5
Hydrogen Sulfide

This chapter summarizes the relevant epidemiologic and toxicologic studies of hydrogen sulfide. It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for hydrogen sulfide. The committee’s recommendations for hydrogen sulfide exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Hydrogen sulfide is a colorless flammable gas with a characteristic odor of rotten eggs (Budavari et al. 1989; Weil et al. 2006). Studies indicate that the odor threshold varies. Ruth (1986) reported an odor threshold of 0.5-10 ppb; others have reported much higher values (ATSDR 2006). The irritating concentration is reported as 10 ppm (Ruth 1986), and olfactory fatigue and nerve paralysis are reported at 100 and 150 ppm, respectively. Selected physical and chemical properties are shown in Table 5-1.

OCCURRENCE AND USE

Hydrogen sulfide is a component of the natural sulfur cycle and is produced endogenously in mammals (Weil et al. 2006). It arises from bacterial reduction of sulfates and decomposition of proteins. Hydrogen sulfide is a



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5 Hydrogen Sulfide This chapter summarizes the relevant epidemiologic and toxicologic stud- ies of hydrogen sulfide. It presents selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the Na- tional Research Council and other agencies. The committee considered all that information in its evaluation of the U.S. Navy’s 1-h, 24-h, and 90-day exposure guidance levels for hydrogen sulfide. The committee’s recommendations for hydrogen sulfide exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps. PHYSICAL AND CHEMICAL PROPERTIES Hydrogen sulfide is a colorless flammable gas with a characteristic odor of rotten eggs (Budavari et al. 1989; Weil et al. 2006). Studies indicate that the odor threshold varies. Ruth (1986) reported an odor threshold of 0.5-10 ppb; others have reported much higher values (ATSDR 2006). The irritating concen- tration is reported as 10 ppm (Ruth 1986), and olfactory fatigue and nerve pa- ralysis are reported at 100 and 150 ppm, respectively. Selected physical and chemical properties are shown in Table 5-1. OCCURRENCE AND USE Hydrogen sulfide is a component of the natural sulfur cycle and is produced endogenously in mammals (Weil et al. 2006). It arises from bacterial reduction of sulfates and decomposition of proteins. Hydrogen sulfide is a 110

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111 Hydrogen Sulfide TABLE 5-1 Physical and Chemical Properties of Hydrogen Sulfide Synonyms Hydrosulfuric acid CAS registry number 7783-06-4 Molecular formula H2S Molecular weight 34.08 Boiling point –60.33°C Melting point –85.49°C Flash point 260°C Explosive limits Lower limit, 4.3% by volume; upper limit, 46% by volume Specific gravity 1.19 (air = 1.00) Vapor pressure 15,600 mmHg at 25°C Solubility 0.398 g/100 g of water at 20°C; soluble in some polar organic solvents, such as methanol, acetone, glycerol, and ether 1 ppm = 1.39 mg/m3; 1 mg/m3 = 0.72 ppm Conversion factors Sources: Budavari et al. 1989; HSDB 2005. byproduct of many industrial processes and is used to make inorganic sulfides that are used to make such products as dyes, pesticides, polymers, and pharma- ceuticals (Weil et al. 2006). The ambient air concentration resulting from natural sources is estimated as 0.11-0.33 ppb (ATSDR 2006). Hydrogen sulfide has been measured in the submarine atmosphere. Data collected on three nuclear-powered attack subma- rines indicate a range of 2-22 ppb (Hagar 2008). Whether the reported concen- trations are representative of the submarine fleet is not known; few details were provided about the conditions on the submarines when the samples were taken. No other exposure data were located. Hydrogen sulfide emissions are thought to arise from the sanitary system (Hagar 2008). SUMMARY OF TOXICITY Occupational exposure to hydrogen sulfide occurs in the agricultural, gas, oil-refining, and other industries, and workers often notice the characteristic rotten-egg odor associated with exposure. Most people readily perceive hydro- gen sulfide because the olfactory detection limit for it is so low (for example, 0.3 ppb or greater as reported by Hoshika et al. 1993). The toxic effects of hydrogen sulfide are characteristically dose-related and most notably involve the nervous, cardiovascular, and respiratory systems (ATSDR 2006). People exposed at low concentrations of hydrogen sulfide and other sulfur gases often report head-

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112 Exposure Guidance Levels for Selected Submarine Contaminants aches, nausea, and other symptoms (Glass 1990; Shusterman 1992). Hydrogen sulfide is a contact irritant, causing inflammatory and irritant effects on the moist membranes of the eyes and respiratory tract; respiratory tract inflamma- tion can result with exposure at about 50 ppm. Eye irritation is the most com- mon complaint associated with single or repeated hydrogen sulfide exposure. There is agreement in the literature that effects on the eye predominate at con- centrations above 50 ppm (Beauchamp et al. 1984; ACGIH 2005). Adverse ef- fects on the human eye after exposure at 20 ppm or less are often associated with concomitant exposure to other chemicals or irritants that would reduce the threshold of corneal irritation (ACGIH 2005). People acutely exposed to hydrogen sulfide at about 100 ppm commonly experience lacrimation, photophobia, corneal opacity, tachypnea, dyspnea, tra- cheobronchitis, nausea, vomiting, diarrhea, and cardiac arrhythmias (ATSDR 2006). Those changes generally resolve on evacuation to fresh air. However, people recovering from hydrogen sulfide exposure can have cough and a variety of effects on the sense of smell, including diminished function (hyposmia), al- tered sensation (dysosmia), and false odor recognition (phantosmia), for a few days to weeks. In humans, inhalation of hydrogen sulfide at as low as 100-250 ppm for only a few minutes can result in incoordination, memory and motor dysfunction, and anosmia (so-called olfactory paralysis). Symptoms become more severe with longer exposure and sometimes lead to pulmonary edema. Exposure at much higher concentrations (about 500 ppm) may result in coma, which is often rapidly reversed when the victim is evacuated, or persistent head- aches, equilibrium loss, and memory loss. Laboratory studies generally indicate that toxic effects observed in ani- mals exposed to hydrogen sulfide at high concentrations are identical with those observed in humans who exhibit acute toxicity of the gas. Compilations of the concentrations of hydrogen sulfide that produce serious systemic toxic effects and death in humans and laboratory animals indicate that species differences in toxicity are not significant (ATSDR 2006). Concentrations that produce effects in the respiratory, cardiovascular, and nervous systems are similar in rats and mice and humans, varying by a factor of less than 10. The mechanism of action to produce serious effects appears to be the same in all species because cellular respiration and energy production controlled by cytochrome oxidase in the mito- chondria are inhibited by hydrogen sulfide in all species tested. That mechanism is consistent with effects observed in multiple organ systems in laboratory ani- mals given acute, high exposures. Laboratory investigations have identified ol- factory lesions in the nasal cavity of the rat after both acute high-concentration and subchronic low-concentration exposures to hydrogen sulfide. As a direct-acting metabolic poison, hydrogen sulfide most profoundly af- fects organs that are critically dependent on oxidative metabolism, such as the brain and heart (ATSDR 2006). Like cyanide, hydrogen sulfide blocks the respi- ratory chain primarily by inhibiting cytochrome c oxidase. Available data on animals suggest that hydrogen sulfide does not cause significant effects on fertility (ATSDR 2006). No studies of the carcinogenic

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113 Hydrogen Sulfide potential of hydrogen sulfide were available for review. There are few studies on the genotoxic potential of hydrogen sulfide, but test results show no indication of toxicity. Effects in Humans Accidental Exposures Hydrogen sulfide is associated with fatal exposures in the workplace. Ac- cording to U.S. Occupational Safety and Health Administration records, there were 80 fatalities in 57 hydrogen sulfide incidents from 1984 to 1994 (Fuller and Suruda 2000). Exposure concentrations and durations in those accidents were generally poorly defined. Most fatalities occur in confined spaces (such as sewers, animal process- ing plants, and manure tanks) and result from respiratory failure, noncardiogenic pulmonary edema, coma, and cyanosis (Adelson and Sunshine 1966, cited in ATSDR 2006; Winek et al. 1968, cited in ATSDR 2006; Arnold et al. 1985). Pulmonary edema is not uniformly seen in fatal hydrogen sulfide poisoning cases, and recovery from coma can be relatively rapid on evacuation of the per- son to fresh air and application of artificial respiration and oxygen. Some people exposed at about 1,000 ppm develop vagal-mediated apnea and hydrogen sul- fide-induced central respiratory arrest (Almeida and Guidotti 1999), and in- creased blood sulfide concentrations are occasionally detected after exposure at high concentrations. Many people exposed to hydrogen sulfide at 500 ppm or higher become unconscious rapidly and then appear to recover. This syndrome is often referred to as knockdown and may result in long-term neurologic deficits, including in- coordination, memory and motor dysfunction, personality changes, hallucina- tions, and anosmia. The clinical effects are consistent with organic brain disease resulting from hypoxia and may occasionally persist for several years after the initial hydrogen sulfide exposure (Arnold et al. 1985; Tvedt et al. 1991a; Tvedt et al. 1991b, cited in NRC 2002 and ATSDR 2006; Reiffenstein et al. 1992; Kil- burn and Warshaw 1995). Vapor concentrations of about 500 ppm or higher are often fatal within minutes (Reiffenstein et al. 1992). Signs and symptoms observed after acute exposure at 100-500 ppm in- clude ocular and respiratory tract irritation, nausea, vomiting, diarrhea, head- aches, loss of equilibrium, memory loss, olfactory paralysis, loss of conscious- ness, tremors, and convulsions (ATSDR 2006). Ocular effects include tearing, burning, and irritation of the cornea and conjunctivae (Lambert et al. 2006). The symptoms generally resolve without intervention after cessation of exposure (ATSDR 2006). The case reports below illustrate the effects of accidental expo- sure to hydrogen sulfide. While drilling a pit to lay the foundation for a municipal sewage pumping station, 37 workers (24-50 years old) were accidentally exposed to hydrogen

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114 Exposure Guidance Levels for Selected Submarine Contaminants sulfide at an undetermined concentration (Snyder et al. 1995). Signs and symp- toms included headache, dizziness, breathlessness, cough, burning and discom- fort in the chest, throat and eye irritation, nausea, and vomiting. Most of the workers recovered uneventfully, but one worker died and another remained in a coma for 5 days. The comatose patient was aggressively treated with hyperbaric oxygen. He was discharged from the hospital on day 16 with slow speech, im- paired attention span, easy distractibility, isolated retrograde amnesia, decreased ability to communicate, impaired visual memory, and poor acquisition, reten- tion, and recall of new information. His condition was unchanged at 12 and 18 months after exposure. In another case report, six patients were examined 5-10 years after accidental exposures to hydrogen sulfide at an unknown concentra- tion (Tvedt et al. 1991a; Tvedt et al. 1991b, cited in ATSDR 2006). The patients had been unconscious for 5-20 min in the hydrogen sulfide atmospheres. Despite rapid evacuation, neurologic symptoms persisted, including impaired vision, memory loss, decreased motor function, tremors, ataxia, abnormal learning and retention, and slight cerebral cortical atrophy. One patient was severely de- mented on long-term follow-up. Numerous other reports of permanent or persistent neurologic effects of exposure to hydrogen sulfide have been published (Wasch et al. 1989; Kilburn 1993, cited in ATSDR 2006; Kilburn and Warshaw 1995; Kilburn 1997). The reports imply that exposure to hydrogen sulfide at relatively high concentrations can cause severe health effects, but as with most case studies, there is a lack of definitive exposure data. Experimental Studies Bhambhani and co-workers (Bhambhani and Singh 1991; Bhambhani et al. 1994, 1996a,b, 1997) performed a series of experiments to examine the dose- related effects of low-concentration exposures to hydrogen sulfide in exercising volunteers. Exercise increased the exposure to hydrogen sulfide by raising the respiratory rate, thereby approximating the exposure situation of an exercising worker. In the first series of experiments, 16 healthy male volunteers undertook increasing increments of bicycle exercise while inhaling hydrogen sulfide at 0 (control), 0.5, 2.0, or 5.0 ppm on separate occasions; multiple physiologic meas- urements were made (Bhambhani and Singh 1991). The subjects inhaled the hydrogen sulfide vapor through their mouths while their noses were plugged with an external clip, so the study does not provide useful information concern- ing the ocular or nasal toxicity of hydrogen sulfide. The results indicated that there were no significant changes in the cardiorespiratory and metabolic process at any exposure concentration and at any exercise level. Heart rate and expired ventilation rate were unaffected. Oxygen uptake increased slightly, carbon diox- ide output decreased slightly, and during exposure to hydrogen sulfide at 5.0 ppm there was a significant increase in blood lactate. The results suggested that anaerobic metabolism is increased by the presence of the sulfide, but whether

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115 Hydrogen Sulfide that is due to inhibition of cytochrome oxidase cannot be determined from the results. In a second series of experiments, 13 male and 12 female healthy volun- teers were exposed to hydrogen sulfide at 0 ppm (control) and 5.0 ppm while exercising for 30 min (Bhambhani et al. 1994, 1996a). The 5.0-ppm exposure did not change arterial blood gases, hemoglobin oxygen saturation, or cardio- vascular and metabolic responses. Citrate synthetase, a marker of aerobic me- tabolism, was the only enzyme that showed a statistically significant decrease in activity. Lactate dehydrogenase and cytochrome oxidase were not altered in muscle tissue taken by biopsy. The results confirmed those from the previous study except that lactate concentrations in blood were slightly higher, but not statistically significantly different, in the 5.0-ppm group. Thus, healthy exercis- ing men and women showed little response to hydrogen sulfide at 5 ppm. Another study showed that healthy people (nine men and 10 women) ex- posed to hydrogen sulfide at 10 ppm for 15 min while exercising showed no changes from control values in a series of respiratory measurements (Bhambhani et al. 1996b). A final study in this series (Bhambhani et al. 1997) used 28 healthy volunteers (15 men and 13 women) exposed to hydrogen sulfide at 0 ppm (control) or 10 ppm while exercising for 30 min. Increased muscle lactate in men and women, decreased muscle cytochrome oxidase in men, and in- creased muscle cytochrome oxidase in women were found, although most changes were not statistically significant. The controlled studies presented above were limited in a number of ways. The exercising volunteers were protected from exposure to their noses and eyes, so they could not smell the gas and were not subject to eye irritation, both sensi- tive outcomes of hydrogen sulfide exposure. In addition, the volunteers were not previously exposed to hydrogen sulfide at the concentrations used in the ex- periments. Jappinen et al. (1990) exposed a group of 10 mildly asthmatic subjects (three men, a mean of 40.7 years old, and seven women, a mean of 44.1 years old) to hydrogen sulfide at 2 ppm for 30 min in a closed chamber. All subjects experienced unpleasant odor at the start of the exposure but rapidly became ac- customed to it. Three of the 10 subjects experienced headache after exposure was completed. There were no changes in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory flow (FEF) as a result of exposure. Calculated airway resistance was slightly decreased in two and in- creased in eight subjects with no significant change in mean values. Specific airway conductance was decreased in six and increased in four subjects. There was over a 30% change in airway resistance and specific airway conductance in two subjects, indicating bronchial obstruction. No adverse symptoms were noted. Fiedler and colleagues (2008) exposed 74 healthy subjects (35 women and 39 men, a mean of 24.7 ± 4.2 years old) to hydrogen sulfide at 0.05, 0.5, or 5 ppm. On the basis of self-reporting, 47% (35) of the subjects were Asian, 35% (26) Caucasian, 8% (six) Hispanic, 7% (five) black, and 3% (two) other. Criteria

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116 Exposure Guidance Levels for Selected Submarine Contaminants that resulted in exclusion of subjects included neurologic disease or brain injury, substantial current or previous exposure to other neurotoxicants, stroke or car- diovascular disease, serious pulmonary disease (such as asthma), hepatic or re- nal disease, serious gastrointestinal disorders (such as colitis), major psychiatric conditions, pregnancy, lactation, or use of specified medications (such as anxio- lytics, antidepressants, and beta blockers). Selected subjects completed a medi- cal history and physical examination that included spirometry, electrocardiogra- phy, blood counts and routine chemistry measures, and visual-acuity testing. For each exposure session, subjects completed ratings and tests before exposure (baseline) and during the final hour of the 2-h exposure period. Subjects used analogue scales to rate pleasantness, intensity, and irritation of the hydrogen sulfide odor and to evaluate environmental qualities. Symptoms were rated on a ratio scale from 0 (barely detectable or no sensation) to 100 (strongest imagin- able). Other tests included evaluation of postural sway, visual-acuity and visual- contrast sensitivity, simple reaction time and continuous-performance test, the finger-tapping test, the symbol-digit substitution test, and the auditory verbal learning test. Increased concentrations of hydrogen sulfide resulted in increased ratings of odor intensity, irritation, and unpleasantness. Total symptom severity, including eye irritation, was not significantly increased in any exposure condi- tion, but anxiety symptoms were significantly greater in people exposed to hy- drogen sulfide at 5 ppm than in people exposed at 0.05 ppm. “No dose-response effect was observed for sensory or cognitive measures. Verbal learning was compromised during each exposure condition.” The authors concluded that “al- though some symptoms increased with exposure, the magnitude of the changes was relatively minor. Increased anxiety was significantly related to ratings of irritation due to odor. Whether the effect on verbal learning represents a thresh- old effect of hydrogen sulfide or an effect due to fatigue could not be deter- mined.” Occupational and Epidemiologic Studies A number of community and occupational studies have examined the ef- fects of exposure to hydrogen sulfide. Because hydrogen sulfide has an objec- tionable odor that is apparent at concentrations below 10 ppb, it is readily recog- nized in ambient air and is often considered a “nuisance odor.” Thus, low concentrations of hydrogen sulfide can cause concern, particularly from the per- spective of community exposure. For example, in the early 1980s, community concerns in Alberta, Canada, related to exposure to natural gas contaminated with hydrogen sulfide (that is, sour gas) resulted in a large cross-sectional sur- vey (Dales et al. 1989; Spitzer et al. 1989) to determine whether there was a higher incidence of health effects in a community living close to a sour-gas fa- cility than in an unexposed community. The results of the investigation were generally unremarkable, although some possible effects on the respiratory sys- tem were reported (Dales et al. 1989). No air measurements were taken, so no

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117 Hydrogen Sulfide direct correlations between health effects and air concentrations of hydrogen sulfide were possible (Spitzer et al. 1989). Data reported from studies of communities experiencing low exposures to hydrogen sulfide and other contaminants from nearby industrial or natural sources could provide an indication of a threshold for adverse health effects. The study results are equivocal because of the mixture of pollutants in the air, which usually includes organic sulfides, sulfur dioxide, and particles. In two communi- ties in Finland that were exposed to pulp-mill emissions, self-reported respira- tory symptoms (wheezing and shortness of breath) and eye irritation or conjunc- tivitis were more frequent than in a community that was not exposed (Jaakkola et al. 1990). Children in the exposed communities did not appear to be more sensitive to the effects of exposure than adults (Marttila et al. 1994). Information obtained from questionnaires in a later study in which exposure concentrations were measured indicated that average 24-h exposures to hydrogen sulfide at less than 0.007 ppm (range, 0-0.059 ppm) did not have significant respiratory or ocu- lar effects, but respiratory symptoms were observed above 0.007 ppm (Marttila et al. 1995). Those studies cannot be given great weight in identifying a thresh- old exposure for hydrogen sulfide toxicity because, as previously mentioned, other air pollutants undoubtedly contributed to the reported effects. At best, the information suggests that hydrogen sulfide may contribute to respiratory symp- toms when mixed with other air pollutants originating in pulp production. Viscose-rayon workers (123 men) repeatedly exposed to hydrogen sulfide or carbon disulfide participated in a health survey that included questions on eye effects (Vanhoorne et al. 1995). Their responses to a questionnaire were com- pared with those of a reference group of 67 workers who were not exposed to either chemical. Workplace hydrogen sulfide exposure was determined by per- sonal sampling devices and ranged from 0.14 to 6.4 ppm. The frequency of ex- posure is unknown, but participating workers had been employed for at least a year. Workers exposed to hydrogen sulfide at 3.6 ppm or less did not have sig- nificantly more ocular complaints than the unexposed workers. Workers ex- posed to hydrogen sulfide at 6.4 ppm did have significantly more eye com- plaints, including pain, burning, irritation, hazy sight, and photophobia. Jappinen et al. (1990) studied a cohort of 26 male pulp-mill workers (mean age, 40.3 years; range, 22-60 years) to assess the possible effects of daily hydrogen sulfide exposure on respiratory function. Most of the exposures were at 2-7 ppm, with a range of 1-11 ppm. Bronchial responsiveness, FVC, and FEV1 were measured at the end of a work day that followed at least 1 day off from work. No significant changes in respiratory function or bronchial respon- siveness were observed after hydrogen sulfide exposure compared with control values. In another study, 21 swine confinement-facility workers were tested with spirometry immediately before and after a 4-h work period (Donham et al. 1984). They had statistically significant (p < 0.05) reductions in pulmonary flow rates: a mean FEF of 3.3-11.9% after the 4-h work period. The work environ- ment was sampled for particles and gases during the exposure period, and there

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118 Exposure Guidance Levels for Selected Submarine Contaminants was suggestive evidence of a concentration-response relationship between car- bon dioxide and hydrogen sulfide exposure concentrations and lung-function decrements. However, the monitoring data were not presented in the study re- port. Barthelemy (1939), using work-area sampling and wet-chemistry analytic methods, reported hydrogen sulfide concentrations of about 30 ppm in the pres- ence of carbon disulfide and acid particles in a rayon-production facility. It was reported that coexposure to carbon disulfide and acid particles reduced the threshold for hydrogen sulfide-induced ocular irritation. Exposure to hydrogen sulfide at about 30 ppm under the mixed exposure conditions caused “quite a number” of workers to develop severe eye irritation sufficient to prevent their ability to work in the facility. Six years of monthly air-monitoring data and worker-complaint records showed that the number of reported conjunctivitis cases increased from zero in December 1932 to 332 by December 1933 (when the plant’s ventilation system failed). Ocular effects included intense photopho- bia, eyelid spasm, excessive tearing, intense congestion, pain, blurred vision, and sluggish pupil reaction. Typical hydrogen sulfide concentrations at the facil- ity when it was operating without eye complaints were 9-18 ppm. Barthelemy concluded that maintaining hydrogen sulfide concentrations below 20 ppm (even in the presence of carbon disulfide at about 30 ppm) eliminated reports of eye irritation. Other investigators have reported that the incidence of eye irrita- tion is “materially increased” at hydrogen sulfide concentrations of 20 ppm or slightly higher (Carson 1963). A hydrogen sulfide concentration of 20 ppm ap- pears to be a threshold for obvious effects on the eye. Table 5-2 summarizes the common clinical signs observed in experimental and occupational studies. Effects in Animals Acute Toxicity ATSDR (2006) reported similar findings on acute toxicity in rats, mice, and rabbits. Zwart et al. (1990) reported that the hydrogen sulfide concentration that was lethal to 50% (LC50) of rats and mice was 684 and 677 ppm, respec- tively, after a 50-min exposure. MacEwen and Vernot (1972) reported LC50s in rats and mice of 712 and 634 ppm after a 1-h exposure. The similarity in re- sponse among mammalian species is typical for contact irritants. Sprague-Dawley, Long Evans, and Fischer-344 rats were exposed to hy- drogen sulfide in whole-body exposure chambers for 2, 4, and 6 h (72 males and 84 females at 2-h and 6-h intervals, 72 of each sex at 4 h) (Prior et al. 1988). The resulting LC50s for 2-, 4-, and 6-h exposures were 587, 501, and 335 ppm, re- spectively. Six exposure concentrations were used in the 6-h study, and eight each in the 2- and 4-h studies. All deaths were attributed to severe pulmonary

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TABLE 5-2 Hydrogen Sulfide-Induced Effects Observed in People Hydrogen Sulfide Cohort Concentration (ppm) Effect Reference Experimental: 10 asthmatics, 30 2 No clinical symptoms or statistically significant changes; Jappinen et al. min headache in three of 10 subjects; airway resistance slightly 1990 decreased in two and increased in eight; specific airway conductance decreased in six and increased in four; over 30% change in airway resistance and specific airway conductance in two of 10 subjects Occupational: 26 pulp-mill 2-7 (range, 1-11) No significant changes in respiratory function or bronchial Jappinen et al. workers, end of workday after at responsiveness 1990 least 1 day off Experimental: 16 men, various 0.5, 2.0, 5.0 NOAEL, 2 ppm for oxygen uptake, carbon dioxide output, Bhambhani and periods up to 16 min and blood lactate during exercise Singh 1991 Occupational: 123 male, viscose- 0.14-6.4 NOAEL, 3.6 ppm, LOAEL, 6.4 ppm for eye complaints of Vanhoorne et al. rayon workers, exposure to pain, burning, irritation, hazy sight, and photophobia. 1995 hydrogen sulfide or carbon disulfide daily, at least 1 year Occupational: unspecified number 9-30 (work-area Concentrations below 20 ppm deemed not to be a problem; Barthelemy 1939 of rayon-industry workers exposed samples over period substantial ocular effects at 30 ppm: intense photophobia, lid to hydrogen sulfide and carbon of 6 years) spasm, excessive tearing, intense congestion, pain, blurred disulfide vision, sluggish pupil reaction Abbreviations: LOAEL, lowest observed-adverse-effect level; NOAEL, no-adverse-adverse-effect level. 119

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120 Exposure Guidance Levels for Selected Submarine Contaminants edema. Groups of five male and five female Wistar rats were exposed to hydro- gen sulfide at various concentrations for 10, 30, or 50 min (Arts et al. 1989, cited in NRC 2002; Zwart et al. 1990). The 10-min LC50 was 835 ppm, and the 30- and 50-min LC50s were 727 and 684 ppm, respectively (see Table 5-3) Brenneman et al. (2002) exposed groups of 10-week-old Sprague-Dawley rats (five rats per concentration per exposure time) to hydrogen sulfide at 0, 30, 80, 200, or 400 ppm 3 h/day for 1 or 5 consecutive days. A concentration of 30 ppm for a single day or 5 days was the no-observed-adverse-effect level (NOAEL) for nasal lesions. The most prominent nasal lesion was olfactory mu- cosal necrosis. Repair of that lesion was complete at 6 weeks after exposure (Brenneman et al. 2002). The primary differences observed in effects between exposure durations of 1 and 5 days were that animals exposed for 5 days had a higher lesion incidence (100%) and more extensive injury of the nasal cavity. Brenneman and co-workers also reported transient metaplasia in the nasal respi- ratory mucosa after exposure at 80 ppm or higher. That lesion is not seen after subchronic hydrogen sulfide exposure, and this finding suggests that the regen- erated respiratory epithelium becomes resistant to further injury. No pulmonary lesions were observed even at the highest concentration tested. The lowest ob- served-adverse-effect level (LOAEL) in the study was 80 ppm for the reversible olfactory mucosa lesion. Lopez et al. (1989) showed that the gross and histologic evidence of pul- monary edema caused by 5-min exposure to hydrogen sulfide at a lethal concen- tration (1,662 ppm) was a direct effect because intraperitoneal injections of 30 mg/kg did not affect the airways or lungs. Brenneman et al. (2000a) exposed 10- week-old male CD rats that had undergone unilateral nasal occlusion to hydro- gen sulfide at 400 ppm for 3 h. A day after the exposure, rats developed olfac- tory neuronal loss on the side of the open nostril. That lesion was absent on the side that had the occluded nostril; this suggests that the observed injury was the result of a direct effect rather than of systemic delivery of the gas. TABLE 5-3 Summary of Rat and Mouse LC50s LC50 (ppm) Exposure Duration Reference Rat Mouse 10 min 835 1,160 Zwart et al. 1990 30 min 727 799 Zwart et al. 1990 50 min 684 677 Zwart et al. 1990 1h 712 634 MacEwen and Vernot 1972 2h 587 Prior et al. 1988 4h 501 Prior et al. 1988 4h 444 Tansy et al. 1981 6h 335 Prior et al. 1988

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128 Exposure Guidance Levels for Selected Submarine Contaminants was used to estimate a human NOAEL of 5 ppm with the EPA (1994) inhalation reference concentration method. INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS A number of organizations have established or proposed acceptable expo- sure limits or guidelines for inhaled hydrogen sulfide. Table 5-4 summarizes selected values. COMMITTEE RECOMMENDATIONS The committee’s recommendations for EEGL and CEGL values for hy- drogen sulfide are summarized in Table 5-5. The current U.S. Navy values are provided for comparison. 1-Hour EEGL The proposed 1-h EEGL of 10 ppm is intended to prevent severe eye irri- tation and is based on a weight-of-evidence approach. That EEGL is consistent with a recent critical review of the available human and animal toxicology data (Lambert et al. 2006). As reviewed by Lambert and co-workers (2006), Nesswetha (1969) studied etiologic factors in 6,500 cases of keratitis superfici- alis punctata (spinner’s eye) that were attributed to occupational exposure to hydrogen sulfide. Mild eye irritation occurred after 6-7 h of exposure at 10 ppm, and similar symptoms developed after 4-5 h at 14 ppm. On the basis of the data, the committee notes that it is unlikely that eye irritation worsens with time. Additional epidemiologic studies support the 1-h EEGL. Barthelemy (1939) reported that typical concentrations of hydrogen sulfide that were not associated with eye complaints ranged from 9 to 18 ppm. He concluded that hydrogen sulfide concentrations below 20 ppm “seemed not to be a problem,” although other investigators have reported a “material increase” in eye-irritation incidence at 20 ppm or slightly higher (Carson 1963). A hydrogen sulfide con- centration of 20 ppm appears to be a threshold for adverse effects on the eye sufficient to impair the ability of workers to perform their jobs. Human chamber studies provide additional support of the 1-h EEGL (Bhambhani and Singh 1991; Bhambhani et al. 1994, 1996a,b, 1997; Fiedler et al. 2008). Taken together, the results of those studies do not indicate changes in healthy adults that signal the initiation of a toxic response to hydrogen sulfide exposure at up to 10 ppm. The magnitude of the few exposure-related changes

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129 Hydrogen Sulfide TABLE 5-4 Selected Inhalation Exposure Levels for Hydrogen Sulfide from National Research Council and Other Agenciesa Exposure Level Organization Type of Level (ppm) Reference Occupational ACGIH TLV-TWA 10 ACGIH 2005 TLV-STEL 15 NIOSH REL-ceiling (10 min) 10 NIOSH 2005 OSHA PEL-ceiling 20 29 CFR 1910.1000 PEL-ceiling (10 min 50 max peak)b Submarine NRC EEGL NRC 1985 10-min 50 24-h 10 CEGL 90-day 1 SEAL 1 (10-day) 15 NRC 2002 SEAL 2 (24-h) 30 General Public ATSDR Acute MRL 0.07 ATSDR 2008 Intermediate MRL 0.02 NAC/NRC AEGL-1 (1-h) 0.51 EPA 2002 AEGL-2 (1-h) 27 AEGL-1 (8-h) 0.33 AEGL-2 (8-h) 17 a Comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regula- tory Standards or Guidance Levels”). b Acceptable maximum peak is relevant only for one 10-min exposure if no other meas- ured hydrogen sulfide exposures have occurred. Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Dis- ease Registry; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; MRL, minimal risk level; NAC, National Advisory Committee; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SEAL, submarine escape action level; STEL, short- term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

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130 Exposure Guidance Levels for Selected Submarine Contaminants TABLE 5-5 Emergency and Continuous Exposure Guidance Levels for Hydrogen Sulfide Current U.S. Navy Committee Recommended Values (ppm) Values (ppm) Exposure Level EEGL 1-h 10 10 24-h 3 2.8 CEGL 90-day 1 0.8 Abbreviations: CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level. that were observed, the sporadic occurrence of the changes, and the lack of a functional change in the cardiorespiratory system are not consistent with a con- clusion that the effects constituted a toxic response. Studies in animals further support the recommended 1-h EEGL. Brenne- man et al. (2002) exposed groups of 10-week-old Sprague-Dawley rats (five rats per concentration per exposure period) to hydrogen sulfide at 0, 30, 80, 200, or 400 ppm 3 h/day for 1 day or 5 consecutive days. The nasal lesions were charac- terized by necrosis of the olfactory mucosa, which was largely repaired within about 6 weeks after exposure. The primary differences observed in effects be- tween the 1-day and 5-day exposure groups were the higher incidence of and more extensive lesions seen in the nasal cavity of rats exposed for 5 consecutive days. No pulmonary lesions were observed even at the highest concentration tested. The LOAEL of hydrogen sulfide in the study was 80 ppm for the reversi- ble olfactory mucosa lesion. The NOAEL for nasal lesions was 30 ppm for a single day or 5 days. 24-Hour EEGL The basis of the 24-h EEGL was the study by Curtis et al. (1975). They exposed three immature pigs in a whole-body inhalation chamber to hydrogen sulfide at 8.5 ppm continuously (24 h/day) for 17 days. Pigs were subjected to a complete gross examination at necropsy, and a histologic examination was con- ducted on tissues from the respiratory tract, eye, and viscera. The results indicate that 8.5 ppm was a NOAEL. Application of an interspecies uncertainty factor of 3 yields a 24-h EEGL of 2.8 ppm. An interspecies uncertainty factor of 3 was considered appropriate because hydrogen sulfide is a contact irritant with a dose-response relationship that is similar among species. The 24-h EEGL is supported by the study reported by Vanhoorne et al. (1995). Viscose-rayon workers (123 men), repeatedly exposed to hydrogen sul- fide and/or carbon disulfide, participated in a health survey that included ques-

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131 Hydrogen Sulfide tions on eye complaints. Their responses to the questionnaire were compared with those of a reference group of 67 workers not exposed to either chemical. Personal exposure to hydrogen sulfide in the workplace was measured with per- sonal sampling devices and ranged from 0.14 to 6.4 ppm. The published study did not report the frequency of exposure but only stated that participating work- ers had been employed for at least 1 year. Job descriptions in a previous report indicated that the hydrogen sulfide exposures occurred daily but were unclear as to the duration of exposure during the workday (Vanhoorne et al. 1991). Work- ers exposed to hydrogen sulfide at 3.6 ppm or lower did not have significantly more eye complaints than the unexposed workers. Workers exposed at higher concentrations averaging 6.4 ppm did have significantly more hydrogen sulfide- related complaints. The most frequent complaints about the eye were pain, burn- ing, irritation, hazy sight, and photophobia. The findings suggest a 3.6 ppm NOAEL for repeated hydrogen sulfide exposure. The 24-h EEGL is also supported by the available epidemiologic data. For example, Jappinen et al. (1990) studied a cohort of 26 male pulp-mill workers (mean age, 40.3; range, 22-60 years) to assess the possible effects of daily hy- drogen sulfide exposure (at 10 ppm or lower) on respiratory function. Bronchial responsiveness, FVC, and FEV1 were measured after at least 1 day off work and at the end of a workday. No significant changes in respiratory function or bron- chial responsiveness were observed after hydrogen sulfide exposure compared with the control values. 90-Day CEGL The study by Dorman et al. (2004) was used to develop the 90-day CEGL. Groups of 10 male and 10 female Fischer-344 rats, B6C3F1 mice, or Sprague- Dawley rats were exposed to hydrogen sulfide at 0, 10, 30, or 80 ppm 6 h/day, 5 days/week for 90 days. Exposure at 80 ppm was associated with reduced feed consumption for the first week in rats and throughout the study in mice. De- creased body-weight gain was observed in high-concentration male Fischer-344 rats, female Sprague-Dawley rats, and mice. No treatment-related effects were observed with regard to gross pathology, hematology, or serum chemistry. All the mice exposed at 80 ppm developed rhinitis. Histologic examination of the nose showed an exposure-related increased incidence of olfactory neuronal loss that occurred after exposure at 30 ppm or higher in both sexes of all experimen- tal groups except that the lesion in Sprague-Dawley rats was seen only at 80 ppm. In the lung, bronchiolar epithelial hypertrophy and hyperplasia were evi- dent in male and female Sprague-Dawley rats at 30 ppm or greater. The experi- mental NOAEL for nasal lesions was 10 ppm, which was used as the basis of the 90-day CEGL. The inhalation study performed by Brenneman et al. (2000b) using rats exposed to hydrogen sulfide in a whole-body chamber (6 h/day, 7 days/week for 10 weeks) is also supportive of the committee’s recommended value. In that

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132 Exposure Guidance Levels for Selected Submarine Contaminants experiment, the NOAEL for lesions in the olfactory mucosa was 10 ppm. Hy- drogen sulfide at 30 ppm was the LOAEL, and 80 ppm caused a marked in- crease in nasal lesions. Later studies have shown that the nasal mucosa is a very sensitive tissue and yield one of the lowest NOAELs (10 ppm) for hydrogen sulfide inhalation exposure (Dorman et al. 2004). The 10-ppm value was time-scaled to account for a continuous (24-h/day) exposure (one-fourth of the 6-h/day NOAEL of 10 ppm, or 2.5 ppm). An inter- species uncertainty factor of 3 was used for animal-to-human extrapolation. An interspecies uncertainty factor of 10 was considered unnecessary because the nasal mucosa is so sensitive, as noted above. In addition, hydrogen sulfide is a contact irritant with a dose-response relationship that is similar among species. A 90-day CEGL of 0.8 ppm was derived. Further support of the committee’s recommended value is derived from studies performed by Schroeter et al. (2006). A pharmacokinetic-driven compu- tational fluid dynamics (CFD) model was used to compare regions of high pre- dicted hydrogen sulfide flux in rat nasal passages with the distribution of hydro- gen sulfide-induced olfactory lesions in a subchronic inhalation study of Brenneman et al. (2000). Because the model yields a quantitative flux measure, the minimum flux value associated with olfactory lesions in rats could be esti- mated. That modeling approach was then used to predict hydrogen sulfide flux in human nasal passages by scaling the kinetic parameters and implementing a similar boundary condition in a human nasal-airflow model (Subramaniam et al. 1998). Olfactory fluxes predicted from the human CFD model were used to de- rive a NOAEL(human-equivalent concentration [HEC]) for hydrogen sulfide. The NOAEL(HEC) value was estimated to be 5 ppm. DATA ADEQUACY AND RESEARCH NEEDS Although there is an extensive literature on the health effects of hydrogen sulfide, questions remain about its possible effects and about concentrations at which effects may occur. Those questions apply particularly in connection with the end points of neurologic, respiratory, behavioral and developmental effects. At airborne concentrations above 20 ppm, the direct irritation effects of hydro- gen sulfide are increasingly apparent. Acute respiratory effects are widely as- sumed to occur after even brief exposures at concentrations above 200 ppm, and acute neurotoxic responses occur at concentrations above 500 ppm. Questions now exist as to whether longer-term neurotoxic and respiratory or pulmonary deficits may occur after short-term high-concentration exposures. There are also concerns about human health effects in the low-exposure region, especially after chronic low-concentration exposure.

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