulin sensitivity and glucose metabolism (Zhang et al., 2013). Hydrogen sulfide may act following acute injury (for example, by stroke or trauma) to maintain perfusion, preserve the integrity of the microcirculation, dampen glutamate-mediated excitotoxicity, preventing overexuberant apoptosis, and to quench oxidative stress.
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On the other hand, it may aggravate the situation by elevating calcium influx and so contributing to calcium overload in secondary neuronal injury (Olson, 2011; Wang et al., 2014). Toxic exposure that interferes with these functions may involve direct effects on the nervous system, perhaps mediating cell responses in stroke (Qu et al., 2006) as well as in other organ systems. The state of “suspended animation” induced during knockdown shows promise as a therapeutic intervention (Olson, 2011; Li et al., 2012).
PROPERTIES Hydrogen sulfide (H2S, molecular weight 34.08) is a flammable, colorless gas that is offensively odorous (smell of rotten eggs or cabbage), soluble in lipid, and poorly soluble in water (vapor pressure in water 18.75 102 kPa), and heavier than air (density 1.19). In aqueous media it dissociates readily into hydrosulfide, but not to sulfide as follows. Undissociated hydrogen sulfide and the hydrosulfide ion are predominant at a 1:2 ratio at pH 7.4 (Reiffenstein et al., 1992; Agency for Toxic Substances and Disease Registry, 2006):
H2 S $ H + + HS $ 2H + + S2 pKa1 ¼ 7:04: pKa2 ¼ 11:96 Biologic sources of hydrogen sulfide tend to release intermittent peaks or pulses of the gas, usually together with methane (which is for all practical purposes nontoxic). Once released, the dense gas may persist until displaced by wind or ventilation in low-lying ground, depressions such as trenches or pits, or in confined spaces. Hydrogen sulfide in water, for example in sewage, swamps, and the deep ocean, tends to accumulate to saturation and then is released spontaneously or with perturbation, such as heating or physical disturbance. This results in “burping” of the gas and a bolus effect, which can then be trapped in confined spaces or pits (Nogue et al., 2011). Sustained release tends to be more common from geologic sources, as in the “oilpatch.” Even there, volcanic activity, tapped pockets of gas, and the vagaries of oil and gas extraction may result in a variable exposure profile over short periods.
CLINICAL TOXIDROME A “toxidrome” in toxicology is a syndrome of symptoms and signs characteristic of the effects of a toxic agent. Hydrogen sulfide is unique in its toxidrome for acute and subacute exposure. Whether a toxic effect exists at low exposure levels remains controversial.
Acute Acute hydrogen sulfide toxicity is one of the most unusual and reliable toxidromes in medical toxicology, and features several bizarre signs that allow clinical differentiation to be made from other toxic gases (Yant, 1930; Burnett and King, 1978; Smith and Gosselin, 1979; Beauchamp et al., 1984; Arnold et al., 1985; Wang, 1989; Reiffenstein et al., 1992; Milby and Baselt, 1999; Woodall et al., 2005; Guidotti, 2010). These will be discussed in order of clinical significance in surviving victims. The toxidrome of hydrogen sulfide includes the following progressive symptoms at increasing exposure levels, such that individual cases, unless occurring suddenly, typically include all the effects that precede them: 1. 2. 3. 4. 5. 6.
odor perception conjunctivitis olfactory paralysis, not to be confused with olfactory fatigue “knockdown” (acute central neurotoxicity, reversible) pulmonary edema (uncommon) apnea (not observed).
Cases of toxicity from hydrogen sulfide always show these features, singly or in combination, almost always in the sequence numbered, regardless of the susceptibility or characteristics of the victim or subject. Atypical presentations are so uncommon as to call the diagnosis into question, even in highly unusual cases. When they are not reported, the history is often incomplete or the victim was overcome too quickly for the progression to be observed or to develop fully. Apnea, immediate paralysis of breathing, is a lethal risk at very high concentrations, and may be the cause of death in victims who are already unconscious from knockdown. Clinically it is not observed separately because the victim invariably is already dead. Apnea is an important effect used in animal studies, however, because it is reproducible of neurotoxicity in the rat, which is more susceptible than human beings. Approximate thresholds for each cardinal effect are given in Table 8.1. The stereotypical toxidrome assumes, of course, that there has not been trauma to the head from falling or a period of anoxia or hypoperfusion, as might occur with near-lethal exposures. It also assumes that there is no premorbid condition or susceptibility state that would substantially modify the presentation; to date, none has been demonstrated.
Knockdown In the oilpatch, “knockdown” specifically means sudden loss of consciousness due to hydrogen sulfide exposure. (The term has other meanings in other industries and
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Table 8.1 Health effects of hydrogen sulfide at various approximate exposure levels (Guidotti, 1994, 1996b, 2007, 2010) Concentration (ppm) 0.01–0.3 1–5 5 10 15 20 20–50 100 150–200 250–500 500 1000
Effects Odor threshold (highly variable) Moderate offensive odor, may be associated with nausea, tearing of the eyes, headaches, or loss of sleep with prolonged exposure; healthy young male subjects experience no decline in maximal physical work capacity Aerobic metabolism inhibited in skeletal muscle (lowest observed effect level, probably close to threshold), no observable signs or symptoms; 8-hour occupational exposure limit in Alberta Ceiling level (15 minutes) in Alberta; OSHA PEL 8-hour time-weighted average; anaerobic metabolism threshold inhibited during exercise; eye irritation 15-minute occupational exposure limit in Alberta; short-term exposure limit OSHA PEL Evacuation level in Alberta; ceiling (15-minute time-weighted average) exposure limit OSHA, odor very strong; conjunctivitis may occur Conjunctivitis (eye irritation) and lung irritation. Possible eye damage after several days of exposure; may cause digestive upset and loss of appetite; 50 ppm is the peak (never to be exceeded) OSHA PEL “Gas eye” and lung irritation; olfactory paralysis, sensation of odor disappears Olfactory paralysis; severe eye and lung irritation Pulmonary edema may occur, especially if exposure is prolonged Serious damage to eyes within 30 minutes; severe lung irritation; “knockdown” (sudden unconsciousness) and death (especially if exposure prolonged by hours); amnesia for period of exposure Breathing may stop within one or two breaths (apnea); immediate collapse
OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit.
working life, and the phenomenon does not have a special name in other industries where it occurs.) Hydrogen sulfide-induced acute central neurotoxicity leads to abrupt and reversible loss of consciousness and collapse, often described by those who witness it as like turning off a switch. A knockdown may easily be fatal if exposure at high concentration (roughly 500–1000 ppm) is prolonged, but if exposure is transient, as it often is in an oilfield due to air movement, it may also be quickly reversible. The victim typically falls down as if letting the strings loose on a marionette. If exposure is transient, as usually happens in the oilpatch, recovery may be equally rapid and apparently complete in functional terms. Survivors have even reported to the author that the experience is not unpleasant and may be mildly euphoric, assuming they have not injured themselves in the fall. Given long experience in the “oilpatch” (areas where oil and gas production are prevalent), the author has interviewed many oil and gas workers who have had near-misses or actual knockdowns associated with hydrogen sulfide, and has been involved in fatality investigations. The histories given by patients or observers told after the fact are remarkably consistent with each other and with the relevant literature (Burnett and King, 1978). Observers who witness a knockdown consistently describe it as immediate and complete collapse, often using the metaphor that it is as if a switch had been turned off or a puppeteer had dropped the strings on a
marionette. Recovery from a knockdown is described as being as quick, almost instantaneous, with the person suddenly realizing that he or she is lying on the ground but experiencing no confusion or postictal effects. Oilfield workers, at least above a certain age, usually immediately recognize what happened and get up easily. In the past it was quite common for them to return to work without reporting the incident. Those who observe recovery from a knockdown often describe it using the metaphor of someone turning a switch back on. Those who actually experience a knockdown and recover from it have sometimes said to the author that it was not an unpleasant sensation and that they woke up immediately without mental confusion.
Pulmonary edema and irritant toxicity The significance of pulmonary edema or apnea (another acute, high-level effect) to clinical neurology is obvious: prolonged hypoxemia resulting in anoxic brain damage. However, this appears to be uncommon. Pulmonary edema is associated with prolonged exposure while the victim is unconscious (Richardson, 1995; Tanaka et al., 1999; Daldal et al., 2010). Hydrogen sulfide is irritating to mucous membranes. This effect mostly involves the deep lung and, as discussed in the next subsection, the epithelium (outer lining) of the eye. Because gaseous hydrogen sulfide is poorly soluble in water, it tends to be carried deeply into the lung, where
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diffuse alveolar damage may occur, resulting in toxic inhalation and a risk of pulmonary edema (Guidotti, 2001, 2006). Older studies suggest that 20% of cases of hydrogen sulfide toxicity reaching the emergency department in a setting where most cases came from the oil and gas sector showed at least some evidence of pulmonary edema (Roth et al., 1997). Although this seems implausibly high, it may reflect the residual cases between those who did not seek care (oil companies now demand it) and early fatalities. Compared to other toxic gases, death by pulmonary edema seems to be quite unusual in hydrogen sulfide toxicity. In one series of 152 cases from China, an overall mortality of only 5% was reported, far below the 50% usually cited for mortality from noncardiogenic pulmonary edema (Wang, 1989). First, concentrations high enough to induce pulmonary edema would in most cases already have induced central effects (at levels well above the threshold for knockdown) that would already be lethal, before progression to alveolar edema. The modulatory effect of hydrogen sulfide on inflammation may also spare the lung from early injury and protect against acute endothelial disruption and diffuse alveolar damage. Also, hydrogen sulfide may be much less toxic to lung than other tissues and may even have profound protective effects. For example, it has a potent effect in reducing experimentally induced oxidative injury in the lung (Cao et al., 2014). Experimental studies have shown that hydrogen sulfide is only moderately cytotoxic for pulmonary cells, it does not initiate severe irreversible changes despite extensive pulmonary edema, and does not seem to disrupt the basement membrane of the alveolar endothelium (Lopez et al., 1988; Cao et al., 2014). Thus, the ultimate prognosis for recovery and lung remodeling is likely to be good if the patient can be supported through the acute episode. There are several possible reasons for this. This may be why there are very few reports of chronic lung disease, either airways or interstitial (Duong et al., 2001) associated with recovery from hydrogen sulfide inhalation, and those in the literature more often suggest relatively mild obstructive rather than restrictive effects (Richardson, 1995).
Gas eye (irritative conjunctivitis) “Gas eye” is a superficial inflammation of the cornea and conjunctiva due to the irritant effect of hydrogen sulfide (Tansy et al., 1981; Lambert et al., 2006). It is often recurrent in workers who are exposed for prolonged periods to relatively low occupational concentrations, 20 ppm and possibly lower. Some workers have said to the author that they relied on eye irritation as a
second warning sign of exposure over the permissible occupational exposure limit, because it occurs at a lower level than loss of olfaction. (This is a dangerous practice.) Gas eye is characterized by microvacuolization and edema in the corneal epithelium, leading to mild refractory and chromatic distortion in the form of a colored halo surrounding objects and other visual changes. Blepharospasm, an acute spasm of the orbicularis oculi muscle, may result in tearing, periorbital pain, and photophobia (Tansy et al., 1981; Guidotti, 1994; Milby and Baselt, 1999; Lambert et al., 2006). This form of blepharospasm is acute and not to be confused with eyelid fasciculation. In Rotorua, New Zealand, there was a statistically significant doubling of risk for admission to hospital due to eye disorders, including conjunctivitis, which is an uncommon reason for hospitalization. Given ambient levels, this is a plausible effect of exposure (Bates et al., 1997).
Olfactory effects The odor threshold and olfactory effects of hydrogen sulfide are critical in occupational health because odor provides the primary warning signal to workers that the gas is present. Hydrogen sulfide is very odorous, with a low olfactory threshold, from less than 0.01 to 0.3 ppm depending on individual sensitivity. By 1–5 ppm, the odor is very offensive, aptly described as rotten eggs. Thus, at lower levels the gas has excellent warning properties. However, at high exposure levels the warning properties disappear because at relatively high concentrations (about 100 ppm) hydrogen sulfide paralyzes the olfactory mechanism, preventing perception of any smell. This effect removes the primary warning sign of hydrogen sulfide exposure and the principal warning to, say, oilfield workers suddenly caught in a plume (Turner and Fairhurst, 1990; Smith and Gosselin, 1979; Milby and Baselt, 1999; Guidotti, 2010). Two distinct mechanisms are involved in loss of olfactory acuity to hydrogen sulfide. As with most strong odors, workers may experience olfactory fatigue at lower levels of exposure and may become accustomed to them in the short term. Olfactory fatigue is common to the sensory processing of many strong odors and leads to behavioral tolerance of the odor. There is also a mechanism specific and almost unique to hydrogen sulfide, known as olfactory paralysis. Olfactory fatigue is a sensory adaptation. Olfactory paralysis is neurotoxicity of the olfactory nerve and bulb. Unfortunately, the two phenomena are frequently confused in the literature.
HYDROGEN SULFIDE INTOXICATION Olfactory paralysis due to both neurotoxicity affecting the olfactory bulb and fibers may be followed by hyposmia or anosmia, a permanent loss of the ability to perceive odor. This pattern of toxicity was demonstrated experimentally to be attributable to selective toxicity to olfactory mucosa in the nasal passages and to olfactory neuron loss after subchronic inhalation (Turner and Fairhurst, 1990; Brenneman et al., 2000; Roberts et al., 2006). Hyposmia has been found to be present in most men who recovered from severe, potentially lethal hydrogen sulfide toxicity (Hirsch, 2002). Human subjects exposed to transient high levels of hydrogen sulfide have been reported to show deficits on standardized tests of smell and taste years later (Hirsch, 2002). This is not invariable, however, because tolerance can be induced in the short term and the olfactory mucosa can recover if exposure does not persist too long (Roberts et al., 2006).
SECONDARY SYMPTOMS AND SIGNS As with all toxic conditions, there are secondary symptoms and signs of hydrogen sulfide toxicity that vary and in some cases are secondary rather than direct effects, and sometimes side effects of treatment (such as hypotension from excessive nitrite). The literature documenting the prevalence and profile of these secondary effects is much weaker than that reporting the cardinal effects, not surprisingly.
Acute respiratory effects Bronchospasm occurs in many, but not all, cases but, remarkably, is not reported to result in bronchitis, chronic irritant-induced asthma, or reactive airways dysfunction syndrome (Shivanthan et al., 2013). This may be an example of the lung-sparing effect of hydrogen sulfide as a physiologic modulator of inflammation. Shortness of breath is to be expected for a respiratory irritant and may be a sign of the onset of pulmonary edema. However, in at least one case, dyspnea and cough were relieved during hyperbaric oxygen treatment following hydrogen sulfide exposure, suggesting that shortness of breath may reflect hypoxia (Gallay et al., 2002). Exposure in the short term at 10 ppm does not appear to be associated with reduced lung function or increased airways reactivity (Bhambhani et al., 1996a). However, other studies have suggested that an isolated reduction in residual volume, occurring in 23% of cases exposed in an industrial setting, in the absence of any radiologic or clinical signs, constitutes a subclinical effect to acute exposure (Buick et al., 2000). If confirmed, this unusual effect may be related to inhibitory effects on pulmonary receptors and reflex activity, rather than an effect on
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lung mechanics, as assumed by the author of the study (Klentz and Fedde, 1978; Almeida and Guidotti, 1999). Further emphasizing the possible significance of a modulatory effect of hydrogen sulfide on the lung is the observation that there is an apparent exposure-related reduction in asthma risk (incidence and prevalence) in Rotorua, where ambient levels of hydrogen sulfide are high.
Acute cardiac effects Given the purported mechanism of sudden cytochrome inhibition and disruption in energetic metabolically active cells, one would expect the heart to be a frequent target organ with a toxic cardiomyopathy resulting on recovery. However, there have been surprisingly few validated reports of cardiotoxicity (Christia-Lotter et al., 2007; Amino et al., 2009). Two case reports suggest myocardial ischemia resulting in the absence of any sign of coronary artery disease in otherwise healthy young male workers. One in Korea initially went into acute heart failure with left ventricular dilation but responded well to the usual treatment of acute congestive failure. After recovery, he was significantly impaired with symptoms of dyspnea on exertion and showed a reduced ejection fraction and reduced ventricular chamber size. He showed no neurologic sequelae (Lee et al., 2009). The other, in Japan, was the second victim in a stereotypical unsuccessful rescue attempt and showed evidence of skeletal rhabdomyolysis but delayed myocardial injury, from which he eventually recovered completely (Hirakawa et al., 2013).
Nonspecific symptoms and signs Unfortunately, the secondary literature usually does not distinguish among secondary symptoms that occur in exposed persons who do not experience knockdown or conjunctivitis (two benchmark clinical symptoms that establish exposure levels) and those that do, and almost never is there an exposure assessment refined enough to establish an exposure–response relationship. Headache and short-term cognitive changes, such as short-term memory loss, are common but very nonspecific, as they may occur in many other situations and as a response to distraction and posttraumatic stress. Headache occurred in about a third of hydrogen sulfide exposures but was a transient phenomenon lasting a day or so (Audeau et al., 1985; Sjaasted and Bakketeig, 2006). One exception involved recovery from a prolonged knockdown and cardiac arrest in which chronic headache followed treatment by heroic measures (Asif and Exline, 2012). Seizure disorders are only reported for 2% of cases, historically, but most such cases have probably been associated with anoxic brain damage in near-lethal cases
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(Arnold et al., 1985). In a case series involving a release in an oil refinery in Sri Lanka, about which exposure details were unavailable, a worker with neurofibromatosis (confirmed after the incident) was found unconscious and cyanotic, and developed decerebrate posturing with repeated generalized tonic-clonic seizures while unconscious. After initially responding to ventilation with 100% oxygen and benzodiazepines, the patient went back into status epilepticus after being started on sodium nitrite (hypotension not reported). Astonishingly, he recovered with initial neurologic, predominantly cerebellar, signs that improved and was left with only residual dysarthria and mild ataxia (Shivanthan et al., 2013). In at least one case in which a detailed clinical description is available, an apparently new-onset seizure occurred during a knockdown and resolved without evolving into a chronic seizure disorder (Audeau et al., 1985). One may speculate that the nerve tissue-sparing effect of hydrogen sulfide may play a role in the favorable outcomes. Gastrointestinal symptoms (including jaundice and diarrhea) were reported in the older literature but not in more recent, systematic case series (Arnold et al., 1985). Nausea and vomiting are to be expected given the malodorous exposure, which most people find disgusting (Guidotti, 2010).
CHRONIC EFFECTS There are many unanswered questions about neurotoxicity from hydrogen sulfide.
Neurotoxicity A central issue in studying neurotoxicity associated with hydrogen sulfide has been to differentiate between the primary effects of toxicity in the vicinity of 500 ppm, which cause knockdown as a neurologic event, and the effects of anoxia which can occur as a result or because the atmosphere was low in oxygen to begin with (as in confined spaces and sewers). Hydrogen sulfide toxicity may be the result of several effects, including interference with oxygen uptake and metabolism and also hypoxia from oxygen deprivation due to apnea or respiratory insufficiency. These mechanisms would produce the constellation of findings identified in anoxic brain injury. There may also be other, direct mechanisms of neurotoxicity. Occupational exposure to hydrogen sulfide in four workers did result in loss of consciousness during a release, associated with abnormal evoked response potentials (assessing cortical function) and subclinical neuropsychiatric clinical findings without overt disease. The subjects had cardinal symptoms (eye irritation), confirming that exposure had occurred, possibly repeatedly,
at exposure levels that must have exceeded 50 ppm much of the time and may have reached 243 ppm, as noted in other incidents at this refinery. The pattern of symptoms and impairment was not uniform among subjects. However, these same subjects also had evidence of posttraumatic stress disorder, which can influence neurobehavioral testing, and were not representative of the exposed population, having been selected precisely because they demonstrated abnormalities (Hirsch, 2002). It is now accepted that neurologic sequelae can follow knockdown in the context of acute high-level exposure. Evidence remains weak for effects associated with chronic, low-level exposure, discussed below. It would be expected that, if these effects occur, they would be observed first and most consistently at higher exposures. However, in the case of hydrogen sulfide, exposures that result in knockdown may easily be confounded by head trauma during falls, which is common (Arnold et al., 1985; Wang, 1989; Gabbay and Perrone, 2001), and hypoxemia from apnea or seizure activity (Wang, 1989; Tvedt et al., 1991; Snyder et al., 1995; Tanaka et al., 1999). Even so, in the past, when these events were far more common, oilfield workers often went back to work after a knockdown.
Peripheral neuropathy Despite the observation that demyelination can occur in experimental models (Solnyshkova, 2003), peripheral neuropathy is not often or consistently reported in cases of hydrogen sulfide toxicity. Some well-documented cases describe a tingling paresthesia which does not appear to be associated with chronic neuropathy (Wasch et al., 1989). The finding does not necessarily imply selective neurotoxicity because a paresthesia of this type could also be central or mediated by vascular changes.
Chronic respiratory effects following recovery It is not clear whether prolonged or repeated hydrogen sulfide exposure is associated with chronic respiratory impairment. A single case report has suggested that interstitial fibrosis followed exposure to hydrogen sulfide, but the case has many other unusual features and may not be representative (Duong et al., 2001). Cross-sectional studies of sewer workers, who are exposed to hydrogen sulfide but also have other risk factors, such as exposure to bioaerosols and endotoxin, suggest that lung function is significantly reduced after accounting for smoking and may show an accelerated rate of decline with age. The relationship between age and lung function was skewed in this sample, however,
HYDROGEN SULFIDE INTOXICATION and showed an exposure–response relationship only at the extremes, and did not take outmigration from the reference group (which may have been exposed to chlorine) into consideration (Richardson, 1995). Longitudinal studies required to confirm this finding are not available. Another cross-sectional study of oilfield workers did not find such an effect. Subjects who had experienced a knockdown did not show a difference from those who had not in this population. However, this study had profound methodologic issues, not least of which was that respiratory symptoms were part of the exclusion criteria for their selection (Hessel et al., 1997). (The subjects had been recruited to be a reference group for another study, a point which was not made clear in the article.) It is a paradox of the hydrogen sulfide literature that exposure is not known to induce airways reactivity or the condition known as “reactive airways dysfunction syndrome,” although this might be expected based on the gas’s known irritant effect. One may speculate that this could be a direct consequence of the physiologic anti-inflammatory role of hydrogen sulfide.
CHRONIC EFFECTS OF LOWER-LEVEL EXPOSURE (
