Toxicology Mechanisms and Methods

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A comprehensive review of treatments for

hydrogen sulfide poisoning: past, present, and
future

Cristina Santana Maldonado, Abigail Weir & Wilson K. Rumbeiha

To cite this article: Cristina Santana Maldonado, Abigail Weir & Wilson K. Rumbeiha (2022): A
comprehensive review of treatments for hydrogen sulfide poisoning: past, present, and future,
Toxicology Mechanisms and Methods, DOI: 10.1080/15376516.2022.2121192

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TOXICOLOGY MECHANISMS AND METHODS
https://doi.org/10.1080/15376516.2022.2121192

REVIEW ARTICLE

A comprehensive review of treatments for hydrogen sulfide poisoning: past,

present, and future
Cristina Santana Maldonado, Abigail Weir and Wilson K. Rumbeiha
Molecular Biosciences, University of California, Davis, Davis, CA, USA

ABSTRACT ARTICLE HISTORY

Hydrogen sulfide (H2S) poisoning remains a significant source of occupational fatalities and is the Received 24 June 2022
second most common cause of toxic gas-induced deaths. It is a rapidly metabolized systemic toxicant Revised 20 August 2022
targeting the mitochondria, among other organelles. Intoxication is mostly acute, but chronic or in- Accepted 23 August 2022
between exposure scenarios also occur. Some genetic defects in H2S metabolism lead to lethal chronic
KEYWORDS
H2S poisoning. In acute exposures, the neural, respiratory, and cardiovascular systems are the primary Hydrogen sulfide poisoning;
target organs resulting in respiratory distress, convulsions, hypotension, and cardiac irregularities. countermeasures; systemic
Some survivors of acute poisoning develop long-term sequelae, particularly in the central nervous sys- toxicity; toxic mechanisms;
tem. Currently, treatment for H2S poisoning is primarily supportive care as there are no FDA-approved therapeutics
drugs. Besides hyperbaric oxygen treatment, drugs in current use for the management of H2S poison-
ing are controversial. Novel potential drugs are under pre-clinical research development, most of
which target binding the H2S. However, there is an acute need to discover new drugs to prevent and
treat H2S poisoning, including reducing mortality and morbidity, preventing sequalae from acute expo-
sures, and for treating cumulative pathology from chronic exposures. In this paper, we perform a com-
prehensive review of H2S poisoning including perspectives on past, present, and future.

Introduction H2S leading to death in the first decade of life (Tiranti

Hydrogen sulfide (H2S) is a toxic gas with a distinctive smell
of rotten egg. The discovery of endogenously produced H2S
led to research aiming to understand its physiological roles
and its potential applications for the treatment of several
chronic diseases via multiple mechanisms including anti-
inflammatory and cytoprotective effects in tissue injury, anti-
oxidant properties, and vasodilation among others (Goodwin
et al. 1989; Savage and Gould 1990; Wallace and Wang
2015). Endogenously, H2S is produced from the amino acids
homocysteine and serine found in the mitochondria and
cytosol (Kamoun 2004; Kimura 2011). Many have cited the
effectiveness of treating patients with respiratory diseases
with low concentrations of H2S. Wang et al. (2020) showed
the successful use of 40 ppm H2S for 8 h daily to treat
chronic obstructive pulmonary disease (COPD) in rats. The
H2S donor sodium hydrosulfide (NaHS) has been cited to
have a protective effect on pulmonary artery endothelial cells
in rat models of COPD (Wang et al. 2020). Notably, however,
genetic defects in the metabolism of endogenously pro-
duced H2S to nontoxic sulfate metabolite such as that
caused by ETHE1 deficiency have been associated with
chronic H2S poisoning (Beauchamp et al. 1984; Szabo 2007;
Tiranti et al. 2009; Tiranti and Zeviani 2013; Di Meo et al.
2015). ETHE1 deficiency and similar genetic defects cause
H2S-induced chronic neurodegeneration from accumulating
et al. 2004).
Besides being produced endogenously, H2S is an environ-
mental toxicant produced from natural and industrial sources
(Beauchamp et al. 1984). It is part of a natural sulfur cycle.
Natural sources include volcanoes, hot springs, and under-
water thermal vents (Bates et al. 1997, 1998). H2S is also a
product of the anaerobic decomposition of organic animal
and plant matter containing sulfur (Donham 2000).
Environmentally produced H2S poses a major risk to workers
in industries where the gas is ubiquitous and cited to cause
multiple injuries and fatalities worldwide. H2S is a hazard in
industrial settings including sulfur mining; petroleum and
gas exploration, extraction, and refining; rayon textile pro-
duction, chemical manufacturing, waste disposal, sewage
treatment plants, and concentrated animal feeding opera-
tions (CAFOs) where it is an occupational and community
hazard (Reiffenstein et al. 1992; Adgate et al. 2014;
Finnbjornsdottir et al. 2015; Ramos et al. 2018). There are
more than 80 occupations in which H2S poses a significant
risk to workers following acute accidental releases or low-
level chronic exposures (WHO 1981; Rumbeiha et al. 2016).
Two historical industrial accidents, one in Poza Rica Mexico
in 1950 stemming from a refinery explosion, and the other in
Kaixian County in China in 2003 stemming from a gas pipe-
line explosion, remind us of the potent lethality of H2S. In
the Poza Rica accident, 320 people were hospitalized and 22

CONTACT Wilson K. Rumbeiha wkrumbeiha@ucdavis.edu Molecular Biosciences, University of California, Davis, Davis, CA 95616-5270, USA
ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
2 C. M. SANTANA MALDONADO ET AL.

died (McCabe and Clayton 1952) while in the Kaixian County
accident in China, 243 people died (Yang 2006). In this
review, we aimed to identify the current understanding of
systemic H2S toxicity and current available treatments.
Methodology
Many reviews have been published on the acute effects of
H2S toxicity and the need to identify countermeasures for
mass casualties and address immediate neurological effects.
To the best of our knowledge, there have not been system-
atic reviews on the long-term effects of acute and chronic
H2S exposure on health, current guidelines, and therapeutics
for the treatment of acute H2S exposure in mass casualty
events, and treatment of chronic H2S exposure arising from
genetic mutations. Therefore, we have decided to perform a
systematic review of the literature available. To achieve our
goal, we used an electronic strategy by using the search
engine PubMed and Google Scholar and the keywords
‘hydrogen sulfide’ AND ‘fatalities’, ‘hydrogen sulfide’ AND
‘countermeasure’, ‘hydrogen sulfide’ AND ‘treatment’,
‘hydrogen sulfide’ AND ‘acute poisoning’, ‘hydrogen sulfide’
AND ‘toxicity’, ‘hydrogen sulfide’ AND ‘chronic exposure’,
‘hydrogen sulfide’ AND ‘ETHE1’, ‘hydrogen sulfide’ AND
‘molybdenum cofactor’. We only included papers dealing
with H2S toxicity. We excluded papers addressing using H2S
as a therapeutic. The analysis was performed by April 2022
and included only papers written in English.
Hydrogen sulfide as a chemical Hazard
Identified in 1731, H2S is heavier than air and tends to con-
centrate at ground level and in valleys topographically. H2S
intoxications vary from acute high-dose exposures following
accidents to chronic low-level exposures in the environment.
An example of a region where chronic H2S exposure is
reported is Rotorua, New Zealand. Large populations that
reside in that volcanic region are constantly exposed to low
levels of H2S in the environment (Bates et al. 1997, 1998,
2002). Epidemiologic studies in Rotorua have shown higher
prevalence of respiratory tract diseases compared to control
sites. Neurologic effects were inconclusive.
H2S is acutely toxic to humans and animals at high con-
centrations (Rumbeiha et al. 2016). Toxic outcomes depend
on concentrations of H2S to which individuals are exposed as
summarized in Table 1. Other effects that are commonly
reported include digestive system disturbances including
vomiting, dysphagia, and diarrhea (McCabe and Clayton
1952). Besides the accidental release of this gas in occupa-
tional settings (Abadin 2013), misuse of the gas for suicide
accounts for the common causes of acute H2S intoxication
(Bott and Dodd 2013; McKirdy 2017).
The Department of Homeland Security is concerned that
this potent gas which was previously used as a chemical
weapon may be used for terrorism, especially in confined
places such as the extensive network of subway system. The
potential of H2S being used as a chemical weapon is high
because H2S is relatively easy to make at home from com-
mon household cleaning products (Rumbeiha et al. 2016).
A recent case of misuse of H2S gas was in a terrorism plot in
Sydney Australia, in which two individuals made an impro-
vised chemical device intended to release H2S gas (Binder
et al. 2018). The sudden, lethal effects of H2S gas make it a
contender for chemical terrorism use. Acute H2S exposure
targets many vital systems, including the cardiovascular,
respiratory, and central nervous systems (Milby and Baselt
1999; Wang et al. 2014). The primary biochemical lesion of
H2S intoxication which is widely recognized is inhibition of
the cytochrome C oxidase enzyme within the electron trans-
port chain in the mitochondria, blocking ATP synthesis.
However, recent mechanism-oriented studies indicate that
other multiple toxicological mechanisms are involved (Jiang
et al. 2016). Much work remains to be done to characterize
these molecular mechanisms to develop effective counter-
measures to treat H2S poisoning (Rumbeiha et al. 2016).
The cause of death following acute H2S poisoning is
still debatable.
Case reports of acute H2S toxicity are common worldwide
in occupational settings such as sewage treatment plants,
landfills, and oil refineries (Rumbeiha et al. 2016). A fatal case
of H2S poisoning in 2014 caused the deaths of two male
tanker drivers outside a fertilizer-producing plant
(Aventaggiato et al. 2020). Autopsies performed revealed
acute cardio-respiratory failure with an edematous brain in
the first victim, and pulmonary edema in the second victim.
Indeed, accidental release of H2S seems to be the most

Table 1. Concentration-dependent effects of H2S in humans adapted from the Occupational Safety and Health Agency website (OSHA 2021).
Concentration in ppm Symptoms/effects
0.00011–0.00033 Typical background concentrations
0.01–1.5 Odor threshold
2–5 Nausea, tearing of the eyes, headaches, or loss of sleep. Bronchial constriction
20 Possible fatigue, loss of appetite, headache, irritability, poor memory, dizziness
50–100 Conjunctivitis and respiratory tract irritation. Digestive system upset and loss of appetite.
100 Coughing, eye irritation, olfactory fatigue. Altered breathing, drowsiness after 15–30 min.
Throat irritation after 1 h. Gradual increase in severity of symptoms over several hours. Death may occur after 48 h.
100–150 Olfactory fatigue or paralysis
200–300 Marked conjunctivitis and respiratory tract irritation after 1 h. Pulmonary edema may occur from prolonged exposure.
500–700 Staggering, collapse in 5 min. Serious damage to the eyes in 30 min. Death after 30–60 min.
700–1000 Rapid unconsciousness, ‘knockdown’ or immediate collapse within 1 to 2 breaths, breathing stops, death within minutes.
1000–2000 Nearly instant death

prevalent cause of H2S reported fatalities (Chaturvedi et al.
2001; Hendrickson et al. 2004; Ago et al. 2008). Many similar
incidents occur following manure agitation in concentrated
animal feeding operations (CAFOs) or exposure to concen-
trated H2S gas produced in sewage systems (Park et al. 2016;
Smith et al. 2017; Matos et al. 2019).
The Occupational Safety and Health Administration
(OSHA) has a published list of 221 reported H2S incidents
and fatalities as recent as August of 2021, indicating a preva-
lence of H2S-induced fatalities to this day (OSHA 2021).
Unfortunately, many of the multiple fatalities at a single
event are caused by individuals attempting to aid their cow-
orkers following ‘knockdown’ or initial symptoms of H2S
intoxication (Hendrickson et al. 2004). A study performed in
Korea looked at the distribution of workplace incident fatal-
ities according to activity (Park et al. 2016). Between 1998
and 2013, there were 30 fatalities in manure handling facili-
ties. Most fatalities were linked to rescue which went bad
(40%), followed closely by manure handling (33%) in manure
storage facilities (Park et al. 2016). Most of these acute poi-
soning cases occur in confined places with poor ventilation.
The most important symptoms experienced by victims of
acute H2S include loss of consciousness or ‘knockdown’,
which directly impacts the victim’s ability to exit the conta-
minated exposure site and is quickly followed by acute car-
diogenic shock (Sonobe and Haouzi 2015). Exposure to acute
H2S gas also causes tonic-clonic seizures, respiratory depres-
sion, apnea, and cardiac arrhythmias (Beauchamp et al. 1984;
Milby and Baselt 1999). McCabe and Clayton (1952) provided
a detailed account of the clinical outcomes in people pois-
oned by acute H2S in the Poza Rica accident. Of the 22
deaths, 40% occurred at the scene, and aproximately 30%
died in hospital 2–6 h post-exposure (Figure 1) (McCabe and
Clayton 1952). Those who died later failed to respond to sup-
portive care and died from neuronal injuries which failed to
respond to symptomatic treatment. This death pattern is
Figure 1. A summary of mortality pattern in victims of acute H2S accident in
Poza Rica, Mexico. Forty percent died at the scene. Others died on arrival or fol-
lowing admission in hospital. Patients who died after 24 h failed to respond to
symptomatic treatment and died of neurological injury. Adapted from mortality
data from McCabe and Clayton (1952).
TOXICOLOGY MECHANISMS AND METHODS 3
interesting considering the metabolism of H2S is ultrafast
and is rapidly excreted as sulfate or thiosulfate metabolites.
H2S is not bioaccumulative (Whitfield et al. 2008). However,
biochemical lesions like inhibition of cytochrome c oxidase
and pathological lesions arising from repeated H2S exposure
are cumulative.
Biotransformation of H2S
Due to the highly reactive nature of H2S gas in vivo, its half-
life is estimated to be seconds or minutes upon exposure
(Whitfield et al. 2008), yet its systemic effects, such as neuro-
logical sequelae, can last for weeks or months. Inhalation is
the relevant route of H2S exposure in humans (Rumbeiha
et al. 2016). This is important because most of the historical
experiments conducted to study the toxicity of H2S have
used parentally injected donor compounds such as NaHS or
sodium sulfide (Na2S) (Lopez, Prior, et al. 1988). Use of such
parenterally injected H2S donors do not recapitulate key out-
comes of exposure by the inhalation route such as pulmon-
ary edema (Lopez, Prior, et al. 1989). Therefore, toxic
mechanisms may differ. H2S from Na2S injections was mostly
found in the exposed liver, followed by the lungs and kid-
neys (Drimal et al. 2010).
Following absorption H2S undergoes rapid phase I oxida-
tion in the mitochondria that leads to detoxification. It is
mainly oxidized by sulfide oxidation pathways in the mito-
chondria (Hildebrandt and Grieshaber 2008). Three enzymes
have been implicated in H2S detoxification including sulfide:
quinone oxidoreductase (SQOR), sulfide dioxygenase (SDO/
ETHE1), and rhodanese, a sulfurtransferase (Billaut-Laden
et al. 2006; Jackson et al. 2012; Tiranti and Zeviani 2013; Wu
et al. 2017). SQOR is a membrane-bound enzyme that cata-
lyzes sulfide oxidation into sulfane sulfur and reduces its
cysteine disulfides producing persulfide groups (SQR-SSH)
(Jackson et al. 2012). Following SQOR, SDO/ETHE1 catalyzes
the oxidation of the sulfane sulfur and persulfide group pro-
ducing sulfite (H2SO3) (Hildebrandt and Grieshaber 2008;
Tiranti et al. 2009). The sulfur transferase rhodanese and
SQOR then transfer sulfur ions from SQR to H2SO2 to synthe-
size thiosulfate (H2S2O3) (Libiad et al. 2014). Thiosulfate
reductase further reduces H2S2O3 to sulfate (H2SO4) (Kashfi
and Olson 2013). It is important to note that H2S oxidation
and thiosulfate production also requires 1.5 moles O2 for
every one mole of H2S from the electron transport chain fur-
ther reducing the O2 supply (Hildebrandt and Grieshaber
2008). Thiosulfate and sulfate can both be excreted through
the kidneys (Schwartz 1942). When the H2S concentrations
within the mitochondria exceed the rate at which the gas
can be metabolized, it becomes cytotoxic as in the case of
ETHE1 deficiency which will be discussed later under chronic
effects of H2S exposure (Eghbal et al. 2004; Tiranti
et al. 2004).
H2S also undergoes phase II metabolism by thiol-S-meth-
yltransferase, which is responsible for methylating H2S to
methanethiol (CH3SH) and dimethyl sulfide (CH3SCH3)
(Weisiger et al. 1980). The net result is addition of two
methyl groups and removal of hydrogen ions. Thiol-S-
4 C. M. SANTANA MALDONADO ET AL.
methyltransferase activity was found to be most active in the
liver and intestines, although this metabolic pathway is said
to be 10 000 times slower than oxidation pathways (Weisiger
et al. 1980; Levitt et al. 1999). This is highlighted by the fact
that defects in H2S oxidation in the mitochondria lead to
chronic H2S intoxication, suggesting the methylation path-
way is not contributing significantly to H2S metabolism and
disposition (Tiranti et al. 2009; Tiranti and Zeviani 2013).
Mechanism of toxicity of acute H2S exposure
H2S is a systemic toxicant with potentially multiple toxic
mechanisms of action. Toxic mechanisms vary depending on
the type of exposure, (i.e. acute, subacute, subchronic, and
chronic). Acute exposures are defined as exposure to high
doses chemicals once or multiple times for less than 24 h
(Klaassen 2013). Single high dose exposures are the most
common form of acute exposure; however, repeated expo-
sures within 24 h may also occur. Acute exposures to H2S
manifest as both immediate and delayed effects, likely via
different toxic mechanisms. It is well established that H2S
inhibits the cytochrome C oxidase enzyme in the electron
transport chain leading to inhibition of aerobic ATP produc-
tion (Jiang et al. 2016). This leads to an increase in anaerobic
respiration (Jiang et al. 2016). The reduction in aerobic respir-
ation causes lactic acidosis, a hallmark in H2S poisoning,
resulting in cytotoxic effects which result in oxidative stress
and cell death (Kubasiak et al. 2002; Lamonte et al. 2013;
Baud et al. 2018). Tissues which depend heavily on oxidative
phosphorylation such as brain and heart are particularly sen-
sitive. H2S exposure may trigger the process of oncotic
necrosis from cells being unable to replenish caspases
responsible for programmed cell death and energy depletion
following cytochrome C oxidase inhibition (Elmore 2007).
Even though H2S is rapidly metabolized, a single acute
exposure typically suppresses cytochrome C oxidase activity
for at least 48–72 h, suggesting a lack of ATP arising from
inhibition of this key enzyme contributes to cell death and
organ pathology.
H2S primarily targets the neurological system
(Anantharam, et al. 2017a). The exact mechanism(s) of H2S
toxicity on the central nervous system is/are likely complex
and not entirely known. However, some strides have been
made toward discovering different pathways directly involved
in H2S-induced neurotoxicity (Kim et al. 2020). Literature
based on human case studies has shown the selective vulner-
ability of brain regions to acute H2S poisoning with the cor-
tex, basal ganglia, and brainstem being most sensitive. The
immediate effects include oxidative stress, and neurotransmit-
ter dysregulation. Dopamine, serotonin, and norepinephrine
are increased during H2S exposure (Warenycia et al. 1989;
Anantharam et al. 2017a). There is immediate activation of
cell death signaling in the most vulnerable brain regions (Kim
et al. 2020). Respiratory depression characterized by reduced
breathing rate is also a common outcome of acute H2S
exposure but the cellular and molecular mechanisms behind
this phenomenon are not entirely known. Nonetheless, we
know that chemoreceptors are severely affected which leads
to immediate respiratory rhythm depression (Haggard et al.
1922). Lactic acidosis from cytochrome C oxidase inhibition
causes a decrease in arterial pH leading to reduced breathing
rate (Haggard et al. 1922). It is widely reported that acute
exposure to H2S concentrations greater than 1000 ppm
caused inhibition of the breathing center following a few
breaths, but here also the underlying mechanisms involved
are not known (Greer et al. 1995). H2S was reportedly found
in the highest concentrations in the brainstem of animals
acutely exposed to H2S (Reiffenstein 1989). This may explain
in part why respiratory nuclei, which are located within the
brainstem, are vulnerable.
The cardiovascular system is another major system
affected immediately following H2S exposure. Cardiac arrhyth-
mias, myocardial depression, and conduction defects are
some of the immediate effects reported following acute H2S
exposure (Mo et al. 2020). Hypotension has also been widely
cited as an immediate response and can lead to death if left
untreated (Doujaiji and Al-Tawfiq 2010; Sonobe and Haouzi
2015). However, as for the brain, the underlying toxic mecha-
nisms responsible for these outcomes remain largely
unknown and uninvestigated. As of now, the proximate cause
of death following acute H2S poisoning remains debatable
but both inhibition of breathing center and cardiovascular
collapse have been cited as the cause of death (Greer et al.
1995; Anantharam et al. 2017a; Haouzi, Tubbs et al. 2019).
A systemic review of clinical effects of acute
H2S exposure
The effects on target systems are summarized in Figure 2.
Effects on the Central nervous system
During acute H2S exposure, victims suffer from a sudden loss
of consciousness, commonly known as knockdown, some-
times followed by seizures, dyspnea, and confusion (Haouzi
et al. 2020). Research has indicated that brain activity is
altered during acute H2S exposure which may account for the
seizure activity exhibited by the victims (Anantharam et al.
2017a). Seizures in epilepsy can be categorized into motor
and non-motor, with many subcategories categories including
focal, generalized, and of unknown onset (Fisher 2017). These
seizures can be identified as atonic, tonic, clonic, hyperkinetic,
myoclonic, or a combination of any of these depending on
the onset (Fisher et al. 2017). H2S-induced seizures are mainly
tonic and clonic seizures (Rumbeiha et al. 2016). Tonic, or
grand mal seizures, are defined by loss of consciousness and
large, full-body jerks of arms and legs while clonic seizures
are characterized by small, centralized activity characterized
by repeated jerking (Fisher 2017).
There are some similarities between acute H2S poisoning
and sudden unexpected death in epilepsy (SUDEP). In acute
H2S poisoning, sudden death follows seizure activity (Luo
et al. 2014). In SUDEP, onset of seizures and the characteristic
respiratory failure most victims have been linked to the dys-
regulation of glutamate, serotonin, and GABA in the brain
(Manolis et al. 2019). In our mouse model of acute H2S

Figure 2. Acute effects of H2S poisoning on key target organs, the brain, heart, and lungs. Please note the multiple systemic effects which occur simultaneously
and collectively contribute to mortality and morbidity. Some of these effects are immediate and reversible while others like neurodegeneration are delayed and
may or may not be reversible. Created with BioRender.
intoxication, similar dysregulation of these neurotransmitters
(and dopamine) has been observed (Anantharam et al.
2017a). SUDEP has, importantly, been linked to cardio-
respiratory autonomic dysfunction as the major cause of
death for epileptic patients (Lee and Devinsky 2005). Death
in acute H2S poisoning is also characterized by seizure activ-
ity and suppressed breathing rate (Rumbeiha et al. 2016). As
such, there are similarities between cardio-respiratory failure
in SUDEP and respiratory failure and sudden death seen in
human victims and animal models of acute H2S poisoning
(Rumbeiha, Whitley, et al. 2016; Anantharam et al. 2017a).
This connection deserves further examination to determine if
underlying mechanisms are similar. If so, the treatment
approach for both conditions may be similar.
Recently, our research group developed an animal model
of H2S poisoning that recapitulates the human phenotype,
with seizures, dyspnea, and knockdown which are all com-
monly seen in human victims (Anantharam et al. 2017a). In
animal models of H2S poisoning, as in humans, neurodegen-
eration is observed in distinct regions of the brain. The sever-
ity of neurodegeneration appears to correlate well with an
increased risk of H2S-induced seizure activity (Sonobe et al.
2015; Anantharam et al. 2017a; Anantharam et al. 2018;
Haouzi et al. 2020). Human victims of acute H2S poisoning
also experience altered mental status, dizziness, loss of appe-
tite, headache, and some brain atrophy and/or permanent
brain damage (Tvedt et al. 1991; Sheikh et al. 2017). The neu-
rodegeneration experienced in these cases of H2S may be
responsible for causing memory loss in certain victims. Other
sequalae noted in victims of acute H2S poisoning include
ataxia or abnormal gait, and predisposition to seizure activity
(Tvedt et al. 1991).
TOXICOLOGY MECHANISMS AND METHODS 5
In our mouse model of acute H2S poisoning, mice
exposed to 700 ppm H2S by inhalation experience tonic-
clonic seizures as early as 15–20 min during exposure
(Anantharam et al. 2017a). The surviving mice develop
lesions in the inferior colliculus and thalamus starting around
72 h post-exposure (Kim et al. 2021). The thalamus and infer-
ior colliculus have been previously identified as main regions
that experience neurodegeneration following acute exposure
(Anantharam et al. 2017a). Research in our group indicates
that multiple pathways in these brain regions are dysregu-
lated. These include the PI3K/Akt pathway, a key pathway in
cell death, GABA and calcium signaling among other key
pathways (Los et al. 2009; Kim et al. 2020). GABA and glu-
tamate are neurotransmitters known to be involved in the
onset of seizure activity (Mathew et al. 2012; Barker-Haliski
and White 2015). Acute H2S exposure causes a decrease in
glutamate concentration (Anantharam et al. 2017a). The
impact of this dysregulation remains and its contribution to
neurodegeneration remains to be determined.
H2S has been reported to impart its physiological func-
tions and/or pathology through calcium dysregulation. H2S
gas induces Ca2þ changes in astrocytes and microglia as well
as readily binds to NMDA receptors in the brain (Kimura
2000). Glutamate-induced cytotoxicity has been reported in
H2S-exposed mouse brains and this seems to be mediated
through calcium dysregulation (Cheung et al. 2007; Kritis
et al. 2015). This glutamate-induced cytotoxicity appears to
play a role in H2S-induced neurodegeneration because pro-
apoptotic pathways in brain cells including neurons, micro-
glia, astrocytes, and glia appear to be triggered through
upstream glutamate receptors (Kim et al. 2020). However, it
is intriguing that although H2S is very lipophilic and likely
6 C. M. SANTANA MALDONADO ET AL.
reaches all parts of the brain, neuropathological lesions are
only induced in a few localized brain regions and of all cells
in the brain neurons are the most sensitive and die following
acute H2S exposure. Why this is the case remains a fertile
area of investigation along with unraveling the molecular
pathways of neuronal cell death in the brain. What makes
H2S-induced neurotoxicity interesting is that H2S is rapidly
metabolized and excreted but triggers a cascade of events
that culminate in neuronal cell death at least 3 days post-
exposure and progresses to neurodegeneration days later. If
the underlying mechanisms are defined it is possible to treat
patients and prevent the neurodegeneration.
Respiratory system effects
Respiratory depression, characterized by reduced breathing
rate, following acute H2S poisoning has been reported
(Tanaka et al. 1999). Symptoms of acute H2S exposure are
also similar to those reported in acute respiratory distress
and acute lung injury (ALI) (Gerasimon et al. 2007). These
include shortness of breath, rapid breathing, bronchospasm,
and lack of spontaneous respiration (apnea) often requiring
mechanical ventilation (Abadin 2013). The exact molecular
mechanism(s) behind these respiratory effects is/are currently
unknown. Other respiratory effects of acute H2S poisoning
include irregular breathing, especially during exposure.
Victims of H2S poisoning also experience pulmonary edema,
which leads to an accumulation of fluid in the lungs. This
fluid accumulation in the lungs contributes to dyspnea and
results in a reduction of gas exchange through the pulmon-
ary epithelium and airways, which in some cases leads to
cyanosis, a blueish discoloration of lips, extremities, and skin
due to hypoxia (Beauchamp et al. 1984; Shivanthan et al.
2013). The hypoxia may contribute to tissue injury in other
parts of the body such as the brain. Victims with preexisting
medical conditions like hypertension, bronchial asthma,
smokers, and diabetes mellitus are predisposed to H2S poi-
soning and present with worse symptoms following acute
exposure (Shivanthan et al. 2013).
Regarding investigations on toxic mechanisms in the
lungs, certain strides have been made toward understanding
the effects of acute H2S poisoning in the lungs. Claudin-5, a
key tight junction protein in the vascular endothelium, was
found to be decreased in an H2S-induced ALI model of
Sprague-Dawley rats (Geng et al. 2020). Epithelial sodium
channels (ENaC) were downregulated in H2S-exposed rats
that experienced acute pulmonary edema (Jiang et al. 2015).
ENaC is associated with lung fluid clearance, and the down-
regulation of these may be a reason for the increased pul-
monary edema experienced by H2S poisoning victims
(Matalon et al. 2015). Respiratory tract irritation is also heav-
ily cited in the literature as an immediate effect of H2S
exposure, whether at low or high concentrations (Sheikh
et al. 2017). Rats exposed to H2S for 4 h experienced severe
respiratory tract irritation characterized by necrosis and
exfoliation of respiratory mucosal and olfactory cells (Lopez
et al. 1988). Certainly, more needs to be done to characterize
the lesions in the lungs, to comprehensively investigate H2S-
induced toxic lung injury, and to unravel potential the brain-
lung axis interactions on lung injury.
Whereas some work has been done to understand the
immediate effects in lungs following H2S poisoning, little is
known about long-term sequalae of acute H2S exposure in
the lungs because victims are typically not followed up once
they leave the hospital following treatment of the acute
effects. Therefore, there is a knowledge gap on long-term
impacts of acute H2S poisoning and how to treat them.
Currently, there is a handful of published manuscripts
describing the effects following acute H2S poisoning and of
these, only one human study is available that followed-up
on long-term outcomes years after the incident (Tvedt et al.
1991; Doujaiji and Al-Tawfiq 2010).
Cardiovascular system
Cases have been reported of H2S poisoning victims experi-
encing myocardial damage with a delayed onset and a
resulting slow recovery after the fact (Mo et al. 2020).
Experiments using infusions of NaHS resulted in decreased
cardiac contractility and cardiogenic shock (Sonobe and
Haouzi 2015). It is important to remember that this type of
exposure does not simulate real-life exposures following
inhalation exposures in humans. Parenterally injected H2S
donor compounds do not cause pulmonary edema.
Pulmonary edema is believed to contribute to the severity of
acute H2S poisoning. Cardiac arrhythmias have also been
cited in victims and in research articles investigating H2S tox-
icity (Chen et al. 2016). Victims of H2S poisoning have
increased troponin I concentrations in the blood, indicating
cardiac injury (Sheikh et al. 2017). Other reported cardiovas-
cular effects include ischemia, myocardial infarction, and
hypotension (Shivanthan et al. 2013; Chen et al. 2016).
Again, as with other key target organs, a knowledge gap
exists on the long-term effects of acute H2S poisoning on
the heart and the rest of the cardiovascular system.
Health effects of chronic exposure to H2S
Chronic exposures are defined as repeated exposures to toxi-
cants for 180 days or longer (Denny and Stewart 2017). Most
chronic exposures to H2S occur in populations that live in
rural areas near CAFOs, geothermal vents, or near volcanic
activity (Bates et al. 1997, 2002; Heaney et al. 2011; Malone
Rubright et al. 2017; Pope et al. 2017). Epidemiological stud-
ies on communities impacted by chronic H2S have served as
the main source knowledge for understanding the effects of
chronic exposure (Heaney et al. 2011; Lim et al. 2016).
Rotorua, New Zealand is a region in which its residents are
exposed chronic low levels of hydrogen sulfide poisoning
from geothermal vents. Due to the population in this com-
munity being chronically exposed to H2S from a natural
source, it is a key region to understand the chronic health
effects of H2S exposure in a diverse population. Although
there was no correlation between changes in cognitive func-
tion and chronic H2S exposure, studies comparing popula-
tions of this region in New Zealand with those living in

other, less H2S-polluted regions found a correlation with
increased morbidity in certain populations (Bates et al. 1997,
1998; Reed et al. 2014). Key findings included a higher inci-
dence of diseases related to circulatory and respiratory sys-
tem in regions with high concentrations of H2S gas
exposure. Females of various ethnicities tended to be more
at risk for respiratory diseases including COPD, pneumonia,
and influenza (Bates et al. 1997). These studies have yet to
be reproduced, although they point to potential health
effects of chronic H2S exposure.
Several epidemiological studies have been conducted to
study chronic H2S exposure in occupational settings (Arnold
et al. 1985; De Fruyt et al. 1998; Elwood 2021). As mentioned
previously, some of the occupations associated with chronic
H2S exposure include gas refineries, water treatment plants,
rayon textile manufacturing, and CAFOs. Subjects from vary-
ing exposed industries have undergone neurological evalua-
tions following chronic H2S exposure from the workplace.
When accounting for compounding factors such as lifestyle,
educational level, and performance, individuals exposed to
H2S had a higher incidence of respiratory irritation, and
some even had decreased cytochrome c oxidase activity
(Elwood 2021).
Individuals exposed to chronic H2S exposure have been
shown to have higher incidences of asthma, chronic bron-
chitis, chronic obstructive pulmonary disease, and methemo-
globinemia (Campagna et al. 2004; Bates et al. 2015; Saeedi
et al. 2015). The full human health effects of chronic H2S
exposure, from occupational and environmental sources,
remain unknown as there are many conflicting published
works from human studies. Additionally, only one of these
studies addressed how these exposures affect the interaction
with other diseases such as asthma, influenza, and COPD.
Controlled animal studies have yet to be performed to con-
firm the epidemiological findings linking respiratory diseases
to chronic environmental H2S exposure.
We previously mentioned genetic defects that lead to
impaired metabolism of H2S. ETHE1 genetic defects cause eth-
ylmalonic encephalopathy, an autosomal recessive neurodege-
nerative condition that results in death in the first decade of
life (Burlina et al. 1991). This defect is characterized by elevated
H2S in muscles and brain tissues leading to toxicity to the brain
because of a defect in H2S metabolism in the mitochondria (Di
Meo et al. 2011). The accumulation of H2S is due to the
absence of sulfide dioxygenase, one of the enzymes respon-
sible for detoxifying H2S in the mitochondria (Kappler and
Enemark 2015). MOCS1, MOCS2, and GPHN deficiency are also
associated with molybdenum cofactor deficiency (MoCD)
(Mechler et al. 2015). MoCD is also an autosomal recessive dis-
order characterized by sulfite oxidase, xanthine oxidoreductase,
and aldehyde oxidase deficiencies, some of which lead to
impaired H2S metabolism. Like ETHE1 deficiency, H2S metabol-
ism is affected through the deficient activity of sulfite oxidase
oxidizing sulfite into the less toxic sulfate (Lee et al. 2002).
Increased H2S and sulfite leads to chronic cumulative inhibition
of the cytochrome C oxidase enzyme (Di Meo et al. 2011). Not
only is there an increase in H2S and sulfite, but increased lac-
tate and thiosulfate are also observed in patient brain
TOXICOLOGY MECHANISMS AND METHODS 7
structures (Teksam et al. 2005). Both ETHE1 and MOCS1 defi-
ciency lead to early death (Edwards et al. 1999; Tiranti et al.
2004). Patients of ethylmalonic encephalopathy and MoCD
experience developmental delays and degeneration of basal
ganglia, brainstem, cerebral cortex, cerebellum, and corpus cal-
losum (Vijayakumar et al. 2011; Kabil and Banerjee 2012; Zaki
et al. 2016). Improving and extending the lives of the afflicted
patients requires addressing the knowledge gaps in treating
the underlying chronic H2S toxicity. Therefore, much remains
to be discovered concerning the chronic effects of H2S expos-
ure and how to treat them.
Current treatment for chemical mass casualties
In order to discuss mass treatment of casualties of acute H2S
poisoning, a brief summary of the approach to the treatment
of casualties of other toxic gases most notably sulfur mus-
tard, chlorine, and cyanide is given. These agents were used
extensively in chemical warfare, especially during WWI
(Eckert 1991; Fitzgerald 2008). For this review, a mass-expos-
ure event was defined as when a significant in which a large
population of people is exposed to a toxicant, especially in
instances where local disaster resources were deemed insuffi-
cient. Like H2S, both sulfur mustard and chlorine gas have
no FDA-approved antidotes and victims rely entirely on sup-
portive care (Rafati-Rahimzadeh et al. 2019; Achanta and
Jordt 2021). Since there are no approved drugs for the treat-
ment of mass casualty victims of acute H2S poisoning, treat-
ment is mainly symptomatic. The supportive care in cases of
mass exposures to H2S and similar toxic gases should follow
a protocol outlined by the Agency for Toxic Substances and
Disease Registry (ATSDR) and occurs in three main phases:
evacuation to a safe zone, assessment of victim condition,
and administration of treatment (DeNolf and Kahwaji 2022).
Sulfur mustard, chlorine, and cyanide are responsible for
countless individual deaths and multiple mass exposure
events. This generalized first responder action model is con-
sistent regardless of the toxic agent used. A summary of the
ATSDR approach for treating mass civilian casualties follow-
ing industrial accidents or acts of terrorism is summarized in
Figure 3. First responders should wear protective gear. The
suggested approach is to remove victims from the contami-
nated ‘hot zone’ or the point of exposure and initiate decon-
taminating the victim in the decontamination zone. After
decontamination, victims are moved to the support zone,
where additional therapy is provided, and supportive care is
offered prior to transportation to a hospital for special-
ized care.
Past, current, and future treatment for hydrogen
sulfide poisoning
Treatment is largely supportive. In the case of mass chemical
casualties, once in the hospital, triage is vital in determining
which patients require the most immediate attention follow-
ing the event and the necessary resources previously
mentioned (Tuorinksy 2008). Much like chlorine and mustard
gas poisoning, there is no FDA-approved antidote to target
8 C. M. SANTANA MALDONADO ET AL.
Figure 3. Graphic summary of procedures recommended for managing mass casualty exposures to H2S. First responders move victims from the hot zone to a
decontamination zone. Subsequently, victims are moved to a support zone which is free of H2S. Emergency treatment is given here before victims are transported
to a medical facility for highly specialized care. Adapted from ATSDR.
H2S-induced toxicity. However, extensive research is being
conducted to discover potential future therapeutics. The fol-
lowing is a summary of the recommended approach for the
treatment of mass casualties of acute H2S poisoning
(Figure 3).
Hot zone
The hot zone is defined as the point of exposure in which
victims typically experience ‘knockdown’. Rescuers are
required to wear proper protective equipment, including
respiratory protection, to protect themselves from intoxica-
tion. Chemical-protective clothing may be worn to avoid dir-
ect contact with liquefied gas as it can cause frostbite.
Victims should be quickly moved from the hot zone to the
decontamination zone to avoid further exposure.
Decontamination zone
In the decontamination zone some H2S can be expected. If a
victim does not show eye or skin irritation signs, they need
not be decontaminated and can be taken to the support
zone. Personnel can wear minimal or a lower level of protec-
tion if the gas concentrations allow. Therefore, it is highly
recommended that first responders consider removing vic-
tims clothing if this could be a hazard (Ruder et al. 2015).
Ensure adequate pulse and respiration. Initiate ventilation
support if needed. If trauma is suspected, stabilize the
cervical spine, and assist ventilation with a bag-valve-mask
device if necessary. Decontamination includes removing and
double-bagging contaminated clothing as there may be H2S
gas remaining on the clothing. Although H2S is poorly
absorbed through the skin, clothing can harbor enough toxic
gas to present a hazard to first responders (Abadin 2013).
Due to the potential for frostbite from liquified H2S gas
exposure, frostbite victims should be handled with caution
and allow circulation to reestablish itself naturally by wrap-
ping affected areas with blankets.
Support zone
Supportive care means identifying life-threatening symptoms
and treating those to keep the patient alive. For example,
aerosolized bronchodilators may be used for victims experi-
encing bronchospasm, and endotracheal intubation may be
performed in the case of respiratory compromise. The
patients should then be rushed to the hospital to specialized
care. At present, there are no FDA-approved antidotes
approved for use in treating mass casualties in the field.
Besides, controversial injectables like sodium nitrite, which
need IV injections, should be reserved for a few victims in
the field and are not recommended in mass casualty situa-
tions that require high technical knowledge and expertise for
administration.

In-Hospital treatment
Hyperbaric oxygen has been used for years and remains a
valuable tool for severe cases of H2S poisoning (Lindenmann
et al. 2010; Price et al. 2021). However, the technique is only
valuable for treating individual cases as this equipment is
not widely available. It is not ideal for the treatment of mass
casualties. Hyperbaric oxygen increases oxygen plasma diffu-
sion which leads to improved oxygenation of tissue
(Smilkstein et al. 1985; Whitcraft et al. 1985). Although there
is no FDA-approved drug for H2S toxicity, certain antidotes
have been used in cases of poisoning in a hospital setting.
Much like inhaled cyanide, it is suggested to use inhaled
nitrite therapy, specifically amyl nitrite, for 30 seconds every
minute until the intravenous (IV) line is started. Once IV is
introduced, sodium nitrite is given intravenously. Early cita-
tions of sodium nitrite therapy suggested clinical efficiency
(Hall and Rumack 1997). Recently, however, nitrite therapy
has become a controversial topic as the efficacy of nitrite
therapy in H2S victims remains inconsistent (Baud et al.
2018). The H2S metabolite thiosulfate and antioxidants have
also been used to treat H2S poisoning victims with lit-
tle success.
Thiosulfate administration has been recommended for H2S
toxicity treatment because it has efficacy for treating cyanide,
a toxicant with similar toxic mechanisms. The goal is for thio-
sulfate to bind H2S. However, the efficacy of thiosulfate for
treating H2S intoxication is doubted. H2S is known to alter
enzyme activity during exposure, thus introducing agents that
bind and remove the free H2S and HS- in the victim may lead
to increased survival. Dithiothreitol as an antioxidant has been
cited to reduce monoamine oxidase inhibition induced by H2S
poisoning and restore contractility in affected cardiac muscle
(Eley et al. 1989; Warenycia et al. 1990).
The future: potential novel experimental drugs for
the treatment of H2S poisoning
Preclinical research on therapeutics for the treatment of H2S
poisoning has centered chiefly around scavenging free H2S,
use of antioxidants to counteract oxidative stress, and for
symptomatic treatment the acute symptoms like seizures,
respiratory depression, and cardiac arrest (Judenherc-Haouzi
et al. 2016; Anantharam et al. 2018; Hendry-Hofer et al. 2020;
Miyazaki et al. 2021). Although there are many experimental
drugs under investigation, they are all still in the preclinical
phase of development.
Scavengers
Scavengers can be defined as molecules that bind to H2S in
the blood, reducing the amount of H2S and reducing the
potential for toxicity after exposure (Fricker 1999;
Anantharam et al. 2017b; Ng et al. 2019; Hendry-Hofer et al.
2020; Miyazaki et al. 2021). Among the H2S scavengers inves-
tigated, cobinamide has been at the forefront of research to
combat H2S poisoning (Ng et al. 2019). Initially formulated to
target cyanide toxicity (Brenner et al. 2010), the vitamin B12
TOXICOLOGY MECHANISMS AND METHODS 9
analog, cobinamide was chosen for its superior binding abil-
ity to sulfides in the blood (Brenner et al. 2014). Many forms
of cobinamide have been used to counter H2S toxicity and
has been found to be successful in small and large animal
models. Randomized swine studies looked at survival follow-
ing H2S exposure between sham and cobinamide treated
(Hendry-Hofer et al. 2020). The primary outcomes investi-
gated by the authors included survival following exposure,
which was improved. Cobinamide has also been attributed
to improving outcomes during and following H2S exposure
in a mouse model. Mice treated with cobinamide experience
a significant reduction in ‘knockdown’ and improved survival,
reduction in seizure activity, and overall improvement in
behavior following H2S exposure compared to untreated
mice (Anantharam et al. 2017b). Cobinamide, given within 15
mins post H2S exposure reduced severity of neurological
injury (Anantharam et al. 2017b). The success of the mol-
ecule in two animal models positions it as a contender for
further development for treatment of H2S intoxication.
Another novel molecule was recently introduced and shown
to have scavenging efficacy for H2S. Methanesulfonyl Azide
(SS20), a sulfonyl azide-based scavenger, appears to prolong
survival during H2S exposure and improve neurological func-
tion (Miyazaki et al. 2021).
The major drawback in using scavengers is that H2S is
rapidly metabolized and these therapeutics need to be
administered almost immediately following exposure, which
is unrealistic in the case of mass casualties first responder
response time varies due to a number of factors including
physical location of incident, time of day, and complicating
factors to name a few (DeNolf and Kahwaji 2022). However,
scavengers have the potential as preventative drugs if given
before anticipated H2S exposure. One potential application
for example is use by first responders within 15 mins of
entering confined spaces with high H2S concentrations. This
certainly can provide an added layer of protection to first
responders in addition to donning self-contained breathing
apparatuses.
Antioxidant therapy
Antioxidants have been proposed to treat H2S intoxication
and prevent sequelae (Sonobe et al. 2015; Judenherc-Haouzi
et al. 2016; Haouzi et al. 2019). A compound that has been
proposed as an effective agent against H2S intoxication is
methylene blue (Haouzi et al. 2020). Its mechanism of action
is to increase NADH-methemoglobin reductase activity and
act as a reducing agent to reduce methemoglobin to hemo-
globin. Methylene blue, typically used to treat methemoglo-
binemia, has been proposed to counteract H2S-induced
cardiac disturbances in IP NaHS injected rats (Judenherc-
Haouzi et al. 2016). This molecule has also been cited to
reduce the onset of necrotic neuronal lesions in NaHS-
induced coma in rats (Sonobe et al. 2015). Although this
compound was efficacious in an IP NaHS injection model of
exposure, its efficacy in an inhalation model is yet to be
demonstrated.
10 C. M. SANTANA MALDONADO ET AL.
Symptomatic therapy
Symptoms of acute H2S poisoning include dyspnea, seizures,
‘knockdown’, respiratory depression, and cardiac irregularities
and arrest (Milby and Baselt 1999). There is ample literature
on treating neurological symptoms like knockdown and seiz-
ures (Anantharam et al. 2018). A contender for treating these
is an existing drug used for seizures, and has shown promise
to treat against nerve-agent neurotoxicity (Reddy and Reddy
2015). Midazolam is a drug in the benzodiazepine class that
acts as a c-aminobutyric acid (GABA) agonist, which leads to
a reduction in seizures. The inhibitory actions lead to a seda-
tive effect, and intramuscular injection has long been used
for epileptic adults. Midazolam reduces H2S-induced seizure
activity. Use of respiratory stimulants like doxopram has
been proposed but their efficacy has not been experimen-
tally investigated demonstrated. Managing symptoms is cru-
cial to improve outcomes following any mass casualty event,
including H2S toxicity (DHHS, DHS, DOT, and the National
Security Council 2018). However, identifying the mechanisms
behind these symptoms will lead to targeted therapy that
will improve victim sequelae.
Treatment of long-term sequalae
Long-term sequelae of acute H2S poisoning remain an issue
following exposure because there are no FDA-approved ther-
apeutics specifically targeted toward the treatment of seque-
lae following acute H2S toxicity. Therefore, research is
needed to develop novel therapies to prevent and/or treat
neurological, respiratory, and cardiovascular sequelae. The
mechanisms development of these sequelae is not entirely
known. It is therefore difficult to prevent/treat them. This
remains a fertile area of investigation to understand mecha-
nisms of these sequelae and development of countermeas-
ures to prevent or treat them.
Treatment of genetic disorders associated with
endogenous chronic H2S poisoning
Genetic disorders of H2S metabolism though rare are lethal.
Affected children die in the first decade of life or early adult-
hood. Currently, there are also no FDA-approved drugs to
cure these diseases or to prolong life. Developing drugs for
treating this segment of population should also remain an
area of high priority to improve the quality of life of affected
children around the world.
The knowledge gaps
There is a lack of understanding of the toxic mechanisms
that lead to acute H2S-induced death. Studies have claimed
different causes of death in fatal H2S exposures at the scene
of accidents and this needs to be addressed. There is a tre-
mendous need for drugs that can be used in the field to
treat mass casualties of terrorism or catastrophic industrial
accidents. Such drugs should be easy to administer, like
autoinjectors for intramuscular drug administration.
Development of suitable drugs requires more studies to
understand mechanisms of life-threatening symptoms follow-
ing acute H2S exposure. Most drug candidates, including
cobinamide, midazolam, and methylene blue are not specific
to the effects of H2S poisoning, and have off-target effects
(Miyazaki et al. 2021). To establish therapeutics that will tar-
get sequelae of acute H2S toxicity, the mechanism(s) leading
to development of these sequelae must be fully understood.
Mechanisms of development of sequelae remains a huge
knowledge gap. Another knowledge gap is full characteriza-
tion of effects of chronic exposure to environmentally rele-
vant concentrations of H2S. This knowledge is necessary to
develop appropriate treatments. Although it affects a small
population of children, developing drugs for genetic diseases
like ETHE1 defects leading to chronic H2S poisoning is
another area of need to cure or prolong the lives of
affected children.
General conclusions and future directions
Hydrogen sulfide is a common environmental toxicant that is
a public health hazard. It is highly lethal with a high poten-
tial for use in chemical terrorism. It is relatively easy to make
and has been used for suicide, endangering first responders
and innocent bystanders. Human acute exposure occurs
from natural disasters like volcanic activity or catastrophic
industrial accidents. Chronic exposure from genetic defects
in H2S metabolism is lethal in early childhood (Tiranti and
Zeviani 2013). Although H2S is a current and present danger,
there are no FDA-approved drugs for use as antidotes to
treat acute or chronic H2S poisoning, a complex toxicant tar-
geting multiple systems. Although it was discovered in the
mid-eighteenth century, many knowledge gaps on toxic
mechanisms remain, which is a significant bottleneck in the
quest for drug development. Therefore, more research is
needed to pave the way for the development of mechanism-
based therapeutics to treat acute, delayed, and chronic
effects of H2S toxicity from endogenous and environmental
sources, including treating mass casualties in the field.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The author(s) reported there is no funding associated with the work fea-
tured in this article.
ORCID
Wilson K. Rumbeiha http://orcid.org/0000-0002-2370-1817
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