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Can chlorine dioxide prevent the spreading of coronavirus or other viral infections? Medical hypotheses

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Can chlorine dioxide prevent the spreading of coronavirus or other viral infections? Medical hypotheses

Abstract

Motivation: Viruses have caused many epidemics throughout human history. The novel coronavirus [10] is just the latest example. A new viral outbreak can be unpredictable, and development of specific defense tools and countermeasures against the new virus remains time-consuming even in today's era of modern medical science and technology. In the lack of effective and specific medication or vaccination, it would be desirable to have a nonspecific protocol or substance to render the virus inactive, a substance/protocol, which could be applied whenever a new viral outbreak occurs. This is especially important in cases when the emerging new virus is as infectious as SARS-CoV-2 [4]. Aims and structure of the present communication: In this editorial, we propose to consider the possibility of developing and implementing antiviral protocols by applying high purity aqueous chlorine dioxide (ClO2) solutions. The aim of this proposal is to initiate research that could lead to the introduction of practical and effective antiviral protocols. To this end, we first discuss some important properties of the ClO2 molecule, which make it an advantageous antiviral agent, then some earlier results of ClO2 gas application against viruses will be reviewed. Finally, we hypothesize on methods to control the spread of viral infections using aqueous ClO2 solutions.
Can chlorine dioxide prevent the spreading of
coronavirus or other viral infections? Medical
hypotheses
K. K
ALY-KULLAI
1
, M. WITTMANN
1
, Z. NOSZTICZIUS
1
and
L
ASZL
O ROSIVALL
2
*
1
Department of Physics, Group of Chemical Physics, Budapest University of Technology and
Economics, Budapest, Hungary
2
Institute of Translational Medicine and International Nephrology Research and Training Center,
Semmelweis University, Budapest, Hungary
© 2020 The Author(s)
INTRODUCTION
Motivation
Viruses have caused many epidemics throughout human history. The novel coronavirus [10]is
just the latest example. A new viral outbreak can be unpredictable, and development of specic
defense tools and countermeasures against the new virus remains time-consuming even in today's
era of modern medical science and technology. In the lack of effective and specic medication or
vaccination, it would be desirable to have a nonspecic protocol or substance to render the virus
inactive, a substance/protocol, which could be applied whenever a new viral outbreak occurs. This
is especially important in cases when the emerging new virus is as infectious as SARS-CoV-2 [4].
Aim and structure of the present communication
In this editorial, we propose to consider the possibility of developing and implementing antiviral
protocols by applying high purity aqueous chlorine dioxide (ClO
2
) solutions. The aim of this
proposal is to initiate research that could lead to the introduction of practical and effective
antiviral protocols. To this end, we rst discuss some important properties of the ClO
2
molecule,
which make it an advantageous antiviral agent, then some earlier results of ClO
2
gas application
*
Corresponding author: Prof. emer. Laszlo Rosivall, MD, PHD, DSc, FERA, FAPS, Institute of Translational
Medicine, International Nephrology Research and Training Center, Semmelweis University, Budapest,
Nagyv
arad t
er 4., H-1089, Hungary. Tel/Fax: 36-1-2100-100, E-mail: rosivall.laszlo@med.semmelweis-univ.hu
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DOI: 10.1556/2060.2020.00015
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against viruses will be reviewed. Finally, we hypothesize on methods to control the spread of
viral infections using aqueous ClO
2
solutions.
PREVIOUS EXPERIENCE AND BACKGROUND OF USING ClO
2
AS AN
ANTIVIRAL AGENT
Inactivating viruses with ClO
2
in aqueous phase
To our present knowledge, an aqueous solution of ClO
2
is able to inactivate all types of viruses.
Disinfectants (in water phase) are compared by their CT values, which is the concentration
(measured in mg/L) multiplied by the contact time (measured in minute). In CT tables, ClO
2
is
indicated for viruses in general, without mentioning any exemptions. For example, according to
[6], a CT value of 8.4 mg 3min/L is needed to achieve a four-orders-of-magnitude (4 logor
99.99%) inactivation of viruses in an aqueous medium at 25 8C.
Chemical mechanism of virus inactivation: reaction of ClO
2
with amino acid residues
In 1986, Noss et al. [19] proved that the inactivation of bacterial virus f2 by ClO
2
was due to its
reactions with the viral capsid proteins, and almost no inactivation of the infectious viral RNA
occurred [8] when that was treated with ClO
2
separately. They found [19], however, that three
discrete chemical moieties in the viral protein, namely the cysteine, tyrosine, and tryptophan
amino acid residues were able to react with ClO
2
rapidly. In 1987, Tan et al. [28] tested the
reactivity of ClO
2
on 21 free amino acids. ClO
2
reacted only with six amino acids dissolved in 0.1
M sodium phosphate buffer, pH 6.0. The reaction with cysteine, tryptophan, and tyrosine was
too rapid to be followed by their technique. Three further amino acids (histidine, hydroxy-
proline, and proline) reacted with ClO
2
much more slowly, at a measurable rate.
The reactivity of the three fast-reacting amino acids (cysteine [12], tyrosine [17], and
tryptophan [27]) was studied in Margerum's laboratory between 2005 and 2008. They found
that cysteine had the highest reactivity among these amino acids. From their experimental data
they calculated second order-rate constants (at pH 7.0, 25 8C and 1 M ionic strength) and
obtained the following sequence: cysteine 6.9 310
6
M
1
s
1
>> tyrosine 1.3 310
5
M
1
s
1
>
tryptophan 3.4 310
4
M
1
s
1
>> guanosine 50-monophosphate 4.5 310
2
M
1
s
1
. (They
studied guanosine 50-monophosphate [18] as a model compound for guanine in nucleic acids.
Data presented here are taken from Table 3 of ref. [18]).
In 2007, Ogata [22] found that the antimicrobial activity of ClO
2
is based on denaturation of
certain proteins, which is primarily due to the oxidative modication of the tryptophan and
tyrosine residues of the two model proteins (bovine serum albumin and glucose-6-phosphate
dehydrogenase) used in his experiments. In 2012, it was again Ogata who showed [23] that the
inactivation of inuenza virus by ClO
2
was caused by oxidation of a tryptophan residue (W153)
in hemagglutinin (a spike protein of the virus), thereby abolishing its receptor-binding ability.
In this context it is interesting to remark that the spike protein of the new coronavirus
SARS_CoV-2 contains 54 tyrosine, 12 tryptophan, and 40 cysteine residues [29]. If we assume
that in an aqueous solution all of these residues are able to react with ClO
2
just like the free
amino acids, then the inactivation of the viruses can be extremely rapid even in a very dilute
(e.g., in a 0.1 mg/L) ClO
2
solution.
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ClO
2
is a water soluble gas
Although chlorinedioxide in itself is a gas, it is highly soluble in water. When both air and water
are present, ClO
2
is distributed between the two phases in an equilibrium ratio determined by
the temperature. This distribution coefcient of ClO
2
was determined by Ishi [11] in 1958. The
distribution coefcient, g5[ClO
2
]
G
/[ClO
2
]
L
gives the ratio of the concentrations expressed in
the same units in the gas and the aqueous phases (e.g., g/L) and changes as a function of the
temperature. For example, at 20 8Cg50.0316, indicating that in equilibrium 1 cm
3
aqueous
phase contains (0.0316)
1
531.6 times more ClO
2
molecules than 1 cm
3
gas phase.
In practice, the concentrations in the two phases are usually given in ppm. However, these
dimensionless numbers are defined in a different way in the gas and liquid phases as ppm (V/V)
and ppm (m/m), respectively. Therefore, for practical purposes, we need a distribution coeffi-
cient, which gives the ratio between these concentrations. Straightforward calculation yields that
the distribution coefficient in terms of ppm is 357 times the distribution coefficient in terms of
(g/L), so at 20 8Cg
ppm
511.3. Thus, the following formula can be used to calculate the ClO
2
concentration of the gas phase being in equilibrium with a ClO
2
solution at 20 8C:
½ClO2gas in ppmðV=VÞ¼11:33½ClO2aq in ppmðm=mÞ
Inactivating viruses with ClO
2
in gas phase
The virus-inactivating reactions (the reactions of ClO
2
with the three amino acids) take place in
an aqueous medium; consequently, ClO
2
can inactivate microbes in their wet state only.
Therefore, ClO
2
gas that is moisturized can be an ideal agent against viruses both in their wet
and dry states. Viruses that are carried by water droplets could be easily inactivated even by
ClO
2
gas owing to the high solubility of ClO
2
in water [11]. A dry ClO
2
gas would be inap-
propriate as the water content of the aqueous droplet could evaporate, and in the absence of
aqueous medium the reactions of ClO
2
slow down extremely. Indeed, Morino et al. [16] reported
that when applying a low concentration of ClO
2
in the gas phase against FCV in dry state,
atmospheric moisture at least a 7585% relative humidity is indispensable to inactivate
viruses. The advantage of using a moisturized ClO
2
gas is that its water content is also able to
wet viruses in dry environment. Most viruses are found on hard surfaces indoor, but a small
fraction of viruses are airborn, attached to dust particles, which can also carry a single microbe
or an aggregate of microbes. Therefore, it is a prerequisite of an effective disinfection that all
microbes in all parts of the room should be wet and should be in contact with ClO
2
. If enough
aqueous ClO
2
solution is sprayed into the room, the droplets will saturate the atmosphere with
water vapor everywhere, moreover, the atmosphere will also contain gaseous ClO
2
everywhere.
The great advantage of this method is that H
2
O and ClO
2
molecules of the gas phase can reach
the microbes in every small corner of the room. Finely dispersed water droplets containing
dissolved ClO
2
can create an advantageous environment to maintain such conditions for a
longer time.
This method using high ClO
2
concentration allows fast disinfection of rooms when people
are not present, e.g., intensive care units, buildings used as quarantine, or public transport
vehicles. However, the application of ClO
2
gas is limited when people are present, as it is
harmful for humans and animals above certain concentrations. The US Occupational Safety and
Health Administration (OSHA) limits the concentration of ClO
2
gas allowed in workplace air to
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0.1 ppm (V/V) time-weighted average (TWA) for an 8-h exposure, and to a temporarily higher
0.3 ppm Short-Term Exposure Limit (STEL) only for a 15-min period [30].
Previous research on preventing viral infections with gaseous ClO
2
Ogata [21] realized rst that ClO
2
is able to inactivate viruses even under the 0.1 ppm (OSHA
TWA) limit that is in concentrations which are not harmful to humans. In 2008, Ogata and
Shibata [25] demonstrated that infection of mice with inuenza A virus applied in an aerosol
can be prevented by ClO
2
gas present at 0.03 ppm concentration in the air, which is only 30% of
the permissible TWA exposure level for humans at a workplace. They concluded that ClO
2
gas
could, therefore, be useful as a preventive tool against inuenza in places of human activity
without necessitating evacuation.They have even made attempts to decrease the incidence of
ue infections among schoolchildren by applying low concentrations of ClO
2
gas in a classroom
[24].
In spite of these promising early results we are not aware of any wider-scale application of
this method in the last decade. There are two problems which could hinder the widespread
adoption of this method:
1. With the technique applied by the above-cited authors it is not an easy task to achieve and
maintain a very low ClO
2
concentration in a large space and for a long time, which is a
prerequisite of achieving a satisfactory level of virus inactivation.
2. It is not understood why low ClO
2
levels are not harmful to humans or animals and still
effective against viruses.
Size selective effect of ClO
2
Although cysteine, tyrosine, and tryptophan residues can also be found in human tissues, ClO
2
is much less toxic for humans or animals than for microbes (bacteria, fungi, and viruses).
Noszticzius et al. [20] found that the main reason for this selectivity between humans and
microbes is based not on their different biochemistries but on their different sizes. Based on
experiments and calculations using a reaction-diffusion model Noszticzius et al. [20] found that
the killing time of a living organism is proportional to the square of its characteristic size (e.g., its
diameter), thus small ones will be killed extremely fast. Their calculations indicated that a
bacterium 1
m
m in diameter would be killed in a 300 mg/L ClO
2
solution within 3 ms, and even
in a much more dilute, 0.25 mg/L ClO
2
solution it would be eliminated in only 3.6 s. During this
time, ClO
2
reaches all parts of the cell and kills it by destroying its cysteine-, tyrosine-, and
tryptophan-containing proteins, which are essential for life processes.
The protective role of glutathione against ClO
2
oxidation in a living cell
According to Ison et al. [12] glutathione reacts with ClO
2
at a rate, which is even higher than the
rate of the very fast ClO
2
cysteine reaction. When ClO
2
contacts a living cell containing
glutathione, at rst the ClO
2
concentration remains very low even at the point of entry into the
cell due to this rapid reaction. As a small molecule, glutathione can also diffuse rapidly to the
point of entry from other parts of the cell consuming most of the ClO
2
there, and preventing it
from reaching the cysteine, tyrosine, and tryptophan residues of the proteins in the bulk of the
cytoplasm. Consequently, the initial low ClO
2
concentration cannot make too much harm.
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However, continuous ClO
2
entry can nally exhaust the cell's glutathione (and other antioxi-
dant) capacity even if the cell produces such antioxidants continuously. At this point, ClO
2
can
enter into the previously protected zones of the cell and react with the reactive amino acid
residues, causing denaturation of the affected proteins and ultimately cell death.
The effect of glutathione and other small antioxidant molecules present in living cells was
not taken into account in the theoretical calculations of Noszticzius et al. [20]. Their experi-
ments were done on a non-living and washed animal membrane, where membrane-xed
reactive proteins were present, but glutathione and other small molecules were absent. A living
cell, however, continuously produces these antioxidants, thus their role cannot be neglected.
Indeed, looking at the experimentally measured disinfection dynamics of a 0.25 mg/L ClO
2
solution against Escherichia coli bacteria [2] we can see a disinfection rate, which is surprisingly
fast but still about one order of magnitude slower than the theoretical estimate. It is reasonable
to assume that the delaying effect of these small reducing molecules is responsible for that
deviation.
Protection of human tissues against the oxidative effect of ClO
2
Human cells also contain glutathione in mM concentrations, as well as other antioxidants like
vitamin C and E, which work together with glutathione to reduce ClO
2
[7]. As a human cell is
much larger than a bacterium, consequently its glutathione reserve and glutathione production
potential are also greater, so even an isolated human cell can survive much longer in a ClO
2
environment than a planktonic bacterium. Considering that human cells are not isolated but
form tissues, their glutathione stock may be many orders of magnitude greater than that of a
planktonic bacterium. Additionally, in multicellular organisms circulation transports antioxi-
dants continuously to the cells of the tissue affected by a ClO
2
attack, helping them to survive.
This strengthens the size-selectivity effect, and explains the surprising observation [15] that
ClO
2
solutions that are able to kill planktonic bacteria in a fraction of a second may be
consumed, because they are safe for humans to drink in a small amount (e.g., drinking 1 L of 24
mg/L ClO
2
solution in two portions on a single day caused no observable effects in humans
[15]).
The effect of ClO
2
on the lung
While human tissues are not very sensitive to ClO
2
in general, lungs should be considered
differently. This is because the interalveolar septum separating the airspace of an alveolus from
the blood stream of a capillary lumen is very thin. That diffusion barrier in the human lung is a
mere 2
m
m thick [1] in order to facilitate an efcient diffusional exchange of oxygen and carbon
dioxide between the air and blood. The alveolus is covered by a thin layer of lining uid called
epithelial lung lining uid (ELF) or hypophase. The ELF is only 0.2
m
m thick in rat alveoli [1,
13]. It contains glutathione [3] and other antioxidants such as ascorbic and uric acids [5]. It is
remarkable, that the ascorbic acid concentration is 2.5 times, and the glutathione concentration
is more than 100 times higher in the ELF than in the plasma. The normal function of these non-
enzymatic antioxidants in the ELF is to protect the epithelial cells from reactive oxygen species
(ROS) like superoxide radicals or hydrogen peroxide, which are toxic products of the meta-
bolism. They can also defend the lung against other toxic gases such as ozone (O
3
), nitrogen
dioxide (NO
2
) or ClO
2
. However, high amounts of ClO
2
can consume all reducing agents in the
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ELF, at which point ClO
2
starts to react with the epithelial cells causing a continuously growing
damage to these cells. It is known that higher concentrations of ClO
2
gas can be lethal. However,
it is reasonable to assume that the effect of ClO
2
on the lung depends not only on its con-
centration in the gas phase but also on the contact time. Thus, when considering the impact of
ClO
2
on the lung, it would be logical to regard the CT (concentration) 3(contact time) product
in a similar way as in the case of the microbes.
Estimating the inactivation time of viruses
In the case of viruses, the inactivation mechanism differs from that of bacteria or other cells. It is
feasible to assume that the inactivation time of a virus is probably much shorter than the
inactivation time of a bacterium under the same conditions (ClO
2
concentration, temperature,
etc.). The following arguments support this assumption:
1. Viruses are about one order of magnitude smaller than bacteria e.g., the diameter of SAR-
S_CoV-2 is about 120 nm [9]. The killing time of a virus as introduced in [20] would be 12
orders of magnitude shorter than that of a bacterium, i.e., the diffusion-controlled reaction
with ClO
2
would happen on a shorter time scale in the entire volume of the virus.
2. It is not necessary for ClO
2
gas to penetrate the virus in order to inactivate it. It is enough if
ClO
2
reacts with one or some of the cysteine, tyrosine, and tryptophan amino acid residues of
the spike, which are located on the surface of the virus. This means that the theoretical
approach of ref. [20] overestimates the inactivation time of viruses. On the one hand, because
diffusion is extremely fast over a 0.1
m
m length scale, thus probably it is not limiting the rate
of the reactions. On the other hand, ClO
2
can reach a large part of the reactive amino acid
residues of the spike without permeating through the protein envelope of the virus.
3. Viruses do not contain protective small molecular thiols like glutathione or other small
molecular protective metabolic products, because viruses have no metabolism. In this respect
viruses should be much more vulnerable than bacteria to an attack by ClO
2
.
These facts all suggest that once ClO
2
contacts the surface of a virus, its inactivation is quick.
However, a virus ready to infect a cell is typically in aqueous phase, e.g., in a uid droplet, or in the
epithelial lining uid covering the mucous membranes. The size of these aqueous phases is much
larger than that of the virus. Therefore, in such cases, the rate-limiting step probably is the diffusion of
ClO
2
in the water and the reaction with other substances. The time required to inactivate the virus
itself would be short compared to the time needed to transport enough ClO
2
molecules to the virus.
SUGGESTIONS FOR PREVENTING THE SPREAD OF VIRAL INFECTIONS
USING ClO
2
Based on the previous arguments, some propositions will now be put forward on how aqueous
ClO
2
solutions could be applied for global and local (personal) disinfection purposes. Many of
these propositions are based on hypotheses, and therefore can only be applied after careful
research. It is a goal of the present work to initiate research to check these hypotheses and
proposals experimentally, which could lead to new applications of high-purity ClO
2
solutions
against viral or other infections. These ideas might be further matured in time, but due to the
threat of a global pandemic, we have chosen to move fast.
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Global prevention
Disinfection of air spaces, hard surfaces, and persons simultaneously with aqueous ClO
2
solutions. What we are proposing here is basically the same idea what has been already pro-
posed by Ogata et al. [21, 24, 25]: it is possible to create ClO
2
atmospheres which can be safe for
humans but at the same time harmful for microbes. There are differences, however, between
their proposals and ours. Ogata's group regarded the ClO
2
concentration (C) of the atmosphere
as the sole important parameter of the treatment. They proposed to apply a ClO
2
concentration
below the 0.1 ppm (V/V) OSHA limit, for a time that is necessary to inactivate the microbes.
With such a method, however, the necessary contact time (T) can be very long. Here we suggest
regarding the CT product as the parameter of disinfection. In this way it is possible to apply
ClO
2
concentrations above the OSHA limit but for a limited time only. The advantage of this
method is that as higher C values are applied, the necessary contact times can be much shorter.
The idea will be illustrated by a numerical example below.
Another important difference is that Ogata's method focuses mostly on the role of the ClO
2
gas, whereas we emphasize the importance of the simultaneous usage of ClO
2
and H
2
O gases, as
conrmed by the observations of Morino et al. [16]. For this purpose, we suggest a new way of
creating a ClO
2
atmosphere: to apply aqueous ClO
2
solutions which can establish equilibrium
ClO
2
and H
2
O concentrations in the atmosphere, when these are sprayed into the air. Aqueous
solutions are also easier to handle than to maintain stable and very low ClO
2
levels in
continuous gas streams.
It is advisable to apply high-purity ClO
2
solutions for spraying to avoid any unwanted side
effects to the persons or the surfaces treated. High-purity ClO
2
solutions evaporate without any
residue or trace.
An illustrative numerical example. Let us assume that we want to disinfect a closed space by
spraying some aqueous stock ClO
2
solution into it. The equilibrium ClO
2
concentration c
air
in
the gas and c
w,e
in the liquid phase can be calculated from the vapor-liquid equilibrium dis-
tribution measured by Ishi [11]:
g¼cair
cw;e
and from the component balance for ClO
2
:
Vw$cw0¼Vw$cw;eþVair$cair
where V
air
is the volume to be disinfected, V
w
is the volume of the ClO
2
stock solution, and c
w0
is
its ClO
2
concentration.
With the help of the above two equations cw;ecan be calculated as
cw;e¼cw0
1þg$Vair
Vw
Suppose we apply V
w
520 mL of c
w0
540 ppm (m/m) aqueous stock ClO
2
solution in a
V
air
51m
3
closed space.
At 20 8C the value of the distribution coefficient is g50.0316 (data of Ishi [11]) when all
concentrations are given in the same units (e.g., in mg/L), and it is g
ppm
511.3 (see section ClO
2
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is a water soluble gas) when ppm (m/m) and ppm (V/V) are used in the aqueous and gaseous
phases, respectively. Substituting our data the results are
cw;e¼0:025 ppmðm=mÞ;
cair ¼gppmcw;e¼0:29 ppmðV=VÞ
This result is just below the OSHA STEL (Short Term Exposition Limit) value which is 0.30
ppm (V/V) for 15 min. According to OSHA, STEL is the acceptable average exposure over a
short period of time usually 15 min as long as the time-weighted average (TWA) is not
exceeded. If a person is exposed to 0.30 ppm for 15 min, and right after that he or she stays in a
ClO
2
-free atmosphere for 30 min, then the TWA value for this whole 45 min period is just the
acceptable 0.10 ppm. All this means that an exposure of a person to a 0.30 ppm ClO
2
atmo-
sphere for 15 min on a single occasion, or even applying that treatment periodically with 30 min
pauses within an 8 h period, should not cause any health problems.
Questions and remarks.
1. It is a major question, whether or not a 15-min stay in a 0.29 ppm (V/V) ClO
2
atmosphere is
enough to inactivate the viruses present? Regarding the wet atmosphere we can assume that
the viruses are also wet, or even that they can be found in small water droplets containing
0.025 ppm (m/m) ClO
2
. We have no direct data for the inactivating time of viruses in such a
solution, but we have an estimated 15 ±5 s killing time value for an E. coli bacterium in a
0.25 ppm (m/m) ClO
2
solution [2]. It is reasonable to assume that the killing time would be
10 times longer in a 10 times more dilute solution, i.e., 150 s 52.5 min. As viruses are
probably inactivated faster than bacteria, and 15 min is six times longer than the estimated
2.5 min for E. coli, such a method can be successful, at least in theory.
2. To test such a method, we suggest constructing special disinfecting rooms with larger vol-
ume. Starting such experiments would be highly desirable, because this method could be an
effective nonspecic defense against all types of viruses and could help to contain viral
outbreaks.
Local prevention. Personal disinfection techniques against viral infections
Disinfection of the mouth and the upper respiratory track with gargling. The current epidemic
coronavirus is known to be present in the mouth and both in the upper and lower respiratory tract,
but causes severe infections only in the lower respiratory tract, especially in the lung. The incu-
bation period of the disease is several days, but the virus can often be detected in samples taken
from the upper respiratory tract a few days before symptoms appear. As discussed in a previous
chapter, chlorine dioxide will certainly inactivate the virus. With gargling, the upper respiratory
tract is accessible except for the nasal cavity, but that is also accessible using e.g. nose drops or
impregnated tampons. These parts can be disinfected by rinsing them regularly with high-purity
chlorine dioxide solutions available commercially [31], thus the number of the viruses can be
signicantly reduced in the mouth and in the upper respiratory tract. We cannot be sure that such a
treatment would be enough to prevent the development of the illness, as viruses living in other parts
of the body can survive. However, inactivating part of the viruses with such a treatment surely helps
theimmunesystemtoght against the disease. In this respect, it is interesting to remark that
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Japanese researchers have proven [26] that regular gargling with drinking water has reduced the
incidence of upper respiratory tract infections to a statistically signicant extent. The effect was
explained by the fact that the drinking water used in the experiments contained 0.5 mg/L of
chlorine, which was used to disinfect the water. We remark here, that in certain places chlorine
dioxide is applied for the disinfection of drinking water instead of chlorine.
Disinfection of the lower respiratory track. The first problem is how ClO
2
can be safely
introduced into the lower respiratory tract. For this purpose any inhalation technique could be
applied using aerosols of water droplets containing ClO
2
[14].
The second and more important problem is how much ClO
2
can be inhaled without damaging
the lung? It would be helpful to know the dose of ClO
2
that is not yet harmful for the lung. To our
knowledge such direct data are not available in the literature, but can be calculated from other
data. The starting point for such a calculation is the OSHA STEL value [30], according to which
0.30 ppm ClO
2
in the workplace atmosphere is tolerable for a 15 min period without any damage.
The volume of air inhaled by a worker during 15 min is 15 times the so-called minute volume
ventilation[32]. According to Table 3 of ref. [32], during light activities e.g., when sitting in a car
the minute volume is around 12 L, thus the total inhaled air is about 180 L. In the case of 0.30 ppm
concentration the total inhaled amount of ClO
2
is 54
m
L, which is (at 20 8C) 2.25
m
mol 0.15 mg
ClO
2
. Assuming a more vigorous activity it can be two times more, 0.30 mg.
This rough calculation indicates that approximately this is the amount of ClO
2
,whichcanbe
tolerated by the lung. The OSHA limit probably applied high safety factors, thus the real limit should be
higher.
We suggest that animal experiments should be performed to obtain experimental values for
the pulmonary toxicity of ClO
2
. Furthermore, it would be important to check in additional
animal experiments, whether ClO
2
applied in a nontoxic amount is able to treat infections of the
lung caused by bacteria or viruses.
CONCLUSION
In this editorial, we summarized the unique properties of chlorine dioxide, which make it an
ideal and nonspecific antimicrobial agent at concentrations harmless to humans, and we
reviewed previous research on preventing viral infections with gaseous ClO
2
. Based on this
background, we suggested some novel hypothetical methods using chlorine dioxide to disinfect
rooms, prevent human infection, and slow down viral spread. These are nonspecic methods,
which could be used against any newfound virus as a rst line of protection until effective
specic countermeasures are developed.
Conflict of interest: Zolt
an Noszticzius, Maria Wittmann and Krist
of K
aly-Kullai are co-in-
ventors of the European patent 2069232 Permeation method and apparatus for preparing uids
containing high purity chlorine dioxide. Zolt
an Noszticzius is a founder and owner of the
Solumium Ltd (a company producing chlorine-dioxide), while Krist
of K
aly-Kullai is its payed
employee.
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International License (https://creativecommons.org/licenses/by/4.0/),which permits unrestricted use, distribution, and
reproduction in any medium, provided the original author and source are credited, a link to the CC License is provided, and changes
if any are indicated. (SID_1)
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... Because most disinfectants come into direct contact with objects used daily, the complete removal of the disinfection agent is sometimes not achieved [5,6]. As a solution to these shortcomings, chlorine dioxide (ClO 2 ) gas is a type of disinfectant that has recently attracted attention [7][8][9][10]. ClO 2 gas is already known for its excellent effects on deodorization [11], sterilization, or inhibition of viral amplification [8,[12][13][14]. ...
... As a solution to these shortcomings, chlorine dioxide (ClO 2 ) gas is a type of disinfectant that has recently attracted attention [7][8][9][10]. ClO 2 gas is already known for its excellent effects on deodorization [11], sterilization, or inhibition of viral amplification [8,[12][13][14]. It is safe and has eco-friendly properties, such as easy decomposition by light and cost-effectiveness. ...
... Therefore, ClO 2 gas has been widely used for the disinfection of various medical apparatus. It can suppress the growth of various microorganisms in the surrounding environment without being applied directly to the object's surface [8,13,15]. Thus, gas-type ClO 2 can be used as an ideal disinfectant that can be applied in daily life at low concentrations. However, practically, its use has been limited due to technical difficulties in maintaining a constant concentration of ClO 2 gas for evaporation [14]. ...
Article
Full-text available
Since the onset of the COVID-19 pandemic, there has been a growing demand for effective and safe disinfectants. A novel use of chlorine dioxide (ClO2) gas, which can satisfy such demand, has been reported. However, its efficacy and safety remain unclear. For the safe use of this gas, the stable release of specific concentrations is a must. A new type of ClO2 generator called Dr.CLOTM has recently been introduced. This study aimed to investigate: (1) the effects of Dr.CLOTM on inhibiting adenoviral amplification on human bronchial epithelial (HBE) cells; and (2) the acute inhalation safety of using Dr.CLOTM in animal models. After infecting HBE cells with a recombinant adenovirus, the inhibitory power of Dr.CLOTM on the virus was expressed as IFU/mL in comparison with the control group. The safety of ClO2 gas was indirectly predicted using mice by measuring single-dose inhalation toxicity in specially designed chambers. Dr.CLOTM was found to evaporate in a very constant concentration range at 0–0.011 ppm/m3 for 42 days. In addition, 36–100% of adenoviral amplification was suppressed by Dr.CLOTM, depending on the conditions. The LC50 of ClO2 gas to mice was approximately 68 ppm for males and 141 ppm for females. Histopathological evaluation showed that the lungs of female mice were more resistant to the toxicity from higher ClO2 gas concentrations than those of male mice. Taken together, these results indicate that Dr.CLOTM can be used to provide a safe indoor environment due to its technology that maintains the stable concentration and release of ClO2 gas, which could suppress viral amplification and may prevent viral infections.
... At 37 • C, the value of the distribution constant is K θ = 0.053 and the molar volume is V m = 25.45 dm 3 /mol. The k constant is derived from the conversion of the units and its value is k = 1 × 10 6 [27]. To evaluate the chlorine dioxide production of the samples the following measurements were carried out: ...
... Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/nano12091481/s1, Equations (S1)-(S3): Chlorine dioxide production via the chlorite ion-acid system, Table S1: [ClO 2 ] g (M)/[ClO 2 ] aq (M) distribution constant (K θ ) at different temperatures, Figure S1: Distribution constant at different temperatures along with the fitted polynomial equation [27,31]. ...
Article
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Background: Preventing infectious diseases has become particularly relevant in the past few years. Therefore, antiseptics that are harmless and insusceptible to microbial resistance mechanisms are desired in medicine and public health. In our recent work, a poly(ethylene oxide)-based nanofibrous mat loaded with sodium chlorite was formulated. Methods: We tested the chlorine dioxide production and bacterial inactivation of the fibers in a medium, modeling the parameters of human exhaled air (ca. 5% (v/v) CO2, T = 37 °C, RH > 95%). The morphology and microstructure of the fibers were investigated via scanning electron microscopy and infrared spectroscopy. Results: Smooth-surfaced, nanoscale fibers were produced. The ClO2-producing ability of the fibers decreased from 65.8 ppm/mg to 4.8 ppm/mg with the increase of the sample weight from 1 to 30 mg. The effect of CO2 concentration and exposure time was also evaluated. The antibacterial activity of the fibers was tested in a 24 h experiment. The sodium-chlorite-loaded fibers showed substantial antibacterial activity. Conclusions: Chlorine dioxide was liberated into the gas phase in the presence of CO2 and water vapor, eliminating the bacteria. Sodium-chlorite-loaded nanofibers can be sources of prolonged chlorine dioxide production and subsequent pathogen inactivation in a CO2-rich and humid environment. Based on the results, further evaluation of the possible application of the formulation in face-mask filters as medical devices is encouraged.
... There are disinfection methods that used sprayed ClO 2 solutions to achieve faster dispersion without reaching limit values, 0.1 ppm TWA and 0.3 ppm STEL. 105 Evidence in COVID- 19. The presence of SARS CoV-2 in the mouth and upper and lower respiratory tract leads to the biological plausibility that disinfection of the nasal and oral cavity through direct application of ClO 2 could decrease the viral load. ...
... The FDA has received reports of ventricular arrythmia, methemoglobinemia, hemolytic anemia associated with liver dysfunction, and diarrhea when oral products are ingested. 105 Safety and monitoring. To date, The Pan American Health Organization (PAHO) does not recommend the use of chlorine dioxide or sodium chlorite by oral or parenteral route in patients with suspected or diagnosed with COVID- 19. ...
Article
Full-text available
During the COVID-19 pandemic, the behavior of self-medication has increased. The dissemination of misleading information regarding the efficacy of certain drugs or substances for the prevention and treatment of COVID-19 has been the major contributing factor for this phenomenon. Alongside with the increase in self-medication behavior, the inherent risks to this act such as drug–drug interactions, adverse events, drug toxicity, and masking of symptoms have also increased. Self-medication in the context of COVID-19 has led to drug misuse leading in some cases to the development of fatal adverse drug reactions. It is important that during this ongoing pandemic drugs with potential clinical efficacy against COVID-19 are adequately analyzed regarding their efficacy, safety, and monitoring. The aim of this review is to describe the available evidence regarding the efficacy, safety, and monitoring of the drugs and substances that have been shown to be frequently used for self-medication in patients with COVID-19 (hydroxychloroquine, non-steroidal anti-inflammatory drugs, ivermectin, azithromycin, vitamins, aspirin, and chlorine dioxide) to adequately characterize their risks, safe use, monitoring strategies, and to reinforce the concept that these substances should not be used for self-medication and require a medical prescription. Plain Language Summary Drug safety of frequently used drugs and substances for self-medication in COVID-19 Dissemination of information about potential COVID-19 treatments has led individuals to self-medicate and expose themselves to risks such as drug–drug interactions, side effects, antibiotic resistance, and misdiagnosis. There is a need to review the medical literature to evaluate the safety and efficacy of the drugs and substances commonly used by the population for the treatment and prevention of SARS CoV-2 infection. In this review, we included drugs that are frequently used for self-medication and commonly advertised such as ivermectin, hydroxychloroquine, chlorine dioxide, azithromycin, and non-steroidal anti-inflammatory drugs, among others. A brief introduction of the drug and its mechanism of action, followed by a summary of the efficacy in COVID-19 and safety, will be described for each drug in order to promote their responsible use.
... Chlorine dioxide is a greenish-yellowish gas, and it is known to be highly effective at alkaline pH [15]. Although this compound is a gas, it is highly soluble in water [16]. Chlorine dioxide has many applications in numerous fields, such as water or wastewater treatment, bleaching, environmental and food disinfection, and sterilization of medical devices. ...
... The study indicates that health misinformation on social media is associated with greater exposure to household cleaners, including bleaching agents [29]. Also, the access to concentrated formulations of chlorine derivatives has increased in recent years due to unsupported claims of efficacy in preventing and treating several medical conditions, now including COVID-19 [16,30]. ...
Article
Full-text available
COVID-19 pandemic is one of the most devastating worldwide crises in recent years. During this pandemic, people have been exposed to products that have not been proven to be safe and effective against COVID-19. We present an adult chronic consumer of chlorine dioxide, in which a fatal outcome is described. This case demonstrates that for people searching products to protect themselves from COVID-19, unregulated access to industrial disinfectants represents a dangerous alternative. To date, there is no scientific evidence to uphold the use of chlorine dioxide or chlorine derivatives as preventive or therapeutic agents against COVID-19. Researchers and general population must take into consideration the fatal possible consequences of not following communications and warnings from health authorities and government institutions.
... This could be attributed to the less complex structure of viruses compared to bacteria. Chlorine oxide gas acts on the genome of the non-enveloped viruses, whereas in enveloped viruses, it interacts with one or more of the cysteine, tyrosine, and tryptophan amino acid residues of the spike proteins as it does not need to invade the enclosed viral surface (Noss et al., 1986;Noszticzius et al., 2013;Kály-Kullai et al., 2020). Factors that have significant effects on the inactivation rates of viruses using ClO 2 include dosage, time, pH, and temperature (Berman and Hoff, 1984). ...
Article
Full-text available
Water contamination is a global health problem, and the need for safe water is ever-growing due to the public health implications of unsafe water. Contaminated water could contain pathogenic bacteria, protozoa, and viruses that are implicated in several debilitating human diseases. The prevalence and survival of waterborne viruses differ from bacteria and other waterborne microorganisms. In addition, viruses are responsible for more severe waterborne diseases such as gastroenteritis, myocarditis, and encephalitis among others, hence the need for dedicated attention to viral inactivation. Disinfection is vital to water treatment because it removes pathogens, including viruses. The commonly used methods and techniques of disinfection for viral inactivation in water comprise physical disinfection such as membrane filtration, ultraviolet (UV) irradiation, and conventional chemical processes such as chlorine, monochloramine, chlorine dioxide, and ozone among others. However, the production of disinfection by-products (DBPs) that accompanies chemical methods of disinfection is an issue of great concern due to the increase in the risks of harm to humans, for example, the development of cancer of the bladder and adverse reproductive outcomes. Therefore, this review examines the conventional disinfection approaches alongside emerging disinfection technologies, such as photocatalytic disinfection, cavitation, and electrochemical disinfection. Moreover, the merits, limitations, and log reduction values (LRVs) of the different disinfection methods discussed were compared concerning virus removal efficiency. Future research needs to merge single disinfection techniques into one to achieve improved viral disinfection, and the development of medicinal plant-based materials as disinfectants due to their antimicrobial and safety benefits to avoid toxicity is also highlighted.
... Under these conditions, ClO 2 is relatively stable and retains its high oxidizing power [5]. ACD can efficiently remove bacteria, fungi, and viruses in the environment [7][8][9][10][11][12]. In contrast, higher concentrations of ClO 2 are harmful to human cells (IC 50 765 ± 18 ppm) [10]. ...
Article
Full-text available
Chlorine dioxide is a safe, environmentally friendly disinfecting agent. In this study, aqueous chlorine dioxide (ACD) was used to improve the water quality of dental chairs. However, chlorine dioxide is readily released from ACD solutions under open atmosphere conditions. Described herein is a water purification and disinfection system using ACD. The system was designed, fabricated, and integrated into an existing dental chair water system. This system is referred to as an ACD dental chair. Because ClO2 readily degasses from ACD, there needs to be a way to maintain and measure the ACD solution in real time. In our studies, we found that pH and oxidation-reduction potential (ORP) change as a function of chlorine dioxide concentration and are easily controlled and measured. The dosing of the ACD was designed to begin at 800 mV and stop dosing at 810 mV in the ACD dental chair. Through use of this continuous monitoring and automatic dosing system, the water ORP was controlled between 800 and 860 mV. This range is the effective concentration of chlorine dioxide that is without chlorine-like odor and microorganism growth. The ACD dental chair controlled the total bacterial count to <5 CFU/mL and the chlorite concentration was less than 0.0004 mg/L, meeting legal standards of Taiwan, the USA, and China. In addition to the application of ACD in dental chairs, it may also be used in closed water systems for food, cosmetics, beverages, and other industries.
... Chlorine dioxide is a chemical compound that occurs as a highly reactive gas, so it is generally marketed and used in its liquid form or solution known as CDS (chlorine dioxide solution) [4]. Due to its strong oxidizing power, chlorine dioxide and its derivatives are used as disinfectant agents in different industrial processes [5]; however, during the pandemic, it has been promoted as an alternative for the prevention and treatment of COVID-19, whose use has been reported by inhalation, oral and parenteral application [6]. ...
Article
Full-text available
Background Chlorine dioxide has been promoted as an alternative for the prevention and treatment of COVID-19, especially in Peru, despite the lack of evidence to support its efficacy. This study aimed to evaluate the factors associated with chlorine dioxide consumption in the Peruvian population. Methods Analytical cross-sectional study. An adult Peruvian population was evaluated where chlorine dioxide consumption was divided into two groups according to the purpose of use: as prevention (individuals without COVID-19 history) and as treatment (individuals with COVID-19 history). The associated factors in each group were evaluated using Poisson regressions with the bootstrapping resampling method. Results Of 3610 participants included, 3213 reported no history of COVID-19, and 397 had been infected. The prevalence of chlorine dioxide consumption to prevent or treat COVID-19 was 8 and 16%, respectively. Factors either positively or negatively associated with chlorine dioxide consumption for prevention were male sex (aPR: 1.36; 95% CI: 1.09–1.71), being an adult or older adult (aPR: 0.54; 95% CI: 0.35–0.82), having a health sciences student within the family unit (aPR: 1.38; 95% CI: 1.02–1.87), using medical information as the main source of information of COVID-19 (aPR: 0.57; 95% CI: 0.40–0.80), having comorbidities for COVID-19 (aPR: 1.36; 95% CI: 1.01–1.82), considering COVID-19 dangerous and deadly (aPR: 0.57; 95% CI: 0.45–0.74), using medications (aPR: 1.59; 95% CI: 1.25–2.06) and plants to prevent COVID-19 (aPR: 1.69; 95% CI: 1.21–2.36), considering chlorine dioxide ineffective (aPR: 0.18; 95% CI: 0.18–0.24), and being uninformed of its efficacy (aPR: 0.21; 95% CI: 0.16–0.28). In addition, factors associated with chlorine dioxide consumption for treatment were considering COVID-19 dangerous and deadly (aPR: 0.56; 95% CI: 0.33–0.96), considering chlorine dioxide ineffective (aPR: 0.22; 95% CI: 0.12–0.42), and being uninformed of its efficacy (aPR: 0.15; 95% CI: 0.07–0.32). Conclusions The prevalence of chlorine dioxide consumption to treat COVID-19 was higher than prevent. It is important to apply information strategies, prioritizing population groups with certain characteristics that are associated with a higher consumption pattern.
... In the last decades, drinking water treatments and industrial processes increase the use of ClO 2 , which replaces other chlorine disinfectants [2,3]. Several studies determined that the consumption of ClO 2 solutions is a preventive and therapy tool against different viral human infections, such as HIV/AIDS [4,5]. The occurrence of ClO 2 had an exponential increase in surface water during the last two years due to its use as treatment and preventive therapy against SARS-CoV-2 [6,7]. ...
Article
Full-text available
Objective The use of chlorine dioxide (ClO2) increased in the last year to prevent SARS-CoV-2 infection due to its use as disinfectant and therapeutic human treatments against viral infections. The absence of toxicological studies and sanitary regulation of this contaminant represents a serious threat to human and environmental health worldwide. The aim of this study was to evaluate the acute toxicity and sublethal effects of ClO2 on tadpoles of Trachycephalus typhonius, which is a common bioindicator species of contamination from aquatic ecosystems.Materials and methodsMedian lethal concentration (LC50), the lowest-observed effect concentration (LOEC), and the no-observed effect concentration (NOEC) were performed. Acetylcholinesterase (AChE) and glutathione-S-transferase (GST) activities, swimming behavior parameters, and cardiac rhythm were estimated on tadpoles of concentrations ≤ LOEC exposed at 24 and 96 h. ANOVA and Dunnett’s post-hoc comparisons were performed to define treatments significance (p ≤ 0.05).ResultsThe LC50 of ClO2 was 4.17 mg L−1 (confidence limits: 3.73–4.66). In addition, NOEC and LOEC values were 1.56 and 3.12 mg L−1 ClO2, respectively, at 48 h. AChE and GST activities, swimming parameters, and heart rates increased in sublethal exposure of ClO2 (0.78–1.56 mg L−1) at 24 h. However, both enzyme activities and swimming parameters decreased, whereas heart rates increased at 96 h.Conclusion Overall, this study determined that sublethal concentrations of ClO2 produced alterations on antioxidant systems, neurotoxicity reflected on swimming performances, and variations in cardiac rhythm on treated tadpoles. Thus, our findings highlighted the need for urgent monitoring of this chemical in the aquatic ecosystems.Graphical abstract
... bleach) are commonly used for cleaning surfaces and to prevent the spread of SARS-CoV-2. The mechanism of chlorine dioxide against CoVs is based on the denaturation of some proteins, such as tryptophan and tyrosine and cysteine residues and when chlorine dioxide reacts with them the virus inactivation results very rapid (Ogata, 2007;Kály-Kullai et al., 2020). Wang et al. (2005aWang et al. ( , 2005b investigated the effect of sodium hypochlorite (NaClO) and chlorine dioxide (ClO 2 ) at various concentrations (5-40 mg/L) and contact times on the inactivation of SARS-CoV-1 in wastewater and other matrices. ...
Article
The fate of Coronaviruses (CoVs) and in particular SARS-CoV-2 in wastewater treatment plants (WWTPs) has not been completely understood yet, but an adequate knowledge on the removal performances in WWTPs could help to prevent waterborne transmission of the virus that is still under debate. CoVs and SARS-CoV-2 are discharged from faeces into the sewer network and reach WWTPs within a few hours. This review presents the fate of SARS-CoV-2 and other CoVs in the primary, secondary and tertiary treatments of WWTPs as well as in sludge treatments. The viral loads decrease progressively along with the treatments from 20 to 3.0E+06 GU/L (Genomic Units/L) in the influent wastewater to concentrations below 2.50E+05 GU/L after secondary biological treatments and finally to negative concentrations (below detection limit) in disinfected effluents. Reduction of CoVs is due to (i) natural decay under unfavourable conditions (solids, microorganisms, temperature) for relatively long hydraulic retention times and (ii) processes of sedimentation, filtration, predation, adsorption, disinfection. In primary and secondary settling, due to the hydrophobic properties, a partial accumulation of CoVs may occur in the separated sludge. In secondary treatment (i.e. activated sludge) CoVs and SARS-CoV-2 loads can be reduced only by about one logarithm (∼90%). To enhance this removal, tertiary treatment with ultrafiltration (Membrane Bioreactors) and chemical disinfection or UV light is needed. CoVs and SARS-CoV-2 in the sludge (1.2E+04–4.6E+08 GU/L) can be inactivated significantly in the thermophilic digestion (55 °C), while mesophilic temperatures (33–37 °C) are not efficient. Additional studies are required to investigate the infectivity of SARS-CoV-2 in WWTPs, especially in view of increasing interest in wastewater reclamation and reuse.
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This study evaluated the inactivation of SARS-CoV-2, the virus responsible for COVID-19, by ozone using virus grown in cell culture media either dried on surfaces (plastic, glass, stainless steel, copper, and coupons of ambulance seat and floor) or suspended in liquid. Treatment in liquid reduced SARS-CoV-2 at a rate of 0.92±0.11 log10-reduction per ozone CT dose(mg.min/L); where CT is ozone concentration times exposure time. On surface, the synergistic effect of CT and relative humidity (RH) was key to virus inactivation; the rate varied from 0.01 to 0.27 log10-reduction per ozone CT value(g.min/m³) as RH varied from 17% to 70%. Depletion of ozone by competitive reactions with the medium constituents, mass transfer limiting the penetration of ozone to the bulk of the medium, and occlusion of the virus in dried matrix were postulated as potential mechanisms that reduce ozone efficacy. RH70% was found plausible since it provided the highest disinfection rate while being below the critical RH that promotes mould growth in buildings. In conclusion, through careful choice of (CT, RH), gaseous ozone is effective against SARS-CoV-2 and our results are of significance to a growing field where ozone is applied to control the spread of COVID-19.
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