Clinica Chimica Acta 520 (2021) 34–42

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Clinica Chimica Acta

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Review

Acute aluminum phosphide poisoning: The menace of phosphine exposure

Deepak Yadav, Rajasri Bhattacharyya *, Dibyajyoti Banerjee *
Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India

A R T I C L E I N F O A B S T R A C T

Keywords: Aluminum phosphide (AlP) is a popular fumigant used widely for the safe storage of food grain. Although A1P is
Pesticides free from toxic residues, it releases phosphine which acts on mitochondrial components of almost all types of
Poisoning pests. Unfortunately A1P is also a common suicidal agent in developing countries with no known antidote. In
Antidote
addition, accidental exposure to phosphine may also occur. AlP poisoning affects cardiac and vascular tissue
Phosphine
Acetylcholinesterase
directly and can result in multiorgan system failure leading to death in severe cases. There is no specific
biomarker for diagnosing AlP poisoning and management depends on a high level of clinical suspicion. Although
acetylcholinesterase has been suggested as a surrogate biomarker of AlP exposure, there are opposing views. In
this review, we analyzed the relevant published material with emphasis on the need to recognize and explore the
use of plasma mitochondrial enzyme activity as a potential biomarker for AlP exposure.

1. Aluminum phosphide use for grain storage
Aluminum phosphide (AlP), commonly known as rice pill or wheat
pill, is widely used as a fumigant for storage of these grains. AlP is
available over the counter in some developing countries and is
commonly used as an outdoor and indoor pesticide. It is also used as a
fumigant in other foodstuffs [1,2].
Highly toxic phosphine gas is released when it comes in contact with
water or with an acidic environment. The availability of phosphine is
directly proportional to humidity [3,4]. Phosphine is slow acting and
effective at low concentrations if the exposure time is prolonged [5].
AlP is a popular fumigant for food storage for the following reasons:
• Free of toxic residues or leaves little residue on grains or foodstuffs
• Does not affect seed viability.
• No harmful effects on the ecosystem, atmosphere or food grains
and prevents significant crop losses [1,6–14].
Therefore, AlP will continue to play a role in grain storage and
transport [15].
Phosphine spreads quickly. It readily diffuses into the environment
through air space present between stored grains and acts on the respi­
ratory system of insects [16]. There is considerable current interest in
understanding the physical interaction of phosphine gas with stored
grains and its pesticide action. Mathematical models on the subject are
proposed [17].
Phosphine is highly toxic to aerobically respiring organisms. It does
not affect anaerobic or metabolically dormant plants. The advantage of
this phenomenon lies in its protection of stored grains.
Apart from toxicity to pests, AlP poses a threat to human life as it is a
common poisoning agent.
2. Epidemiology of AlP poisoning
AlP is a common suicide pill. From the data at hand, it appears that
the world is facing an epidemic of AlP poisoning. Pesticide poisoning is a
public health problem, particularly in the developing world. In partic­
ular, AlP poisoning is critical because 500 mg AlP tablets containing
56% of the chemical are lethal to human life. Exposure to 400–600 ppm
phosphine gas from any source is life-threatening [8]. Some highlights of
the epidemiological data are provided in Table 1.
Apart from suicide attempts, accidental phosphine exposure is
prevalent among workers in grain stores and the chemical industry
[18,19]. It also occurs during grain transportation in ships [20]. In low-
income countries, AlP fumigation is sometimes performed to eliminate
bed bugs. It may cause accidental phosphine exposure [21]. The lives of
pet animals such as horses are sometimes in danger due to phosphine
exposure from AlP [22]. Phosphine is heavier than air, but it can travel a
certain distance after release. Therefore, proximity to gas once released
is not always essential for unintentional phosphine exposure (both
accidental and homicidal) [23]. It is believed that this phenomenon is a
severe issue related to AlP-induced phosphine release. There is potential
for accidental phosphine exposure from grain storehouses in the case of
phosphine leakage. A similar kind of incident has been reported in flats

* Corresponding authors.
E-mail addresses: bdr.rajasri@yahoo.in (R. Bhattacharyya), dibyajyoti5200@yahoo.co.in (D. Banerjee).

https://doi.org/10.1016/j.cca.2021.05.026
Received 13 October 2020; Received in revised form 19 May 2021; Accepted 24 May 2021
Available online 30 May 2021
0009-8981/© 2021 Elsevier B.V. All rights reserved.
D. Yadav et al. Clinica Chimica Acta 520 (2021) 34–42

Table 1 phosphine gas is highly toxic to insects, burrowing pests, and other
Some facts and figures showing epidemiology of acute AlP poisoning. forms of animal life [29]. In this context, there is concern regarding the
Continent Country Year Cases emergence of phosphine-resistant pests. This issue has been aggravated
primarily due to the lack of alternative fumigants [30]. Fortunately,
Europe Denmark – Poisoning is rare [42]
Germany 1983–2003 188 [42] phosphine resistance does not confer cross-resistance to other fumigants
France – Poisoning is rare [42] [31]. Therefore, in pests with strong phosphine resistance, coadminis­
United 1997–2003 93 [42] tration of other fumigants is recommended [32]. This is indeed a
Kingdom dangerous trend, as it can result in the reintroduction of non-ecofriendly
Asia Iran The death rate is high [114]
fumigants. Therefore, the time is ripe for intense research into alterna­
–
Sri Lanka – The death rate is high [114]
Saudi 2006–2015 68 [115] tive fumigants that are equally as efficient as phosphine but less toxic.
Arabia 2000–2007 471 [42] The concept of bio-fumigation is in its infancy [33,34]. We feel that it is
India 2018 35,862 total poisoning suicide cases a promising concept, but a great deal of research is required to identify
[116] and majority of poisoning cases
an approach that can compete with AlP at this time. Nevertheless, we
due to aluminum phosphide [117]
should continue learning about phosphine toxicity, as another effective
fumigant is not presently at hand.
Apart from toxicity to pests, AlP poses a threat to human life, and the
Africa Morocco – The death rate is high [114] exact mechanism described above occurs in the case of accidental or
(– Data not available). suicidal exposure to phosphine.

where AlP fumigation was performed in the basement for storage [24]. 3.2. Mechanism of toxicity in human beings

3. Mechanisms of toxicity
3.1. Mechanism of toxicity in pests and rodents
The mechanism of phosphine toxicity has been investigated in pests
and rodents in detail. Phosphine inhibits enzymes of the electron
transport chain (ETC) in insect and rodent mitochondria. It disrupts
energy metabolism and mitochondrial function. Most in vitro studies
point towards the inhibition of cytochrome C oxidase and other ETC
enzymes [25]. Phosphine acts at complex IV of the ETC to inhibit elec­
tron flow [26]. Respiration is inhibited by phosphine in insect and rat
liver mitochondria [26,27]. Catalase activity and gene expression are
also reduced. Furthermore, phosphine inhibits glucose-6-phosphate
dehydrogenase activity and reduces the glutathione concentration
[28]. Cellular hypoxia is induced, which leads to the formation of highly
reactive hydroxyl radicals (Fig. 1a). For the reasons mentioned above,
The exact mechanism of action of phosphine in humans that causes
lethality is yet to be determined. Nevertheless, phosphine blocks cellular
respiration at the mitochondrial level. It leads to the formation of highly
reactive hydroxyl radicals and other reactive oxygen species (ROS) and
causes severe oxidative stress. Phosphine also inhibits oxygen uptake,
which causes tissue injury. There may be direct adrenal and cardiac
myocyte toxicity and consequent decreased blood pressure. Further­
more, phosphine is associated with less perfusion to vital organs. There
is a decrease in overall ATP (adenosine triphosphate) production. Dur­
ing severe poisoning, multiorgan system failure occurs [35]. Phosphine
reduces ferric iron to ferrous iron and releases iron from its protein-
bound form. This phenomenon has the potential to aggravate injury
due to oxidative stress [36]. All these mechanisms account for the
toxicity of phosphine.
Notably, in in vitro studies, phosphine was shown to be an ETC poi­
son. In in vivo studies, direct evidence of ETC inhibition was not

Fig. 1a. Toxicity by oxidative stress: Aluminum

phosphide in the presence of moisture and/or
gastric hydrochloric acid release phosphine gas.
Phosphine inhibits the catalase, cytochrome c oxi­
dase (ETC) and glucose-6-phosphate dehydrogenase
(G6PD) activity. G6PD inhibition reduces gluta­
thione concentration. All these generate ROS. It
disrupts the mitochondrial function so, there is a
decrease in overall ATP production. Phosphine de­
creases oxygen uptake. This phenomenon leads to
hypoxia. The injury in AlP poisoning is a combina­
torial effect of hypoxia and oxidative stress that may
lead to multiorgan failure.

35
D. Yadav et al.
Fig. 1b. Toxicity by reducing property of PH3: Phosphine reduces the protein-bound Fe+
ROS, accelerates oxidative damage. It breaks the disulfide bonds of the proteins. For example, breakage of the disulfide bond of insulin may cause altered insulin
function and hyperglycemia.
observed. However, phosphine inhibits several enzymes, such as cata­
lase, peroxidase, and glycerol-phosphate dehydrogenase. Additionally,
it reduces the glutathione concentration. Therefore, the toxicity of
phosphine is mostly due to oxidative stress-induced cellular injury [25].
Apart from the inhibition of antioxidant enzymes and production of
ROS due to inhibition of ETC, phosphine has been shown to react with
hydrogen peroxide and generate ROS. As stated earlier, phosphine re­
duces iron. It can aggravate the generation of lethal ROS from hydrogen
peroxide (such as hydroxyl radicals) in the presence of phosphine. In
vitro, phosphine causes peroxidation of lipids, which supports the above
findings [36]. Since hydrogen peroxide is abundantly present in the
human body, it has been reported that the chemical reaction of phos­
phine with hydrogen peroxide in the presence of iron in vivo is a major
mechanism of oxidative tissue injury in humans in the case of AlP
poisoning [37]. Focused research in this direction is recommended, and
if the above hypothesis is proven to be true, iron chelators can attenuate
phosphine toxicity.
The reducing property of phosphine can affect the human body in
numerous ways. Phosphine can reduce disulfide bonds [38]. The
reduction of disulfide bonds in several proteins will alter their structure.
Insulin is a peptide that has disulfide bonds, and insulin receptor also has
disulfide bonds [39]. If phosphine reduces the disulfide bonds of insulin
or its receptor, glucose homeostasis will be abnormal [40]. Hypergly­
cemia is reported following phosphine exposure, but it is due to the
reduction of the disulfide bond of insulin or its receptor [41]. The
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Clinica Chimica Acta 520 (2021) 34–42
3 to Fe2 and releases the protein-bound iron. This phenomenon, along with
+
authors recommend investigation along these lines of research because
apart from oxidative stress, destruction of the structure of vital proteins
may be a possible mechanism underlying the lethality of phosphine
exposure. The major mechanisms of AlP toxicity are pictorially repre­
sented in Figs. 1a & 1b.
4. Clinical features of AlP poisoning
Poisoning may be due to direct AlP ingestion or inhalation of phos­
phine released from AlP [42]. After ingestion, AlP releases harmful
phosphine gas in the stomach. Gastric HCl favors this release. Phosphine
is rapidly absorbed throughout the gastrointestinal tract (GIT). Acci­
dental phosphine exposure is also lethal to humans, as the lungs rapidly
absorb it.
Phosphine mainly affects the cardiac and vascular tissues. Specif­
ically, phosphine is directly cardiotoxic; it induces cellular respiration
inhibition and depresses the aerobic metabolism of heart muscles [43].
This leads to congestive heart failure, myocarditis, conduction abnor­
malities, hypotension, pericarditis and subendocardial infarction [44].
The signs and symptoms of AlP are nonspecific and depend on the
dose, method of exposure and time since exposure to the poison. After
accidental exposure to AlP, patients feel breathlessness, tightness in the
chest and headache [45]. The release of lethal phosphine gas from the
AlP primarily affects most of our body’s vital organs, including the
heart, lungs, GIT, and kidneys [43,45]. Other clinical features of acute
D. Yadav et al.
AlP exposure include nausea, vomiting, jaundice, diarrhea, ataxia,
paraesthesia, tremor, muscle weakness and diplopia [1].
In the case of mild ingestion of AlP, acute features generally devel­
oped within 1–2 h of poisoning [46]. In moderate to severe cases of oral
poisoning, almost all patients develop acute features immediately after
ingestion, including vomiting, nausea, sweating, hypotension, retro­
sternal burning, tachycardia, shock and coma [47]. In the case of shock,
plasma renin activity is often observed to be elevated. This correlates
with the dose of the poison consumed [48].
The unusual complications of acute AlP exposure include atrial
infarction, hepatic toxicity, skeletal muscle damage, ascites and renal
failure [49]. Consistent with expectations, a case report study showed
that there was an increase in cardiac enzyme markers such as creatine
kinase-MB and troponin T [50,51].
Patients show respiratory features such as cough, cyanosis, dyspnea,
pulmonary edema and respiratory failure [45]. Elevation of blood
cortisol with corresponding changes in adrenal gland histopathology is
seen [52]. In cases of mild poisoning, patients usually show slow re­
covery, but death is the rule in severe poisoning [53].
AlP poisoning can have exceptional atypical presentations, and pri­
mary care physicians should have a high suspicion of phosphine expo­
sure in appropriate cases. This high suspicion is necessary as there is no
established biomarker of AlP poisoning. There can be a wide range of
complications of AlP poisoning. For example, a patient may have pre­
dominantly pleural effusion. Others may present as acute renal failure.
Some other patients may develop pancreatitis.
The clinical features profoundly differ in these cases [49]. Among
them, hemolysis and methemoglobinemia may complicate the course of
AlP poisoning [54]. Severe hypoglycemia may be observed occasionally
[55].
Polyserositis occurred in a case series. The patients developed pleural
effusions, pericardial effusion and ascites. Mitochondrial damage in the
endothelium leads to capillary leakage syndrome, which accounts for
this condition’s possible mechanism [56]. The delayed complication of
polyserositis has been associated with or without acute respiratory
distress syndrome (ARDS) [57].
Other atypical symptoms of AlP poisoning reported from time to time
may include drowsiness, cold body, hypotonicity, pale skin, abdominal
pain and loose motion [58,59]. A hypotensive state with reduced SPO2
levels is observed. ECG findings can be associated with ventricular
ectopic and atrial fibrillation following AlP exposure [60]. Intravascular
hemolysis occurs in patients with glucose-6-phosphate dehydrogenase
enzyme deficiency [61]. Methemoglobinemia, acute pancreatitis,
esophagobronchial fistula, restlessness, tachypnea, altered sensorium,
peripheral cyanosis, and cold sweaty skin may predominate in some
cases of AlP poisoning [58,62–63].
Spontaneous self-ignition is also a rarely observed physical phe­
nomenon in the case of AlP poisoning. This may occur due to the
contribution of released phosphine coupled with heat and negative
pressure generated by suction [64]. Dramatic hot vomiting is reported
after potassium permanganate gastric lavage following AlP ingestion
[65].
5. Management of AlP poisoning:
To date, there is no specific antidote for AlP poisoning, and in the
absence of an antidote, the only option is supportive treatment [66].
With time, various experimental and clinical investigations have pro­
posed substances that can counteract AlP toxicity. However, active
research in the field is ongoing [35].
The current treatment aims to provide supportive care to patients
until phosphine is excreted from the GIT, kidneys and lungs. In the case
of accidental exposure to phosphine, the first step is to bring the patient
into fresh air, whereas in the case of ingestion, decontamination of the
gut is the priority [67].
The basic principles proposed by researchers to be kept in mind
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Clinica Chimica Acta 520 (2021) 34–42
while dealing with AlP poisoning are as follows:
• Inhibition of phosphine absorption through GIT and enhancement
of phosphine excretion through the lungs and kidneys
• Prevention of the release of phosphine from AlP
• Attenuation of organ toxicity
• Supportive measures are necessary as soon as possible [68].
Gastric lavage with magnesium sulfate (MgSO4) or potassium per­
manganate (KMnO4) (1:10,000) is widely used [44]. Some studies have
also highlighted the use of sodium bicarbonate (NaHCO3) and coconut
oil for gastric lavage [69]. The combination of KMnO4, NaHCO3 and
MgSO4 in the lavage formulation oxidizes and neutralizes gastric HCl.
This inhibits the release of phosphine from AlP. Coconut oil forms a
protective layer over the gastric mucosa, preventing the absorption of
phosphine [68]. Activated charcoal and antacids adsorb and reduce the
absorption of phosphine from GIT, respectively [1]. Liquid paraffin is
also used for the same purpose [70]. Melatonin administration has been
suggested as a potential approach for managing cardiotoxicity, as it
scavenges ROS, accelerates ATP production and prevents apoptosis by
inhibiting cytochrome c release [71]. Goharbari et al., 2017 suggested
the oral administration of liothyronine post gastric lavage as a promising
adjuvant therapy for AlP toxicity. This treatment enhances systolic
blood pressure, catalase activity, and total thiol groups and improves
total antioxidant capacity [72]. The most critical factor for the suc­
cessful treatment of AlP toxicity is the resuscitation of shock. Various
measures have been suggested for this, such as administering normal
saline intravenously to keep central venous pressure at approximately
12–14 cm of water. Low-dose dopamine and hydrocortisone have been
recommended to keep systolic blood pressure above 90 mm Hg and
combat shock [70]. The SPO2 level is maintained by delivering 100%
oxygen through a face mask, which further helps in managing ARDS. In
a case study of a 21-year-old man with AlP poisoning, a combination of
glucagon and digoxin with antioxidant agents successfully treated the
patient [73].
As stated above, there is no specific antidote available for AlP
poisoning; however, various substances have been proposed to achieve a
better outcome and supportive care [74–82]. The effects of these mea­
sures vary from patient to patient. The outcome mainly depends upon
the route of exposure, duration of exposure, amount of poison, avail­
ability of supportive measures and time interval between consumption
and resuscitation.
6. Diagnosis:
There is no biomarker recommended for the diagnosis of AlP
poisoning. Some basic principles can be used as a diagnostic tool to some
extent. The diagnosis of AlP poisoning is made mainly by clinical
suspicion.
1. Clinical history obtained from the patient or attendants is often
helpful in disclosing the substance used for suicide [47].
2. Some symptoms may rarely be present following acute AlP exposure.
These include vomitus smelling of decaying garlic or fish, shock,
hypotension and abnormalities in cardiac rate [47].
3. The silver nitrate test is not entirely reliable but is proposed to detect
phosphine either from the stomach content or directly from the pa­
tient’s breath. Exposure to phosphine converts freshly prepared sil­
ver nitrate-dipped filter paper to a blackish color precipitate. There
are chances of false negatives in patients receiving oxygen, which
converts phosphine into phosphorus pentoxide, and false-positive
results due to hydrogen sulfide in the air [47]. For phosphine
detection in gastric samples, the silver nitrate test is generally used as
a screening test. This conclusion is confirmed by other sophisticated
tests, such as gas chromatographic phosphine detection [83]. The
gastric lavage content in AlP poisoning may be heated to obtain the
phosphine liberated for detection by the silver nitrate test [15]. Apart
from silver nitrate, silver diethyldithiocarbamate is used for
D. Yadav et al.
phosphine detection. This approach is even used for quantitative
detection of phosphine by spectrophotometry. Nevertheless, silver
diethyldithiocarbamate has not yet been examined in hospital
emergencies to detect phosphine from gastric content (or breath of
the patient) [84]. In this context, it is pertinent to mention that
mercuric chloride impregnated strips are used to detect the presence
of phosphine in the air. However, their use in clinical cases of acute
AlP poisoning has never been reported [85].
4. The availability of phosphine detector tubes and bulbs can also be
used to diagnose phosphine exposure [1]. Several detector tubes are
available, mostly to detect phosphine in the environment [86].
Currently, a wireless sensor approach integrated with a cloud com­
puter is a promising technology for environmental monitoring or air
sampling of phosphine [86]. There is absolutely no experience with
phosphine detection using these methods in cases of AlP poisoning.
We believe that these technologies require urgent trials in a primary
health care center setting to devise a point of care (POC) instrument
for phosphine detection for the early diagnosis of AlP.
5. The most recent advancement is the development of gas chroma­
tography with a nitrogen–phosphorous detector, which can detect
even minute amounts of phosphine [1]. In severe AlP poisoning,
postmortem phosphine concentrations have been detected in various
tissues using gas chromatography coupled with mass spectrometry.
The injector temperature is approximately 180 ◦ C, and a m/z ratio of
34 is used for such analysis [87]. Unique chemical strategies have
been applied for trace amounts of phosphine detection in postmor­
tem samples. Phosphine is oxidized to phosphite and hypophosphite
in a biological system. This is reduced back to phosphine as an
analytical strategy and detected by headspace GC–MS. However,
antemortem use of such techniques is not yet reported from a bio­
logical sample [88].
6. Serial blood phosphine estimation is reported in antemortem cases of
acute AlP poisoning [89]. Postmortem analysis of AlP poisoning
samples has revealed that blood phosphine may not be detectable.
However, the blood of AlP poisoning cases may contain a high
amount of aluminum [90]. Much antemortem experience with
aluminum estimation in biological samples is not reported in the
context of AlP poisoning. We believe that this is a promising
approach for screening AlP poisoning, and focused research should
be carried out to address this issue.
Phosphine is more frequently detected either in the gastric content or
in the breath but generally not in blood or urine samples. In these
samples, phosphine is easily and quickly oxidized to phosphite and
hypophosphite in vivo [65,91]. Nevertheless, urinary phosphite and
hypophosphite may be estimated by chromatographic techniques [91],
but such an approach has yet to be explored in a clinical case of acute
AlP poisoning.
Analytical assays are more frequently conducted with postmortem
samples, and in the emergency department of hospitals, such tests (such
as urine hypophosphite detection, etc.) are generally not done. In pri­
mary health care platforms, gas chromatography is usually not avail­
able. Therefore, there is an urgent need to determine a biomarker for
poisoning that can be detected in the practical realities of a primary
health center.
In search of a serum-based biomarker for patients who have ingested
AlP, Kariman et al., 2012 analyzed antioxidant capacity, total plasma
thiol concentration and lipid peroxidation by chromatography and
compared them with healthy controls. The results of the study were
similar to those of previously reported animal studies. There was a sig­
nificant increase in lipid peroxidation and a reduction in total thiol
groups and total antioxidant capacity in the AlP ingested group
compared to the control. This confirmed that AlP significantly enhances
oxidative stress in the body [92].
There may be acute cardiotoxicity following AlP ingestion. These
patients often develop hypomagnesemia and hypomagnocytia. ECG
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Clinica Chimica Acta 520 (2021) 34–42
abnormality is also common in these cases. Several laboratory-based
assessments have been reported in AlP cases where leucopenia is an
indicator of severe toxicity. Metabolic acidosis is seen in moderate
toxicity. In these cases, serum SGOT (serum glutamic oxaloacetic
transaminase) and SGPT (serum glutamate-pyruvate transaminase) ac­
tivity may be elevated [93]. Another study reported a direct relationship
between plasma renin level and mortality and the dose of AlP. Plasma
renin levels are significantly elevated, while cortisol levels are decreased
in AlP toxicity [94].
7. Status of acetylcholinesterase (AChE) activity in AlP
poisoning
AlP exposure is believed by some researchers to affect AChE activity
as one of its primary mechanisms of toxicity [95]. In the last few de­
cades, much research has been conducted to examine the effect of AlP/
phosphine on the level and activity of AChE. Most of the data reported
suggest that AlP inhibits various mitochondrial enzymes, but a signifi­
cant reduction in AChE activity has also been observed in serum.
However, some studies oppose these findings. There is no effect on
erythrocyte cholinesterase activity in accidental phosphine inhalation
cases [42]. Therefore, this controversy can be approached by consid­
ering two components of AlP, aluminum and phosphine, and examining
the effect of these two components on AChE activity. Nevertheless, some
clinical and experimental reports suggest that both phosphine and
aluminum inhibit AChE [96,97].
An in vitro study conducted by Mohammad J et al. in 1989 reported
that the levels of AChE in mouse and human serum were significantly
reduced after exposure to phosphine gas. This reduction was also found
to be correlated with the dose and exposure time [98]. Other studies
support these results by stating that AlP poisoning causes the inhibition
of cholinesterase in rats, and repression in the treatment group was as
high as 47% and 40% compared to the control group [95,99].
An exciting finding was pointed out in a review article by Alfred et al.
in 2016, showing that phosphine exposure decreases serum cholines­
terase activity. However, brain AChE activity was not reduced in pa­
tients after metal phosphide ingestion [94].
The baseline value of AChE has yet to be determined. AChE activity
shows significant intra- and interindividual variation. Therefore, in
organophosphorus (OP) poisoning, AChE reactivation following oxime
treatment is considered a parameter. Reactivation induced by oximes
predicts OP exposure. AlP inhibits AChE activity in vitro. However, the in
vitro inhibition is not reactivatable by oximes [100].
Therefore, we believe that AChE activity cannot currently be used as
a biomarker for phosphine exposure.
Phosphine can inhibit AChE [94]. This is also the case with AlP and
aluminum ions [100,101]. Other studies from time to time have also
supported this fact and stated that aluminum inhibits brain AChE ac­
tivity [102,103]. Therefore, as a solution to the controversy, the effects
of aluminum and phosphine on serum AChE activity need to be assessed
separately to achieve any conclusion about the reason for AChE inhi­
bition in AlP-exposed patients [104]. We believe that AChE is an
essential target for intense research in the context of AlP poisoning. The
behavior of the biomarker may not mimic OP compound exposure.
Additionally, it may not be reactivatable by oximes [100]. Following OP
compound exposure, there are cholinergic symptoms. Both erythrocyte
cholinesterase and brain cholinesterase are inhibited [105]. However,
with AlP exposure, the clinical picture suggests that there is peripheral
cholinesterase inhibition. There may not be cholinergic symptoms, and
brain cholinesterase activity may not be reduced [106]. All of these
observations point towards the fact that aluminum ions are the culprit
for AChE inhibition. It is important to emphasize that aluminum ions are
not expected to cross the blood–brain barrier to inhibit brain cholines­
terase activity. However, focused research is necessary in this area as
nothing can be concluded with certainty.
D. Yadav et al. Clinica Chimica Acta 520 (2021) 34–42

Table 2 lethal human toxicity. Additionally, AlP poisoning is a public health

A table summarizing the key points of acute AlP poisoning.
Issues
I. Major toxic effects of AlP
poisoning at organ system
level
AlP liberates phosphine. It causes toxicity
II. Chemical reactions
liberating PH3 from AlP
III. Chemical reactivity of PH3
problem. Therefore, apart from phosphine exposure biomarker research,
Particulars we urgently need to find better alternatives to AlP for grain stores.
Active research in this direction is highly recommended and, indeed,
i)Congestive heart failure [44]
ii)Hypotension [44] essential, as phosphine resistant pests have emerged. To meet these
iii) Pericarditis [44] demands, work is ongoing to develop indicators of pest phosphine
iv) Subendocardial infraction [44] resistance [109]. The mechanism of phosphine resistance in pests is also
v) Tachycardia [47] an area of current research. Phosphine resistance in some pests in vitro is
vi) Shock [47]
vii) Coma [47]
a function of the antioxidant enzyme response. The increased antioxi­
viii) Abdominal pain, diarrhea, Jaundice, dant enzyme activity is likely to scavenge ROS and cause phosphine
vomiting, nausea and diplopia [1] resistance. However, all of this speculation requires more detailed
ix) Affects mainly lungs, gastrointestinal tract research in the field [110].
and kidneys [45]
The critical issues concerning acute AlP poisoning are summarized in
AlP + 3H2O → Al (OH)3 + PH3 [1] Table 2. Considering current research on the development of alternative
AlP + 3HCl → AlCl3 + PH3 [1] fumigants, we believe that AlP will be used for decades to come
[111–113]. Therefore, biomarker research for AlP exposure should be a
1.PH3 → forms complex with metal ion co- prioritized. We recommend focused research on mitochondrial enzyme
factors → Inhibits cytochrome c oxidase,
catalase etc. → produces ROS → oxidative stress
activities in biological fluids following AlP exposure.
→ lipid peroxidation
2. PH3 + 2 O2 → H3PO4, PO3− 4 → Non toxic
Molecular effects Declaration of Competing Interest
a) Inhibition of cytochrome c oxidase [25]
b) Cellular injury due to lipid peroxidation [35] The authors declare that they have no known competing financial
c) Decrease in level of catalase and glutathione
interests or personal relationships that could have appeared to influence
concentration [25]
d) Reduction in activity of SOD [28] the work reported in this paper.
e) Cellular hypoxia [29]
f) Release of Fe from membrane bound
transferrin receptors [36] Acknowledgement

DY acknowledges PGIMER, Chandigarh for providing fellowship.

8. Plasma mitochondrial enzymes: The proposed biomarker of
AlP exposure
There is current interest in developing a POC test for the detection of
AlP poisoning. In this context, we believe that mitochondrial enzymes
should be tested for their screening potential for poisoning. The toxicity
of AlP is due to liberated phosphine, a mitochondrial poison [94].
Phosphine exposure results in swollen and dysmorphic mitochondria in
vivo [107]. Therefore, mitochondrial enzymes are expected to be leaked
in the extracellular site. These biomarkers should be screened for the
development of acute AlP overdose. After AlP exposure, mitochondrial
enzyme activities are enhanced following isolation of mitochondria
[94]. Therefore, phosphine may not inhibit mitochondrial enzyme ac­
tivities, so elevated mitochondrial enzymes in plasma/serum following
AlP exposure are expected to be detected in terms of elevated enzyme
activity.
There may be an elevation of mitochondrial enzymes in the plasma
or urine samples of AlP patients. If that is the case, then this elevation
will serve as a biomarker of AlP intoxication. In many parts of the globe,
such poisoning is epidemic. However, there is no effective biomarker for
screening such cases. We believe that mitochondrial enzyme activity in
plasma should be urgently investigated to develop such a biomarker
[108]. It is important to emphasize that the mitochondrial enzymes/
proteins that are exclusively present in mitochondria and not present in
any other organelle and the cytosol should qualify for such investiga­
tion. We list below a few such proteins/enzymes that fulfill the above
criteria and should be investigated for this purpose.
1. Succinate dehydrogenase
2. Citrate synthase
3. Malate dehydrogenase − 2
4. Superoxide dismutase − 2
5. Coproporphyrinogen oxidase
9. Summary and conclusion
Workers in grain storehouses are at increased risk of phosphine
exposure, and phosphine leakage from grain storehouses can cause
DB and RB acknowledges PGIMER Chandigarh (Sanction No. 71/2-
Edu-16/1915) for providing financial assistance.
The authors acknowledge the language editing and formatting ser­
vices of Dr. Sheemona Chowdhary, Research Associate, Department of
Experimental Medicine and Biotechnology, PGIMER, Chandigarh
160012 and Elsevier Web shop at the stage of finalizing the revised
manuscript.
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