H₂S is noted for its strong and offensive odor, which resembles rotten eggs. WHO (2006) and many others observe that H₂S is often accompanied by other odorous compounds from the same source: kraft mills emit reduced sulfur compounds such as methyl mercaptan, dimethyl disulfide, dimethyl trisulfide, dimethyl sulfide and dimethyl monosulfide; the viscose industry emits carbon disulfide; and CAFOs emit reduced sulfur compounds, VOCs including phenyls (fresh sludge), ammonia (in the absence of H₂S), dusts and bioaerosols (Blanes-vidal et al. 2009). Co-pollutants can change the odor quality of the mixture (NRC 1979).

It is important to distinguish between odor detection, odor recognition, odor threshold, olfactory fatigue, and olfactory paralysis. In community settings, the literature shows a degree of consistency with respect to odor detection and nuisance thresholds for acute exposures (30 min to 24 hr) at concentrations in the range of 0.0001 to 0.05 ppm.

Odorant compounds can affect human health through several mechanisms (e.g., Schiffman et al. 2005; Wing et al. 2008; Woodall et al. 2005). Odor emissions, odor perception, and odor nuisance present quality of life issues that can cause individuals to modify certain physical and social activities (e.g., outdoor physical activity), which can then lead to other health-related issues. Odor perception is often associated with odor nuisance and complaints, and sometimes with psychological responses, e.g., headache, nausea, and loss of sleep. Ocular effects and nasal lesions are discussed in Sections 2.3.2 and 2.3.3, respectively. The WHO (2006) Air Quality Guidelines state that H₂S levels should not exceed 0.005 ppm (7 μg/m³) over a 30-min period to avoid substantial complaints about odor annoyance. OEHHA (2008) in California makes the same statement but uses a higher exposure level, 0.03 ppm, developed in 1984 to reduce odors and physiological symptoms (headache and nausea) with a notation that this may need to be revisited. Several other studies have investigated odors and included H₂S measurements around CAFOs and landfills with the following findings:

Irritation of the eyes, nose, and throat or other toxicological effects through properties of the odorous molecules and stimulation of the trigeminal nerve, typically at concentrations above the nuisance threshold. This is the “Type 1” classification of Woodall et al. (2005), in which symptoms are produced by irritant properties, rather than being odor-induced, often with the odor providing a “warning” of potential adverse health effects.

Livestock rearing systems include CAFOs as well as manure storage and treatment. As noted above, these facilities emit H₂S and other odiferous co-pollutants, e.g., reduced sulfur compounds, phenyls, and ammonia; these facilities can also emit biological contaminants (e.g., endotoxins, fungi and bacteria), aerosols and particulate matter (e.g., entrained dust).

Many surveys have been conducted in communities with or near CAFOs where individuals experience chronic exposure to CAFO-related pollutants (Donham 2010). Occupational studies at CAFOs have documented health complaints, e.g., eye irritation, sinusitis, chronic bronchitis, nasal mucous membrane inflammation, nasal and throat irritation, headaches, and muscle aches and pains, as well as objective health effects, e.g., respiratory inflammation, cross-shift decline in lung function, and chronic respiratory impairment (Schiffman et al. 2005). Acute high level H₂S exposure due to releases from agitated manure can lead to reactive airway distress syndrome (RADS), permanent neurologic damage, and death (Bardana 1999; CDC 1993). A review of health and social issues associated with CAFOs found over 70 papers addressing health issues affecting workers and communities (Donham et al. 2007). In reviewing health effects associated with airborne exposures at CAFOs, Heederik et al. (2007) noted the uncertainty regarding which effects were due to CAFO emissions; uncertainty also applies to attributing the effects to H₂S as compared to other odiferous and irritation-causing CAFO-related pollutants. Below we examine studies since 2004 focusing on odors and nasal irritation from CAFOs. (Later sections address ocular, nasal lesions, respiratory, neurological, and immune effects associated with CAFOs).

The newer studies examining nasal irritation associated with livestock rearing systems follow:

Bullers (2005) studied residents living near hog farms in North Carolina, U.S. in 1998 and 1999 enrolled using snowball recruitment methods (n = 48), who were compared to a group without this exposure studied in 1999 enrolled using flyers (n = 34). The exposed group showed increases in 12 of 22 self-reported physical symptoms, including sinus problems. (Additional symptoms are discussed in subsequent sections.) The authors discussed theoretical models regarding effects of environmental stressors. Study limitations include a modest sample size, a non-random sample, lack of control of covariates, differences in interview protocols (interviews in-home, by telephone), payments to participants in the comparison group but not the exposed group, non-simultaneity of interview periods for the two groups, and the lack of objective health and exposure measures.

We identified several newer studies conducted at landfills, compost and wastewater facilities. As noted earlier (Section 1.2), these facilities produce H₂S under anaerobic conditions, and thus emissions will include other reduced sulfur gases. In addition, VOCs and fugitive dust containing odiferous or irritating components may arise from active landfills (i.e., operating faces without grass or other cover) and composting facilities. The dispersal of dusts is likely to be limited to locations very near the source given the rapid settling and dust fall expected for larger particles, e.g., greater than 2.5 μm in diameter.

A community-based study in Pennsylvania, U.S. measured ambient and indoor levels of H₂S at two elementary schools, one of which was located near a composting plant, in two seasons (spring and fall; Logue et al. 2001). School nurses recorded symptoms and medical history from 749 “exposed” and 518 “unexposed” students. At the control school, concentrations never exceeded 0.01 ppm (1-hr average); at the exposed school, concentrations exceeded 0.01 ppm on 9 days in autumn and 3 days in spring). H₂S was not associated with irritation or olfactory symptoms. (Other outcomes from this study are discussed in later sections.) The negative results may have been due to the minimal exposure contrast between the schools, and other exposures that might have caused exposure misclassification.

Few controlled or occupational epidemiological studies have examined odor and/or irritation related to H₂S. Several community-based studies have evaluated individuals living near H₂S emitting facilities, however, comparisons and synthesis are impeded by the very different exposure assessment methods, which include perception-only studies (i.e., without H₂S measures; Horton 2007), both indoor and ambient H₂S measurements (Logue et al. 2001), ambient odor and ambient H₂S measures (Schinasi et al. 2011), and indoor odor and ambient H₂S measures (Heaney et al. 2011; Horton et al. 2009). Simultaneous odor and H₂S measures, collected both indoors and outdoors, are lacking, and information on individual-level exposures is also lacking. In studies using objective H₂S measures, odor was associated with ambient H₂S and nasal irritation, as has been shown in toxicological studies examining the irritant properties of H₂S, however, other symptoms did not show robust associations. H₂S odors may induce or exacerbate conditions such as stress or behavior modification. Importantly, studies using only odor as an exposure metric can be problematic for several reasons: they do not account for other pollutants that may be present; outcomes may be affected by response enhancement bias, i.e., an increase in reported symptoms since respondents are both aware of and potentially sensitized to the exposure (Farahat and Kishk 2010); odor thresholds among individuals vary enormously; and finally, odor perception can trigger a range of responses that may be contextual and difficult to assess.

In summary, odors associated with sources that emit H₂S, including agricultural, waste, wastewater, and industrial facilities, are clearly associated with odor-triggered nuisance, complaints and physiological symptoms that can result in health and quality of life impacts. These impacts occur at concentrations above an individual’s odor detection threshold, up to the odor nuisance threshold, at short-term H₂S concentrations from roughly 0.001 to 0.050 ppm (Finnbjornsdottir et al. 2016; Heaney et al. 2011; Horton 2007; WHO 2006). Odor sensitivity to H₂S varies greatly among individuals (by over four or more orders of magnitude), and some individuals can detect H₂S at concentrations well below 0.001 ppm. Because the observational and community studies focus on waste management, industrial and agricultural facilities that emit a mixture of odiferous and irritation-causing pollutants, the reported health effects are not necessarily caused by H₂S exposure alone. However, a recent study suggests that H₂S may be the most important odorant at CAFOs, explaining 45 to 68% of the odor, with the remainder attributable to volatile organic compounds (Blanes-vidal et al. 2009). Given these and other study limitations noted above, the relationship between odor detection and harmful health effects has not been consistently found in epidemiological studies.

Bustaffa et al. (2020) has recently reviewed the health effects associated with populations exposed to emissions from natural geothermal events and geothermal energy plants. Evidence of increased eye damage is based on a few studies that are all ecological in design and limited to a single area of New Zealand. Lambert et al. (2006) reviewed several ocular studies, including community studies in Finland and New Zealand (the latter are discussed in Bustaffa et al. (2020) and reviewed below), and concluded that in community settings, short-term H₂S exposures of ~0.025 ppm appears to be the lowest concentration observed that irritates the eyes, and that chronic exposure is associated with serious ocular effects.

Pulp and paper production is the single largest source of H₂S emissions (Section 1.2). A series of Finnish studies have studied populations living near sulfate pulp mills.

The Finnish studies around pulp mills (Haahtela et al. 1992; Marttila et al. 1995, 1994) addressed both acute and chronic exposures and showed statistically significant increases in eye symptoms at (24-hr) concentrations as low as 0.007 ppm. However, these are ecological studies using small populations that likely involve co-exposures to other sulfur gases. In the geothermal area of Rotorua, New Zealand, an ecological approach was also used by classifying the city into high, medium, or low H₂S exposure areas (Bates et al. 2002, 1998). These studies also involve co-exposures, but to different pollutants than the Finnish studies given the different (volcanic) H₂S source. While ocular effects may be experienced at lower concentrations, as concluded by Lambert et al. (2006), the evidence is more consistent that single or repeated short-term H₂S concentrations in the range of 0.007 to 0.025 ppm can produce eye irritation. However, the available observational studies have limitations: they incompletely address the nature of ocular effects other than irritation, their exposure assessments provide limited detail regarding exposures (e.g., short-term but high concentration events are not characterized), and they do not address whether chronic low level H₂S exposure causes irreversible effects on the eye.

In summary, concentrations from about 0.007 to 0.025 ppm correspond with the low end of the range that has been associated with eye irritation in the older cross-sectional studies examining short- and long-term exposures in Rotorua (Bates et al. 2002, 1998) and Finland (Haahtela et al. 1992; Marttila et al. 1995, 1994). Several recent community studies around CAFOs and similar facilities have reported eye irritation (Heaney et al. 2011; Kilburn 2012; Schinasi et al. 2011), as have short-term controlled tests at 0.024 ppm as part of a CAFO mixture containing ammonia and other contaminants described earlier (Schiffman et al. 2005). However, a short-term controlled test of H₂S alone at 0.05, 0.5 and 5 ppm H₂S did not present eye irritation (Fiedler et al. 2008), which suggests the possible role of co-pollutants, rapid fluctuations in H₂S concentrations (that are averaged out in sampling), or longer exposure periods. The available studies have limitations: they do not address the nature of ocular effects other than irritation (Lambert et al. 2006); the exposure assessments provide little spatio-temporal information; the exposure contrasts may be minimal; and the question of whether chronic low level H₂S exposure causes irreversible effects on the eye is not approached.

Using interspecies pharmacokinetic computational fluid dynamics (PK-CFD) models, Schroeter et al. (2006) derived a human NOAEL of 5 ppm by extrapolating the nasal lesion and extraction data observed in rats to humans. The modeling used a conservative physiologically-based dosimetric approach for interspecies extrapolation and differences in exposed nasal surface areas, airflows, partitioning, diffusivity and reaction kinetics. Although some data were lacking to support the extrapolation, modeling was consistent with interspecies clearance data, and results showed good correlation with the incidence of olfactory lesions in rats. An investigation of interhuman variability, which simulated H₂S uptake on olfactory epithelium for 5 adults and 2 children using anatomically correct models of the olfactory region generated from magnetic resonance imaging (MRI) or computed tomography (CT) scan data and steady-state inspiratory airflows, showed similar dosimetry (within 20%) over a range in olfactory airflow (Schroeter et al. 2010). While the modeling may incompletely represent population variability, it suggests that differences in nasal anatomy and ventilation do not significantly affect H₂S uptake in the olfactory region. Additional discussion regarding derivation of the NOAEL and modeling contrasting nasal airflows rat and human noses are given by Dorman (2004).

A recent case-report assessed symptom frequencies of oil field workers (n=34) in Iraq exposed to a wide range of H₂S levels (daily ambient average concentrations from 4 – 50 ppm) and an unexposed comparison group (Mousa 2015). No median or interquartile range (IQR) for exposures was reported. 53% of the exposed workers experienced nasal bleeding, and a few experienced additional bleeding.

The effect of the PK-CFD modeling used to extrapolate nasal lesions in rats to humans (Brenneman et al. 2000; Schroeter et al. 2006) would be to halve the current NOAEL of 10 ppm to 5 ppm. This modeling is consistent with observations, and the rat-to-human extrapolation reduces uncertainty compared to simpler dosimetric approaches. However, human data in this concentration range are insufficient for confirmation, and the NOAEL remains at 10 ppm. As discussed later in Section 4, these studies are important as the risk of nasal lesions remains the basis for several H₂S standards and guidelines.

Several controlled experiments examined biochemical markers of respiratory-related function during and after H₂S exposure, most recently in the 1990s. The two studies discussed below (Bhambhani et al. 1996; Bhambhani and Singh 1991) were used to establish Occupational Exposure Limits (OELs) in the United Kingdom (Costigan 2003) and are cited in the REL documentation (OEHHA 2008). More recent studies on lactate or oxygen stress were not identified. The two studies involved short-term exposure to small numbers of healthy individuals, and they may be most relevant to occupational settings. They update an older controlled study by Jappinen et al. (1990), which may be the first controlled study of H₂S effects on respiratory function.

Respiratory impacts of H₂S are not limited to high exposures; low levels also increase the risks of respiratory symptoms, respiratory disease mortality, and anti-asthma drug use (Bustaffa et al. 2020) as shown by studies examining communities near geothermal and volcanic H₂S sources including Reykjavik (Iceland), Rotorua (New Zealand), the Azores (Portugal), and Mt. Amiata (Italy). (Geothermal emissions and hazards have been reviewed by Bustaffa et al. (2020) and Hansell and Oppenheimer (2004).) Portions of these communities experience chronic exposure to H₂S, estimated to be between 0.02 and 1.0 ppm; Nuvolone et al. (2019) found a lower range of 0.0003 to 0.0224 ppm. Both the older and the newer studies have associated chronic exposure with noninfectious respiratory symptoms and disease. For example, in Rotorua, Durand and Wilson (2006) used improved exposure mapping to show greatly elevated risks of a variety of respiratory symptoms and diseases; in Furnas, Amaral and Rodrigues (2007) showed a greatly increased rate of chronic bronchitis with exposure; in Reykjavik, Carlsen et al. (2012) found adverse impacts on individuals with asthma at H₂S concentrations in the range of 0.0067 ppm; and in Tuscany, Nuvolone et al. (2019) found that an increase of 0.0047 ppm (90-day avg) could have both harmful and beneficial respiratory effects, results that may be partly explained by not testing for multiple outcomes. These studies do not demonstrate causal linkages to H₂S exposure given potential confounding with other pollutants and, in some cases, issues regarding the comparability of the populations. The Reykjavik study (Carlsen et al. 2012) appears the strongest given its multiyear time series analysis, large sample, inclusive population, and objective measures of H₂S and other pollutants. Further details on these studies follow.

Respiratory effects associated with H₂S emissions from livestock rearing systems, including CAFOs, have been investigated in a few controlled and occupational epidemiological studies. However, a number of community-based studies have suggested increased prevalence of respiratory and asthma symptoms and lung function impacts among children and adults experiencing chronic exposure. While designs of these studies vary considerably, as summarized below, all but one identified respiratory-related disease or health symptoms, including breathing difficulty, chest tightness, wheeze (Bullers 2005; Campagna et al. 2004; Mirabelli et al. 2006a, 2006b; Radon et al. 2007; Schinasi et al. 2011), increased asthma prevalence and/or aggravation (Campagna et al. 2004; Merchant et al. 2005; Radon et al. 2007; Sigurdarson and Kline 2006) lung function (PEF and FEV₁) decrements (Radon et al. 2007; weakly in Schinasi et al. 2011), and COPD (Eduard et al. 2009), though the latter association was weak and only present in in farmers with atopy. The single negative study, Villeneuve et al. (2009), had significant limitations: it examined a relatively small farm, had a small sample size, and the “high” exposure group extended 3 km radius from the farm, longer than the distance usually considered for CAFO impacts. Many of these studies used residential proximity to livestock as an exposure surrogate, but several recent studies used objective air quality measurements. Other issues include selection bias, measurement error, and multiple exposures (Section 2.4.3). Of particular note, H₂S exposure due to livestock rearing systems can be accompanied with elevated levels of endotoxins, ammonia, and organic dusts, all of which are strongly implicated in the development of respiratory disease (Woodall et al. 2005). Two studies with objective pollutant measures used time series analyses to show increased rates of unscheduled hospital visits for aggravation of asthma and respiratory disease at 30-min H₂S concentrations above 0.03 ppm in Nebraska (Campagna et al. 2004), and a dose-response relationship for breathing difficulty and wheeze with odor and H₂S at mean levels of 0.0003 ppm in North Carolina (Schinasi et al. 2011).

Health effects of H₂S exposures have been examined in industrial settings other than CAFOs.

Most of the controlled studies examining acute H₂S exposures are older studies that remain important in the regulatory context. Using 30-min exposures and H₂S concentrations from 2 to 5 ppm, these studies show changes in several indicators of respiratory function in both healthy and (mild-to-moderate) asthmatic adults (Bhambhani et al. 1996; Bhambhani and Singh 1991; Jappinen et al. 1990). The only newer controlled study is Schiffman et al. (2005), who used 1-hr exposures of dilute swine confinement with H₂S at a concentration of 0.024 ppm to show increase prevalence of headache, eye irritation and nausea, but no significant effects on vital signs, lung function, nasal inflammation, salivary IgA, mood, attention or memory were found.

The recent epidemiological studies have examined chronic exposure near volcanic areas, CAFOs, and industrial sources, often extending on older studies. Community studies around geothermal and volcanic emission sources in Iceland, the Azores, Tuscany, and New Zealand tend to show higher prevalence rates of respiratory symptoms and disease. Carlsen et al. (2012), the strongest of these studies, found exacerbation of asthma at H₂S concentrations of 0.0067 ppm; Durand and Wilson (2006) and Amaral and Rodrigues (2007) showed greatly elevated risks of a range of respiratory symptoms and disease; while Nuvolone et al. (2019), Bates et al. (2013) and Finnbjornsdottir et al. (2016) found weak or contradictory associations. A number of new studies examined CAFOs and similar sources, adding to some 70 earlier studies that examined these sources. These show many common impacts, including sore throat, cough, nasal irritation, difficulty of breathing, chest tightness, wheezing, increased asthma prevalence and/or aggravation, lung function decrements, and other impacts. Many of these studies use distance from emission facilities as a proxy for exposure, and the role of H₂S cannot be isolated in most of the studies (Sections 2.4.3.4 and 2.4.3.5). Two studies are notable for their rigor and methodological contributions: Campagna et al. (2004) found statistically significant though small increases in unscheduled hospital visits for asthma aggravation and respiratory disease at 30-min H₂S concentrations above 0.03 ppm; Schinasi et al. (2011) found a dose-response relationship between breathing difficulty and cough with odor and H₂S at mean levels of 0.0003 ppm.

In addition, the recent epidemiology literature has suggested populations that are susceptible to chronic low level H₂S exposure: Campagna et al. (2004) identified that individuals with asthma are more susceptible to respiratory disease aggravation; Eduard et al. (2009) found that farmers with atopy are more susceptible to increased prevalence of COPD; and Mirabelli et al. (2006a) remarks that children using cigarettes or experiencing second hand tobacco smoke are susceptible to increased prevalence of wheeze with H₂S exposure. Such results are unsurprising given the increased sensitivity of individuals with asthma and/or allergies to odors and respiratory irritants (EPA 2017).

The community and occupational studies hint that industrial emission sources such as wastewater facilities may affect respiratory health (Lee et al. 2007), although evidence is severely lacking and scattered across many industries.

Livestock rearing systems have been studied in relation to various health effects, as discussed earlier. Only one study by Kilburn (2012) has evaluated possible cardiovascular effects associated with proximity to CAFO facilities. Kilburn (2012), described in Section 2.3.2.3, found significant differences between exposed and control populations for 18 of 35 symptoms, including chest tightness and palpitations.

Epidemiological studies of cardiovascular effects are inconclusive, suggesting both weak positive and negative associations with outcomes such as ischemic heart disease mortality, acute myocardial infarction mortality, and vein or lymphatic disease hospitalization among others. The studies assessing additional cardiovascular outcomes generally found no significant effects.

Two recent controlled studies examined neurological and neurobehavioral effects:

A number of occupational studies have investigated neurological endpoints associated with mostly acute H₂S exposures above 10 ppm. Headaches have been associated with acute (30 – 60 min) and high (240 – 500 ppm) H₂S exposures, followed by neuropsychiatric clinical disorders, unconsciousness, and respiratory failure (Hirsch 2002; Kilburn 1993; Sjaastad and Bakketeig 2006). In a survey of residents of Vågå, Norway, Sjaastad and Bakketeig (2006) found 2 cases of “hydrogen sulphide headaches” among 1,838 WWTP workers exposed to at least 100 ppm, but no individuals in the (mostly soapstone) mining industry reported such headaches. Kangas et al. (1984) reported headaches at 20 ppm. More commonly, headaches are reported following acute exposures at concentrations of 300 – 500 ppm (Sjaastad and Bakketeig 2006). In addition to headaches, earlier studies have investigated neurobehavioral function among acutely exposed workers (n = 16) in several industries in Texas, Louisiana, and elsewhere, among residents living downwind of oil fields in Kentucky and Texas (Kilburn 1997), and among highly exposed individuals (n = 19) in several states and Canada (Kilburn 2003).

The following studies have examined chronic, low-level exposure in occupational settings.

Neurological symptoms and outcomes in community settings were examined in a number of older studies, mostly using self-reported questionnaires. For example, Partti-Pellinen et al. (1996) used a cross-sectional design and a self-administered questionnaire to examine central nervous system symptoms (as well as eye irritation and respiratory-tract symptoms) in adults (n=336) living near a pulp mill and an unpolluted reference community (n = 380) in South Karelia, Finland. In the exposed community, TRS levels averaged approximately 0.001 – 0.002 ppm (2 – 3 μg/m³) and 24-hr levels ranged from 0 to 0.038 ppm (0 – 56 μg/m³) and SO₂ averaged 1 μg/m³ and 24-hr levels ranged from 0 – 24 μg/m³; TRS levels were below 0.0007 ppm (1 μg/m³) in the reference community. An elevated risk of headache was found in the exposed community for the prior 4 week and 12 month periods. (Risk of cough also increased for the preceding 12-month period.)

The newer studies examining neurological outcomes in community settings are diverse.

Recent studies examining neurological and neurobehavioral effects potentially associated with exposures due to livestock rearing systems are discussed below.

Memory and learning impairment lead complaints that are associated with H₂S exposure (Partlo et al. 2001), although a broader set of persistent neurological effects (e.g., headaches, poor concentration ability and attention span, impaired short-term memory, and impaired motor function) have been reported in persons recovering from H₂S-induced unconsciousness resulting from very high concentration exposure (ATSDR 2006). Animal studies have demonstrated effects on brain function, e.g., rats exposed to 125 ppm for 4 hours/day, 5 days/week for 5 consecutive weeks showed impaired performance and learning of spatial tasks (Partlo et al. 2001), findings stated to have relevance for humans (Woodall et al. 2005). Other animal studies with H₂S inhalation exposure suggest decreased motor activity and task response rates from which a LOAEL of 80 ppm for 3 hr/day for 5 days has been derived (ATSDR 2006). Biochemical changes include decreased brain stem total lipids and phospholipids shown in guinea pigs exposed to 20 ppm H₂S for 1 hr/day for 11 days (Haider et al. 1980), and harmful CNS myelination after chronic exposure to 6.7 ppm (Solnyshkova 2003; Solnyshkova and Shakhlamov 2002). Still, the NOAEL for impaired performance in rats remains 100 ppm for 2 hr (Elovaara et al. 1978). No new animal studies on learning relevant to this review were identified.

We identified two recent controlled studies of humans. Schiffman et al. (2005) used 1-hr exposures of dilute swine confinement with H₂S at 0.024 ppm and showed increased prevalence of headaches, eye irritation, and nausea. Fiedler et al. (2008) used 2-hr exposures of H₂S alone at 0.05, 0.5 and 5 ppm and found dose–response relationships for odor intensity, irritation and unpleasantness; compromised verbal learning was shown without a dose-response relationship. A small and older controlled study reported headaches among 3 of 10 asthmatics exposed to 2 ppm H₂S for 30 min (Jappinen et al. 1990). Additional neurobehavioral effects in humans and animals include alterations in balance, reaction time, visual field, and verbal recall, with effect severity depending on exposure duration and concentration (ATSDR 2006). While the few controlled human studies have shown odor, irritation and nuisance symptoms, e.g., irritation and headache, neurological or neurobehavioral affects have not been observed. However, many of the studies examined a single acute exposure event with a small number of healthy individuals, and the ability to capture subtle neurological impairments may be limited (EPA 2011). Additionally, these studies may not be generalizable to other populations, e.g., communities and workers experiencing chronic exposure, or individuals that have greater susceptibility due to their health conditions and age (Fiedler et al. 2008).

The observational studies, both occupational and environmental, complement the controlled studies, but can be challenging to evaluate and synthesize. In comparison to community conditions, both the controlled and occupational epidemiological studies tend to reflect higher concentrations, as do the case reports. Further, all of the observational studies have significant limitations in their exposure assessments that preclude an understanding of potential dose-response relationships pertinent to neurological and neurobehavioral outcomes. As has been noted (and see Sections 2.4.3.4 and 2.4.3.5), other pollutants often accompany H₂S in community and occupational settings, and isolating effects of H₂S in a mixture can be challenging. In addition, objective evaluation of many neurological and neurobehavioral outcomes can be difficult for due to their linkage to educational attainment and other factors, the potential of measurement bias, the likely wide range of sensitivity among individuals, the influence of psychological responses to odor, irritation and nuisance perceptions accompanying H₂S exposure (e.g., headache and nausea), and the flight response, though such biases in outcome ascertainments can be controlled using blinded assessments, objective tests, and other means. Additional issues in cross-sectional studies include generally modest sample sizes, the comparability of groups, and adequate control of potential covariates and confounders. Several of the newer epidemiological studies, which tend to better address these issues, highlight behavioral and neurological effects at low but chronic exposure, and often report similar outcomes as earlier studies. The older studies show, for example: persistent cognitive impairment (reaction time delay, neurological and neurobehavioral deficits) in individuals acutely exposed to high but unknown concentrations of H₂S, but unremarkable neurological and physical examinations (Wasch et al. 1989); reduced perceptual motor speed, impaired verbal recall and remote memory, visual field performance decrements, and abnormal mood status was found in subjects (n = 16) referred for evaluation of effects of reduced sulfur gas exposure compared to referents (n = 353; Kilburn 1997); differences in neurophysiological outcomes (reaction time; balance, color discrimination, digit symbol, immediate recall) and mood state scores (Kilburn and Warshaw 1995); and some memory impairment (Kilburn 1999). Among the newer studies, Nuvolone et al. (2019) assessed a variety of neurological-related mortality and hospitalization diagnoses, but a dose-response effect was seen only for peripheral nervous system hospitalizations (per 0.0047 ppm increase in ambient H₂S); and Legator et al. (2001) reported elevated risks of self-reported central nervous symptoms (e.g., fatigue, headache, and difficulty sleeping) in Odessa, Texas (n = 126) and Puna, Hawaii (n = 97), two communities with H₂S levels averaging from 0.007 to 0.027 ppm, compared to reference communities (n = 170); short-term H₂S levels (1–8 hr averages) were reported to reach 0.5 ppm. The effects observed in these and the other newer studies examining workplace and community populations are not well understood mechanistically, and some of the past literature has been criticized (Guidotti 2010).

Sixteen new observational studies evaluated a range of neurological and neurobehavioral effects among workers and communities in geothermally active regions or around CAFOs, sewer, oil and gas facilities. Three of these studies had negative findings for visual and verbal episodic memory, attention, fine motor skills, psychomotor speed, mood, peripheral nerve function, or stroke (Finnbjornsdottir et al. 2016; Pope et al. 2017; Reed et al. 2014); each of these studies employed spatially modeled estimates of ambient H₂S exposure. A study using universal kriging to estimate residential exposure positively associated H₂S and some neurological outcomes (Inserra et al. 2004). The dozen other studies with positive associations used a variety of designs and instruments, and showed a degree of agreement with respect to non-specific neurological symptoms (headache, memory defects, memory or concentration difficulties (Farahat and Kishk 2010; Inserra et al. 2004; Kilburn 2012; Kilburn et al. 2010; Lee et al. 2007; Partti-Pellinen et al. 1996), more objective neurophysiologic outcomes (e.g., peripheral sensation and discrimination; Inserra et al. 2004; Kilburn 2012; Kilburn and Warshaw 1995; Nuvolone et al. 2019), affect (Fiedler et al. 2008; Kilburn et al. 2010), and mood states or feelings of stress, hopelessness or depression (Bullers 2005; Horton et al. 2009; Kilburn et al. 2010; Kilburn and Warshaw 1995; Lee et al. 2007; Saadat et al. 2006; Villeneuve et al. 2009). The relatively few studies with robust H₂S measures more commonly associated non-specific neurological symptoms and mood states than objective neurophysiologic outcomes (Farahat and Kishk 2010; Inserra et al. 2004; Kilburn et al. 2010; Kilburn and Warshaw 1995; Nuvolone et al. 2019; Partti-Pellinen et al. 1996). Finally, several community studies indicated health-related quality of life impacts on populations living within ~3.6 km (2 miles) of large-scale farming operations (e.g., Horton et al. 2009; Villeneuve et al. 2009), a finding which diverges from (short-term) controlled studies that show only irritation and anxiety (e.g., Fiedler et al. 2008). Full explanations for the dichotomy between controlled and observational studies, the identification of specific and plausible neurological and neurobehavioral mechanisms at play, and the dose-response relationships involved, all remain unresolved.

Animal studies examining exposures above 10 ppm have not shown reproductive or developmental toxicity. Of the few human studies, several suggest that maternal or paternal exposure to H₂S is associated with an increased risk of spontaneous abortion (ATSDR 2006; Xu et al. 1998), however, these studies likely are confounded by simultaneous exposures to multiple pollutants.

Two of the three recent studies that examined cancer found some effect on the incidence of some cancers with H₂S exposure, but each study had methodological weaknesses, including a lack of direct exposure measurements. The finding by Nuvolone et al. (2019) of a protective association between H₂S and neoplasm(s) is likely spurious. The strong positive associations with risks of pancreatic cancer, breast cancer, basal cell carcinoma, and non-Hodgkin’s lymphoma found by Kristbjornsdottir and Rafnsson (2012) might be explained by factors other than H₂S. Overall, the literature on carcinogenic effects of H₂S is inconclusive.

Earlier sections of this review have discussed a variety of health endpoints associated with livestock rearing systems; here we focus on immune effects.

Very few studies have examined immune effects of low-level H₂S exposure. At higher exposure levels, an occupational study has associated H₂S exposure with lower ICAM-1 levels although CPR, SpD, CC16, IL-8, and MIP-1 alpha levels were unchanged (Heldal et al. 2019). Other studies have not found significant results, and are limited by a lack of H₂S measures, often using proximity or odor as an exposure proxy. Overall, the literature on the immunological impact of H₂S is inconclusive.

In an attempt to better understand the relationship between external and internal exposure, H₂S measures may be combined with biological monitoring of sulfhemoglobin or urinary thiosulfate. Several studies, noted above, lack H₂S measurements and instead utilize biological monitoring. Depending on the circumstance, biomarkers in blood and urine may be more difficult to obtain than ambient or indoor air samples. However, if a biomarker is not specific to the compound of interest and data for potential confounding factors are not collected, the biomarker may not be useful in assessing true exposure.

Urinary thiosulfate is the most common biomarker of H₂S exposure (ATSDR 2016). Thiosulfate is produced through oxidative metabolism of H₂S. The process occurs in two steps, which may explain the delayed buildup of thiosulfate in the body following H₂S exposure (WHO 2003). Urinary thiosulfate can be used to confirm low-level exposures, although the responsiveness of this biomarker to low-level exposures may vary significantly between individuals (Durand and Weinstein 2007). H₂S can promote red blood cells (RBCs) to form sulfhemoglobin, a sulfheme protein complex (Kurzban et al. 1999; Ríos-González et al. 2014). H₂S is produced endogenously (see Section 3.10) but at levels too low to form sulfhemoglobin, while exogenous H₂S may occur at levels high enough to warrant the use of sulfhemoglobin to assess its presence in tissues and cells (Ríos-González et al. 2014). However, blood sulfhemoglobin is not specific to H₂S, and can be formed following exposure to drugs (e.g., phenacetin, dapsone, and sulfonamides) as well as other sulfur-containing agents (Gharahbaghian et al. 2009; Bhagavan 2002). If sulfhemoglobin accumulates, it can cause sulfhemoglobinemia and cyanosis, although these are rare conditions.

Biological monitoring of H₂S in epidemiological studies is rare; exceptions are a few studies that measure urine thiosulfate (Farahat and Kishk 2010) or blood sulfhemoglobin (Al-Batanony and El-Shafie 2011). Other studies have measured these biomarkers to assess exposure in humans (Ensabella et al. 2004; Saeedi et al. 2015) and animals (Drewnoski et al. 2012). In Italy, Ensabella et al. (2004) used ambient workplace H₂S measures to verify blood sulfhemoglobin as a reliable measure of individual worker exposure to environmental H₂S. In contrast, Saeedi et al. (2015) found that workers exposed to higher levels of H₂S had lower mean sulfhemoglobin levels, yet these results are largely inconclusive due to the study’s minimal exposure contrast and the limited statistical analysis. Drewnoski et al. (2012) investigated cattle exposed to environmental sulfate, which is converted to H₂S in the rumen of cattle, by measuring both urine thiosulfate and blood sulfhemoglobin. To date, use of H₂S biomarkers is uncommon, and all of the human biological monitoring studies discussed occurred in occupational settings. Validation of H₂S biomarkers for low level exposures in community settings must consider sources of H₂S – endogenous or exogenous, clearance rates, sensitivity, and other factors to avoid exposure measurement error. Thus, at present, it would be prudent to collect ambient or personal H₂S air samples in addition to urine thiosulfate or blood sulfhemoglobin. Further, the invasiveness and inconvenience of conventional blood draws may limit the use of biomonitoring in community studies to clinical settings, however, this may change as techniques evolve that allow convenient and minimally invasive (e.g., finger prick) sampling and analytical techniques.

Exposure to H₂S (and other chemicals) in community and occupational settings will involve both acute and chronic exposures. In practice, these terms are not well defined. Acute exposure events, vary in concentration, length of exposure period, and their periodicity. For many pollutants including H₂S, acute exposures are characterized as the maximum 15-min, 1-hr, or 24-hr average concentration. (Section 4 discusses the form of standards and guidelines that utilize different averaging periods.) Additionally, acute exposures can be a once-in-a-lifetime event, e.g., a result of a rare natural disaster or major industrial failure. In contrast, chronic exposures result from repeated exposure events over multiple years, and sometimes from a continuous or an ongoing release. Chronic exposures also vary in concentration, and are usually represented as an annual average concentration. For some pollutants (e.g., lead), intermediate durations are also sometimes used, e.g., a 3-month average.

Real-world H₂S exposures can include both acute events, e.g., one or few events in a lifetime, intermediate or intermittent exposures, e.g., multiple events in a week or month, and chronic exposures, e.g., occurring on nearly a daily basis due to occupational exposures or proximity to emission sources.

Exposures in community settings near H₂S emission sources (e.g., volcanoes, CAFOs, oil and gas facilities) will likely include intermediate duration and chronic exposures, although acute exposures also may occur. For example, upsets due to malfunctions at an industrial source may greatly increase levels over the chronic exposure normally expected, as documented by Haahtela et al. (1992). More generally, for pollutants like H₂S that are primarily emitted by localized outdoor sources, community exposures will be time varying due to the combined effects of: (1) the emission rate, which changes depending on activity, temperature, and other factors; (2) meteorological influences on dispersion, which is determined by winds, insolation, atmospheric stability, boundary layer height, precipitation, landscape features, and other factors; (3) sheltering or attenuation of H₂S concentrations in buildings and other “microcompartments”, which are affected by air change rates, mixing, filtration, etc.; and (4) an individual’s activity patterns (movement between microcompartments), breathing rate, and other individual-level factors. A key point in community settings is that time-averaged concentrations of H₂S are likely to be low, but occasional concentration spikes at much higher levels for periods of minutes to hours may occur. High pollutant events lasting several days can occur if sufficient H₂S emissions are released and if certain meteorological conditions that inhibit dispersion are persistent, e.g., prolonged subsidence inversion. These factors produce considerable spatial and temporal variation in H₂S concentrations, including daily and seasonal patterns, that affect both occupational or environmental exposures, discussed further the following section.

The time-varying (dynamic) behavior of pollutant concentrations can be captured with fast-response real-time instruments, which are available for H₂S and some other pollutants (e.g., SO₂, CO, PM_2.5, O₃), but not for other pollutants (e.g., endotoxin). Several studies have used continuous monitors for H₂S at locations designed to reflect population exposure, and several studies have used (short-term) indoor measurements in residences. Unlike the low-cost PM_2.5 sensors now being widely deployed across the world, low-cost (less than say $200) H₂S sensors that operate reliably at low concentrations (0.001 – 0.1 ppm) are unavailable.

The use of biomarkers or personal exposure monitoring, the “gold standard” in exposure assessment, has not been attempted in community studies of H₂S. As described earlier (Section 2.4.3.1), H₂S biomarkers have limitations, and personal monitoring can involve substantial cost, logistical and participant burden impacts. As noted, only a subset of studies reviewed employed monitoring for H₂S and other pollutants. In the studies that did use monitoring, there was little discussion of the temporal nature of exposures. Because different averaging times were used, it can be difficult to compare studies examining acute impacts. Generally, temporal fluctuations of H₂S levels in a community would be expected to be similar to that of other pollutants arising from localized outdoor sources. A recommendation is to collect and analyze long-term (ideally ≥1 year) continuous monitoring records of H₂S at sites representative of population exposure around various types of sources. Such data for several other pollutants exist in both public and industry-operated ambient air quality monitoring networks in the U.S., Canada and elsewhere. Occasionally, citizen complaints or permit violations may initiate such monitoring for a limited period, in the U.S. most typically conducted by the U.S. ATSDR, states or industry as part of a exposure and health assessment, e.g., MDHHS (2023). While primarily used to compare community exposure to reference levels (discussed in Section 4.1), such initiatives rarely yield peer-reviewed publications that advance epidemiology, possibly a missed opportunity.

Ideally, data with 5-min or higher time resolution would be obtained and used to analyze concentration distributions at 5-min, 10-min, 30-min, 1-hr, and 24-hr averaging periods. In recent years, new technology has enabled the measurement of H₂S with ppb precision e.g., cavity ring-down technology with high performance.

For mostly the same reasons just discussed, ambient H₂S concentrations in a community will vary from place to place. Spatial variation will always occur from localized outdoor sources and can lead to measurement error. Issues of cost and logistics generally preclude the use of a sufficient number of monitors to fully understand spatial variation across a community, although reasonable estimates can be made with a small set of monitors. Several (Finnish) epidemiological studies have used dispersion models to attempt to “fill-in” the inevitable data gaps from monitoring data (Häkkinen et al. 1985; Marttila et al. 1994; WHO 2006), an approach which is reasonable if data exist to confirm (“ground-truth”) model predictions. Using measured or modeled concentrations, researchers may divide a region or city into zones based on concentration levels (i.e., high, medium, and low). The definition of cut-off points for exposure categories should consider climate factors such as wind direction and good characterization of background levels. For example, in the geothermally active city of Rotorua, New Zealand, the main emission sources of H₂S are spatially clustered and thus not all residents are equally exposed; three zones were defined as high (~1 ppm), medium (0.5 ppm), and low/background levels (0 – 0.04 ppm) (Bates et al. 2002). Considering the lack of standardized exposure category definitions, it is vital to consider each study’s definition of exposure and exposure groups. The use of spatially-defined groups or zones (defined by monitoring, modeling, proximity, or other data) in an cross-section epidemiological study design requires careful consideration and control of covariates to avoid potential bias and confounding..

The majority of community studies around geothermal sources or livestock rearing operations used indirect proxy exposure measures, most often residential or school proximity to a facility or the number of facilities in the community (Bustaffa et al. 2020). Such indirect measures do not capture differences among sources and emissions, effects of meteorology and terrain on contaminant dispersion, impacts from other emission sources, and other factors that affect exposure (Huang and Batterman 2000). Thus, it is not expected that concentrations will be proportional to inverse distance from the source, or radially symmetric around the source, assumptions that have been used in the literature. Urban/rural differences are additional spatial challenges in studying the health effects of environmental exposures around geothermal plants or CAFOs. Urban and rural populations may differ with respect to sensitization and acclimatization to CAFO pollutants, e.g., a potential bias may result due to the lower prevalence of respiratory allergies sometimes seen among populations with early farm-animal contact (Radon et al. 2007).

Exposure assessments for H₂S are just beginning to use the hybrid approaches that have become common in air pollution epidemiology for pollutants like PM_2.5 and NO₂. These approaches synthesize a variety of data sources (satellite and remote sensing, in situ or ambient monitoring, land use features, emission inventories, chemical transport modeling, and sometimes housing features) to improve accuracy in comparison to any single approach. These techniques are particularly applicable to obtaining intermediate to long-term (e.g., weekly to annual) concentration estimates over large areas with high spatial resolution. A recent pilot study couples in situ and satellite data to estimate concentrations and emissions of several pollutants (CO₂, CH₄, H₂S, and NH₃) from a California dairy (Leifer et al., 2020), an approach that may have considerable value when linked to health data.

Air pollution exposures experienced in communities and often workplaces involve mixtures of many chemicals. Measurement error can occur in trying to characterize exposure to an individual pollutant without considering potential co-pollutants. Both the components in the mixture, and the relative concentrations of components in the mixture depend on emission sources that are present. Thus, the “typical” exposure can vary considerably between individuals and between studies. As examples, H₂S exposures from oil and gas facilities will likely include other reduced sulfur compounds and combustion-related compounds like SO₂ and CO; H₂S exposures associated with CAFOs and manure management will likely be accompanied with other gases such as ammonia, mercaptans, sulfides, and ketones, and may also include particulate matter containing organic dusts containing bioactive substances (endotoxins, glucans, fungi and molds) (Donham 2010; NRC 2003). In addition, the composition and rate (strength or intensity) of emissions from most sources (e.g., oil and gas facilities, geothermal plants, or CAFOs) will differ among facilities and during different operations. For example, emissions may increase during hot weather and during manure spraying, an intermittent activity. Thus, the composition and concentration of exposures in community settings will vary in time and space, and the correlation among mixture components will also vary.

Ideally, each individual pollutant would be separately and objectively measured, otherwise effects of individual pollutants will be difficult to disentangle. Of the newer community-based livestock rearing studies identified, only five measured H₂S (Campagna et al. 2004; Eduard et al. 2009; Inserra et al. 2004; Kilburn 2012; Schinasi et al. 2011). Even fewer measured additional co-pollutants likely to confound observed health effects (Campagna et al. 2004; Eduard et al. 2009; Schinasi et al. 2011); these may provide the best dose-response information for setting air quality standards. In their controlled exposure study, Schiffman et al. (2005) opines that while individual components of the mixture at low concentrations were not expected to produce health effects, the observed health effects may represent a combined and potentially synergistic effect. To date, no attempt has yet been made to evaluate health effects of components isolated from real CAFO mixtures, although this is technically possible. For example, subjects could be exposed only to CAFO-related gases by using filters to remove particulate matter and microorganisms. However, for practical reasons, controlled chamber studies are limited to short-term exposures and small sample sizes. Although exposure to the entire mixture may be more relevant to community exposure, such tests could be useful in demonstrating the effectiveness of occupational interventions e.g., N95 masks for workers and mechanical ventilation with particulate filtration for facilities. The results of both controlled and observational studies suggest the need for or desirability of a multipollutant approach to control emissions from livestock-related and potentially other types of facilities. Thus, controls should include both regulation of individual pollutants and broader technology or performance requirements. This approach would be more responsive to health impacts resulting from additive or synergistic effect of multiple pollutants from H₂S sources.

The presence of pollutant mixtures is a real-world condition. In observational studies it may be difficult to discern effects of an individual pollutant when present in a mixture, however, effects may still be discerned despite spatial, temporal, and compositional variability if a study involves a sufficiently large sample of subjects, large geographic domain, sufficient duration, and appropriate pollutant measurements. Moreover, observational studies usually are the only practical approach to examine chronic and low-level exposures, to investigate potential synergies between mixture components and host factors like susceptibility, and to study large populations. The nascent but evolving hybrid models noted in the prior section may be valuable to provide exposure estimates for these studies.

If multiple pollutants are present and reasonably likely to influence a particular health outcome due to their concentration and toxicity, then ideally each pollutant should be objectively measured. It may be sufficient to screen for co-pollutants, or use the threshold olfactory technique (Section 2.3.1.2) in certain studies, to target the exposure assessment. Otherwise, effects of an individual pollutant in the mixture may be difficult or impossible to disentangle. Given information regarding the major components of the mixture, then controlled, occupational and community studies can utilize a variety of experimental and statistical techniques to understand effects of individual components, including potential interactions (e.g., synergies) with other mixture components, as discussed in the next section.

The term “cumulative effects” refers to the overall impact of concomitant exposures to multiple chemicals and other stressors in a particular condition or scenario. For exposure to chemical mixtures, this can include effects that are equal to (additive), less than (antagonistic), or greater than (synergistic) predictions based on the effects observed with exposures to individual chemicals.

As discussed above, H₂S exposures often occur with exposures to other pollutants. Of the current literature, few studies provided information that can shed light on cumulative effects. Schiffman et al. (2005) addressed CAFO emissions, which involve a mixture of H₂S, other reduced sulfur compounds, endotoxin and dust that may act on the same target tissues. One of few controlled human studies, it offers some evidence that the mixture may increase the hazard of H₂S at low concentrations (documented as headaches, eye irritation, and nausea), since no single component was present at sufficiently high concentration to be wholly responsible for these symptoms (H₂S levels were only 0.024 ppm) (Schiffman et al. 2005). Lee et al. (2007) also opined that symptoms observed may result from synergistic or additive effects of the mixture components; they found WWTP workers to have higher risks of respiratory symptoms (dry cough, cough with phlegm, wheeze, chest tightness, breathlessness), although H₂S concentrations averaged 0.15 ppm and 95% of measurements were below 1 ppm (although the maximum value was high, 42.5 ppm). Finally, Mirabelli et al. (2006a) suggested that children using cigarettes or experiencing secondhand tobacco smoke were susceptible to increased prevalence of wheeze, suggesting co-exposure to environmental exposure as an additional risk factor.

Although more complex than investigating a single component, multipollutant studies are needed to provide the most meaningful approach to deal with actual exposures and health effects from pollutant mixtures (Dominici et al. 2010; Greenbaum and Shaikh 2010; Mauderly et al. 2010). Multipollutant approaches may lead to better management strategies because real world H₂S exposures often occur with other toxic pollutants.