Elucidating mechanisms of chlorine toxicity: reaction kinetics,
thermodynamics, and physiological implications
Giuseppe L. Squadrito,1,2Edward M. Postlethwait,1,2and Sadis Matalon2,3
1Department of Environmental Health Sciences, School of Public Health,2The Centers for Free Radical Biology
and Pulmonary Injury and Repair, and3Department of Anesthesiology, School of Medicine, University of Alabama
at Birmingham, Birmingham, Alabama
Submitted 9 March 2010; accepted in final form 2 June 2010
Squadrito GL, Postlethwait EM, Matalon S. Elucidating mechanisms of
chlorine toxicity: reaction kinetics, thermodynamics, and physiological implica-
tions. Am J Physiol Lung Cell Mol Physiol 299: L289–L300, 2010. First published
June 4, 2010; doi:10.1152/ajplung.00077.2010.—Industrial and transport accidents,
accidental releases during recreational swimming pool water treatment, household
accidents due to mixing bleach with acidic cleaners, and, in recent years, usage of
chlorine during war and in acts of terror, all contribute to the general and elevated
state of alert with regard to chlorine gas. We here describe chemical and physical
properties of Cl2 that are relevant to its chemical reactivity with biological
molecules, including water-soluble small-molecular-weight antioxidants, amino
acid residues in proteins, and amino-phospholipids such as phosphatidylethano-
lamine and phosphatidylserine that are present in the lining fluid layers covering the
airways and alveolar spaces. We further conduct a Cl2penetration analysis to assess
how far Cl2 can penetrate the surface of the lung before it reacts with water or
biological substrate molecules. Our results strongly suggest that Cl2will predom-
inantly react directly with biological molecules in the lung epithelial lining fluid,
such as low-molecular-weight antioxidants, and that the hydrolysis of Cl2to HOCl
(and HCl) can be important only when these biological molecules have been
depleted by direct chemical reaction with Cl2. The results from this theoretical
analysis are then used for the assessment of the potential benefits of adjuvant
antioxidant therapy in the mitigation of lung injury due to inhalation of Cl2and are
compared with recent experimental results.
hypochlorite; lung epithelial lining fluid; antioxidants; exposure; therapy
THE TOXICITY OF INHALED CHLORINE (Cl2) and the treatment and
mitigation of chlorine-induced lung injury have been of interest
due to industrial and transport accidents (37, 84), accidental
releases during recreational swimming pool water treatment (5,
15, 55), and household accidents due to mixing bleach with
acidic cleaners (10, 17, 35, 46). In recent years, Cl2 has
received renewed attention because of its use during war and in
acts of terror (12). It is striking that so little attention has been
given to study the mechanism of action of Cl2, and the genesis
and development of the lung injury in terms of the chemical
reactivity of Cl2, especially when one considers the morbidity
and mortality that exposures to Cl2gas have produced and can
still produce in the future. At present, therapy for Cl2inhalation
injury consists in alleviating pulmonary symptoms (73). Only
recently, a mechanism-oriented, chemically specific approach
to prophylactic and postexposure therapy is being employed
(45, 74) wherein antioxidant replenishment as well as various
agents to restore compromised alveolar function (such as
surfactant and ion transport) are being used to counteract Cl2
toxicity and to decrease morbidity. This review represents an
attempt to elucidate the transient species generated during
exposure to Cl2 and their modes of action. We believe such
investigation will be conducive to new and improved mecha-
nism-oriented therapeutic strategies.
We here describe chemical and physical properties of Cl2
that are relevant to the chemical reactivity of Cl2with biolog-
ical molecules present in the fluid layers covering the airways
and alveolar spaces. This analysis is then used for the assess-
ment of the potential benefits of adjuvant antioxidant therapy in
the mitigation of lung injury due to inhalation of Cl2 and is
compared against recent experimental results.
The biological response to a Cl2 exposure depends on the
concentration of Cl2 and the duration of the exposure in a
manner described by the generalized Haber’s law (52). In
addition, one must consider individual susceptibility and that
the injury will progressively extend to more distal sites as Cl2
concentrations increase (8, 57). Chlorine more rapidly damages
the wet mucosal tissues and thus it seems appropriate to first
discuss the aqueous solubility of Cl2 and its reaction with
water. It is interesting to note that histopathological analysis
may not reveal the true extent of tissue injury compared with
the results from physiological and biochemical analyses [e.g.,
bronchoalveolar lavage protein (45), surfactant function (45),
Address for reprint requests and other correspondence: G. L. Squadrito,
Dept. of Environmental Health Sciences, School of Public Health, RBPH 530,
1530 3rd Ave. South, Univ. of Alabama at Birmingham, Birmingham, AL
35294-0022 (e-mail: firstname.lastname@example.org).
Am J Physiol Lung Cell Mol Physiol 299: L289–L300, 2010.
First published June 4, 2010; doi:10.1152/ajplung.00077.2010.
1040-0605/10 Copyright © 2010 the American Physiological Societyhttp://www.ajplung.orgL289
antioxidant levels (45), and sodium-dependent transport (74)]
that suggest underlying injury may be more serious than
histopathological analysis alone would suggest.
The Solubility of Chlorine in Water
At ambient temperature, Cl2is an oxidant gas that is mod-
erately soluble in water, being approximately five times more
soluble than are ozone (O3) or nitrogen dioxide (NO2), two
common oxidant gases of much environmental interest (2, 14,
31, 70, 75). However, Cl2rapidly reacts with water, contrasting
sharply with O3and NO2in this regard. Because of the high
reactivity of Cl2 toward water, reactive uptake of Cl2 by
aqueous solutions is favored relative to other oxidant gases,
such as O3 and NO2, that do not react with water under
physiologically relevant conditions to any significant extent.
Thus, it becomes important to distinguish between the physical
solubility and the reactive absorption of Cl2.
The Reaction of Chlorine With Water
Chlorine reacts with water according to Eq. 1:
HOCl? H?? Cl?
KH2O? 1.8? 10?3M2
The reaction of Cl2with water is not a benign reaction that
merely scavenges Cl2 as it penetrates the aqueous milieu.
Although Eq. 1 partially destroys Cl2, it results in the formation
of hypochlorous acid (HOCl), yet another powerful oxidant,
and the strong acid hydrochloric acid (HCl). HOCl is a weak
acid with pKa? 7.54 at 25°C and pKa? 7.45 at 37°C (53); for
the surface of the lung, where the pH ? 7.0, ?74% of the
hypochlorite would exist as HOCl and 26% as OCl?, if
equilibrium was achieved.
The value for equilibrium constant KH2Ofor Eq. 1 is small
and is somewhat deceptive because it may suggest the equi-
librium will lie to the left of Eq. 1. However, when one
considers that pH ? 7.0 and [Cl?] ? 0.1 M for the surface of
the lung, and that these values will remain relatively un-
changed as a result of Cl2exposures, one determines: [HOCl]/
[Cl2] ? KH2O/[H?][Cl?] ? 1.8 ? 10?3M2/(1.0 ? 10?7
M)(0.1 M) ? 1.8 ? 105, indicating that ?99.999% of the Cl2
that is absorbed within the respiratory tract will be converted to
HOCl and OCl?, at equilibrium, and if Cl2were to react only
The reaction kinetics for the hydrolysis of Cl2is relatively
fast and was studied using stopped flow spectrophotometry
(87). Thus, using data published by Wang and Margerum (87),
and correcting for temperature effects, one can compute k1and
k?1for Eq. 1 as 61.7 s?1and 34.6 ? 10?3M?2s?1, respec-
tively, at 37°C. With these values, and assuming the pH and
[Cl?] will remain unchanged at pH ? 7.0 and [Cl?] ? 0.1 M,
respectively, a computer simulation using the software package
Gepasi v. 3.30 (50) of the reaction kinetics associated with Eq.
1 and the acid dissociation of HOCl indicates that equilibria
will be established in ?11 ms. However, as discussed shortly,
lung epithelial lining fluid (ELF; airway and alveolar) contains
high concentrations of reactive biological molecules, in partic-
ular low-molecular-weight antioxidants, which are potential
targets for reaction with Cl2and may compete with the hydro-
lysis of Cl2by reacting with Cl2before it can undergo hydro-
The toxicity of Cl2 is generally attributed to hypochlorite
formed as a result of Cl2hydrolysis according to Eq. 1 (1, 19,
26, 33, 56, 58, 89). (In this article, the term hypochlorite is used
to refer to the sum of HOCl and its conjugate base OCl?
present in prototropic equilibrium, i.e., the stoichiometric con-
centration of hypochlorite. When a discussion is specifically
limited to one of these species, its formula will be given.) The
concomitant formation of the strong acid hydrochloric acid
(HCl) is not considered important to the mechanism of Cl2
toxicity because of the large ELF buffering capacity that can,
in most cases, neutralize the acid insult. The ELF has an
appreciable bicarbonate concentration (11 mM) (48), and the
large volume of lung blood flow serves a source to resupply
buffering agents. HCl is nearly 33 times less irritating than Cl2
(7), supporting that HCl is not pivotal in the mechanism of
toxicity of Cl2.
The Direct Reaction of Cl2with Biological Molecules on the
Surface of the Respiratory Tract
Direct, fast reactions of Cl2 with biological molecules
present on the respiratory tract surfaces are possible, but
certain conditions must be met for these reactions to compete
with the rate of Cl2 hydrolysis. Once Cl2 penetrates into the
aqueous ELF, reactions of Cl2with biological molecules will
prevail when kapp? [S] ? k1? 61.7 s?1, where kappis the
apparent second order rate constant for the reaction of Cl2with
biological molecule S, at pH 7, and k1is the pseudo-first order
rate constant for the forward reaction in Eq. 1. (It becomes
necessary to employ apparent rate constants, kapp, to account
for differences in reactivities for acid and base forms of
ionizable substrates. kapprepresents the global reactivity of a
substrate S and is a function of pH and pKa. Calculations are
done at pH 7.0, which is close to the pH of the ELF. This will
be discussed in more detail below.) Thus, the ability of a
biological molecule S to compete with Cl2 hydrolysis is a
balance between its kapp (its intrinsic reactivity towards Cl2)
and its concentration in the physiological compartment where
the reactions occur. Due to the law of mass action, large values
of kappand high [S] will trend to favor reaction of Cl2with S
over its hydrolysis. The line depicted in Fig. 1 represents the
pairs of kappand [S] for which the rate of reaction equals the
rate of Cl2hydrolysis. For a given value of kapp, any value [S]
above this line represents a scenario where the Cl2 rate of
reaction with the biological molecule S exceeds the rate of
hydrolysis. It is apparent that there are neither physical nor
biological limitations for the rate of reaction of Cl2with S to
exceed the rate of hydrolysis of Cl2. For example, for values of
kappsmaller than the limit for two species to diffuse together in
aqueous solution (?1 ? 1010M?1s?1) but larger than 1 ? 105
M?1s?1, the minimum required [S] for reaction to compete
with hydrolysis will vary between ?6 nM and 0.6 mM. This
range of concentrations for biological molecules is not partic-
ularly unusual in a fluid like the lung ELF. It appears we are the
first to consider that direct reaction of Cl2 with biological
molecules may indeed occur on the surface of the respiratory
tract (for the current and contrasting view, see, for example,
Refs. 1, 19, 26, 33, 56, 58, 89).
MECHANISMS OF Cl2 TOXICITY
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