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Ocular Toxicology in Military and Civilian Disaster Environments

  • Derek L. Eisnor
  • Brent W. Morgan
Chapter
  • 153 Downloads

Abstract

The eye is vulnerable to chemical exposure from both external contact and systemic (vascular) absorption. The vast majority of CW exposures occur through external contact and the potential for penetration into the eye. For this reason, all parts of the eye can be affected by chemicals, the limitations mainly subject to the pharmacokinetics of a particular agent.

Keywords

Ocular toxicology Military disaster Civilian disaster 

Introduction

Visual proficiency is essential to the efficient function of any soldier in theater. Chemical injuries to the eye are true emergencies that necessitate prompt recognition and effective treatment.

The use of chemical weapons (CW) in warfare is well documented throughout history, but not until the industrial revolution did the mass production and deployment of chemical agents become a reality. Most would consider the Germans’ effective use of chlorine gas at Ypres, Belgium, in 1915 as the birth of modern chemical warfare. The use of these chemicals including phosgene, sulfur mustard, and lewisites caused nearly 100,000 deaths and over 1 million casualties during World War I (WWI) [1]. Building on the Versailles Treaty of 1919, the Geneva Gas Protocol of 1925 restated the prohibitions previously laid on the wartime use of chemical weapons and added a ban on bacteriological warfare. The United States finally ratified the Geneva Gas Protocol in 1975. In April of the same year, President Ford signed an executive order to prohibit the use of riot control agents (RCAs) in war, except in defensive modes to save lives. Today, dispersal is only allowed in US military operations by presidential order.

In April 1997, the world’s first multilateral chemical disarmament Treaty (Chemical Weapons Convention) went into force [2]. Headquartered in Hague, the Organization for the Prohibition of Chemical Weapons (OPCW) is an independent, autonomous international organization with over 500 staff members. As of today OPCW has 190 Member States working toward a collective goal of preventing the use of chemical weapons, thereby strengthening international security. To this end, the Convention contains four key provisions:
  1. 1.

    Destroying all existing chemical weapons under international verification by the OPCW

     
  2. 2.

    Monitoring chemical industry to prevent new weapons from re-emerging

     
  3. 3.

    Providing assistance and protection to States Parties against chemical threats

     
  4. 4.

    Fostering international cooperation to strengthen implementation of the Convention and promote the peaceful use of chemistry [2]

     

The treaty requires member signatories to destroy existing chemical agents and chemical weapon production facilities under its jurisdiction. Key components of the treaty include strict inspection and verification of compliance, as well as provisions for protection and force assistance from State Parties if needed.

Despite these efforts, humanity will continue to suffer the malicious use of chemical agents. The ubiquitous presence of toxic chemicals in today’s society, and the ability to effectively weaponize many of these agents, makes them particularly attractive to terrorists. Yet the development of RCAs with improved safety profiles allows for effective and humane riot control measures by police, with little or no resultant morbidity to civilians. The answer lies in ongoing research, not only to better our understanding of these agents but also to address possible future threats. It is essential that medical personnel are familiar with the systemic and ocular effects of chemical exposures, as well as their specific treatments.

“Amat Victoria Curam.”

Ocular Anatomy and Pharmacology

The eye is vulnerable to chemical exposure from both external contact and systemic (vascular) absorption. The vast majority of CW exposures occur through external contact and the potential for penetration into the eye. For this reason, all parts of the eye can be affected by chemicals, the limitations mainly subject to the pharmacokinetics of a particular agent.

After contact with the outer surface of the eye, many factors determine the extent of damage and penetration into deeper structures. The first site of contact is the tear film, a three-layered structure of alternating hydrophobic and hydrophilic areas. The outermost area is a thin (0.2 μm) layer of lipids secreted by the meibomian glands. This covers the intermediate aqueous layer (0.5 μm), which is maintained by the lacrimal glands. The deepest layer is a thin mucoid layer (0.1 μm) secreted by goblet cells of the conjunctiva and functions as an interface between the hydrophilic tears and the hydrophobic layer of corneal epithelial cells (Fig. 14.1).
Fig. 14.1

Three components of tear film. Dr. Philip Morgan, Tear film proteins: examining production, role and interaction with contact lenses, http://www.clspectrum.com/articleviewer.aspx?articleID=104177

At the corneal epithelium, desmosomes form tight junctions underlying a well-organized stratified squamous multicellular layer. This represents the primary barrier to xenobiotic penetration of the anterior chamber. Only relatively hydrophobic chemicals (lipid soluble) will readily pass through this layer. Below this is Bowman’s membrane, which separates the epithelium from the stroma. Much like the alternating layers of the tear film, the stroma is a hydrophilic layer comprising primarily of collagen and glycosaminoglycans. Although it may slow the absorption of lipid-soluble agents, it may also act as a reservoir for water-soluble chemicals, which may prolong damage to these structures (Fig. 14.2).
Fig. 14.2

Left: Diagram of the cornea (Janice M. Epstein, New Research Using Regenerated Corneal Cells Shows Positive Results, http://blog.bostonsight.org/wp-content/uploads/2013/12/corneal_endothelium.jpg). Right: corneal endothelium under a microscope. Wikipedia. Professor Yann Gavet. Cornea endothelium specular https://fr.wikipedia.org/wiki/Fichier:Cornea_endothelium_specular.jpg

At the most proximal layer of the stroma is Descemet’s membrane, which functions as the basement membrane, secreted by the innermost layer or corneal endothelium. These specialized, mitochondria-rich cells govern fluid and solute transport across the posterior surface of the cornea.

The primary function of the corneal endothelium is to allow for “passive leak” of nutrients, solutes, and glucose from the aqueous to the more superficial structures of the cornea and stroma. At the same time, the endothelium actively pumps water back out from the stroma into the aqueous. This is required to maintain the cornea in the slightly dehydrated state that is required for optical transparency. These processes are heavily dependent on functioning Na/K/ATPase transport mechanisms and the enzymatic activity of carbonic anhydrase.

Damage to limbus structures can lead to limbal stem cell deficiency (LSCD). These progenitor cells function to replace corneal epithelial cells and form a barrier to encroachment by conjunctival epithelium (Fig. 14.3). Loss of function leads to chronic inflammation, scarring, and corneal opacification [3].
Fig. 14.3

Schematic representation of corneal epithelial cells. (Kayama et al. [203], Copyright © 2007 Dove Medical Press Limited. Open access)

Since corneal endothelial cells are postmitotic and rarely divide, damage to the corneal endothelium results in healing via lateral spread and enlargement of adjacent endothelial cells. In severe cases, there is a loss of cellular architecture, leading to irregular cell size and shape variations (polymegathism). This is also accompanied by corneal edema, which disrupts regular spacing between stromal collagen fibrils and causes surface irregularities in the epithelium. The resulting light scatter causes decreased visual function. Further damage leads to neovascularization, chronic keratitis, and recurrent corneal scarring, causing long-term visual loss. Although typical of blister agents, these injury patterns have been described with higher concentrations of RCAs [4].

Blood supply to the eye comes from the ophthalmic artery (OA), which arises as the first branch off the internal carotid artery (ICA). Branches of the OA can be subdivided into two groups: an orbital group, which includes the lacrimal artery, supplying the orbit, adnexa and surrounding structures, and an ocular group, supplying the muscles and bulb of the eye. The retina has dual arterial supply from both choroidal and retinal vessels. There are tight junctions within the retinal endothelium that function much like those that form the blood-brain barrier in cerebral capillaries. However, at the optic disk, these junctions are lacking, and therefore, hydrophilic molecules can enter the optic nerve by diffusion from the extravascular space [5]. This also represents an area where substances may penetrate into the CNS. The outer retina consists of the retinal pigment epithelium (RPE), rod and cone outer and inner segments, and the outer photoreceptor nuclear layer. This portion of the retina is supplied by the choriocapillaries of the posterior ciliary arteries. These vessels do not possess tight junctions and are highly permeable to large proteins such as albumin [6].

Systemic exposure to chemicals results in distribution to all parts of the eye via uveal and retinal blood vessels. As mentioned above, due to lack of tight junctions, the outer retina and RPE are highly susceptible to hydrophilic molecules less than 200 daltons, which can cross the ciliary and iris capillaries and diffuse into the aqueous humor [6]. This represents the most likely target site for xenobiotic-induced retinal injury.

Melanin is synthesized from tyrosine in melanocytes. In addition to providing pigmentation (eumelanin) for skin, hair, and eyes, melanin is capable of binding chemicals and acts as a buffer against oxidative injury. Melanin has a high binding affinity for heavy metals, aromatic hydrocarbons, and free radicals. Binding to and buffering of harmful agents may limit potential damage at cellular receptor sites. However, the same mechanism may lead to the accumulation and slow release of chemicals, resulting in chronic toxicity [7]. The retinotoxic drug chloroquine accumulates in very high concentrations in the choroid, RPE, iris, and ciliary body due to its affinity for melanin [8].

The retina is a multilayered structure that occupies the inner lining of the posterior globe. The retina and optic nerve developmentally are considered part of the CNS [9]. Visual images transmitted from the cornea and lens are projected onto the retina, initiating a series of neurochemical events leading to the transmission of neural impulses from retinal ganglion cells across the optic nerve to the brain.

Interpretation of light stimulus is mediated by two main groups of specialized photoreceptive neurons: rods and cones. Below a certain luminescent level, night vision (scotopic) is mediated by rods. At higher luminescent levels, cones provide predominant function over daylight (photopic) vision. The range where two mechanisms are working together is called the mesopic range.

The retina comprises many layers of specialized cell types. From anterior to posterior orientation, first is the basement membrane formed by Muller cells, which help separate the nerve fiber layer from the ganglion (nerve cell bodies) layer. Beyond this are the inner nuclear and outer plexiform layers, which synapse with the dendrites of bipolar cells (which transmit signals from photoreceptors and pass on to ganglion cells). Finally, the outer nuclear layer, which contains the photoreceptor cell bodies (rods and cones) and the external limiting membrane (separates the photoreceptor layer from their cell bodies). Last or innermost is the rod/cone photoreceptor layer and the retinal pigmented epithelium (RPE). It is counterintuitive how light must pass through several outer layers to reach the photoreceptor layer.

The optic disc (at the optic papilla) is where optic nerve fibers leave the eye and is devoid of photoreceptors (AKA the blind spot). Temporally opposite to this is the macula, which contains the highest density of photoreceptors. At its center is the fovea, which is responsible for sharp central vision.

Metabolism of xenobiotics occurs throughout the eye via phase I and phase II biotransformation reactions. Specific drug-metabolizing enzymes such as acetylcholinesterase, carboxylesterase, alcohol and aldehyde dehydrogenases, aldehyde and aldose reductases, superoxide dismutase, and monoamine oxidase are some of the proteases represented in the ciliary body and tears, choroid, and retina. A number of cytochrome P450 enzymes are present in various ocular tissues, and most are represented in the retina [10]. Apart from the lens, ocular tissues such as the cornea, choroid, and retina contain the most biotransformation enzymes including phase II enzymes. This is intuitive given that these tissues have high rates of metabolism and regularly interact with both lipid- and water-soluble xenobiotics and free radical forming UV radiation.

Injury Patterns

Over the last 20 years, we have extensive data of ocular injury patterns from our military efforts in the Middle East. This has led to significant advances in prehospital management of trauma patients. Apart from conventional weapons, the regular use of improvised explosive devices (IEDs) has caused devastating ocular injuries. In an observational study of ocular war injuries during the Iraqi insurgency, blast fragmentations from munitions accounted for over 80% of all injuries, and the most common single cause of injury (51%) was IEDs [11].

Explosives may be categorized as high-order (HE) or low-order explosives (LE). HE produce a defining supersonic overpressurization shock wave, and examples include TNT, C-4, Semtex, nitroglycerin, dynamite, and ammonium nitrate fuel oil (ANFO). LE create a subsonic explosion, which lacks the overpressurization wave. Examples include pipe bombs, gunpowder, and most pure petroleum-based bombs [12]. Common devices used in recent civilian incidents consist of a HE core packed in oil products and a variety of shrapnel.

Explosions cause a variety of injuries by different mechanisms. A positive phase is marked by a massive increase in atmospheric pressure or blast wave that frequently produces injuries to the lungs, CNS, gastrointestinal, auditory, and ocular systems. Open globe injuries in this setting are complicated and result in complete surgical excision in more than half of cases. A negative phase follows, in which there is a drop in atmospheric pressure, which draws debris into the blast area. Secondary penetrating injuries from explosive debris as well as thermal injuries are common. Unlike isolated projectile injuries, these injury patterns present a unique challenge for rapid and accurate triage of victims. In addition to type, composition, and amount of explosives used, victim locations relative to the blast, enclosed space, and the presence of protective equipment or barriers can help determine the severity of injuries sustained. Ongoing research in the use of colorimetric blast dosimeters, which change color in the presence of a blast exposure, may help more rapidly identify victims of threshold ocular and brain injuries [13].

Gross contaminants from secondary projectiles can commonly complicate traumatic injuries. In addition to a variety of debris causing penetrating injuries, tissue damage may be compounded with exposure to chemical agents, causing extensive burns or direct chemical injury. Some IEDs have been compounded with jellied gasoline or diesel fuel mixed with ammonium nitrate (AN-FO) causing severe burns. Often planted in trees, resulting blast injuries may also be contaminated with biological debris. Some of these injuries may have been prevented by the use of protective eyewear. Only a minority of cases reported using protective lenses at the time of injury [11]. Enhanced vehicle shielding particular to IEDs, as well as improvements in protective lenses, will no doubt help to reduce the morbidity associated with these enemy devices.

Apart from open globe trauma, periorbital hemorrhages second-degree burns to adnexa and corneal injuries are common. Traumatic optic neuropathy (TON), although not as frequent, is an ominous injury and should be suspected in any patient presenting with decreased visual acuity or a relative afferent pupillary defect (RAPD). Thermal burn injuries involving the cornea frequently have moderate visual loss at follow-up. In studies looking at firework injuries, corneal injuries accounted for almost 40% (16 of 42 patients), and as many as 31% had moderate-to-severe visual loss at 3-month follow-up, with evidence of corneal scarring [13]. A similar series of firework injury pattern reported corneal injuries as the most common, and as many as 28% (32 of 116 patients) had permanent visual loss secondary to corneal or retinal injury [14].

Today, isolated battlefield chemical ocular injuries are rare, and thus, the majority of our understanding in the areas of chemical-induced injury patterns is derived from animal models. Injuries are largely dependent on exposure concentration or dose, time of exposure, and composition of the specific chemical agent. Historically, the effects of mustard agents are well known. Ocular injuries appear in over 75% of all mustard gas casualties with reports of delayed ocular morbidity including keratopathy, stromal keratitis, recurrent corneal erosions, and permanent blindness years later [15].

Chemical Injuries

Chemical exposures to the eyes represent a true ophthalmic emergency. Injuries occur both on the battlefield and during peacetime operations, and treatment principles are very similar. As soon as ocular exposures are suspected, immediate and copious irrigation to the eyes is indicated with any neutral solution available. Regardless of the particular xenobiotic, the foremost priority is rapid dilution of the chemical exposure. The timing and efficiency of this process cannot be overstated and may be vision-saving.

Chemical warfare (CW) agents have varying degrees of local and systemic toxicity. Some exposures may present with delayed toxicity. Familiarity of these effects, early signs and symptoms, and treatment priorities are essential to all battlefield medics. Operators should maintain a high index of suspicion concerning the use of chemical warfare agents in the presence of multiple casualties within a finite time and locale. Our discussion will focus specifically on ophthalmic injuries with these and other agents. Structured approaches for general medical interventions to exposures from CW agents, as well potential natural and terrorist disasters, are outlined in comprehensive preparedness courses such as TERT (Technical Emergency Response Training) for CBRNE (Chemical, Biological, Radiological, Nuclear and Explosive) incidents or AHLS (Advanced Hazmat Life Support).

The potential for ocular chemical exposures is everywhere. Common occupational hazards that can cause significant eye injuries include acids (e.g., refrigerants, car battery acids, and pool cleaning chemicals) and alkalis (e.g., drain cleaners, household cleaning supplies, ammonia, fertilizers, and building supplies). Eye protection is most effective in injury prevention when practiced.

In the training environment, both military and law enforcement are exposed to various riot control agents (RCA). These agents are classified as tear agents or lachrymators and quickly cause irritant effects to eyes, skin, and mucosal membranes. When used within confined spaces, these agents have been shown to induce significant edema and chemosis with loss of corneal epithelium [16]. Permanent injuries have been attributed to close dispersal via direct spray or grenade mechanisms [17]. There is also risk of thermal and explosion injuries in these training scenarios.

Acids are defined as chemical substances in aqueous solution that react with bases and certain metals to produce salts. In solution, they have a pH of less than 7, which reflects a higher concentration of hydrogen ions (protons). Normal physiologic pH of the human eye is nearly 7.4. Significant damage to ocular structures usually occurs from solutions with a pH of less than 4. Contact with ocular surfaces results in corrosive destruction via coagulative necrosis. Cellular injury results in precipitation of tissue proteins, creating a barrier to further penetration. Sulfuric acid from car batteries frequently causes significant damage to the conjunctiva and corneal epithelium.

Compared to alkaline solutions, acids do not typically cause deep penetrating injuries. Hydrofluoric acid (used in rust removers and glass etching) is one of a few notable exceptions. Hydrofluoric acid (HFA) rapidly penetrates and destroys the corneal endothelium. Latent complications include epithelial erosions, keratoconjunctivitis, symblepharon, and progressive vascularization of the cornea, leading to scarring and decreased visual function. Often, anterior chamber paracentesis and irrigation are required to limit further injury [18]. Damage is largely due to fluoride ion toxicity, which binds calcium and can lead to life-threatening hypocalcemia. Depending on the concentration of HFA, this can result with total body surface area (TBSA) exposures of less than 3%. Following rapid and copious irrigation, many authors advocate eye instillation with calcium gluconate drops, although clinical research in this area is lacking. Recommended concentrations vary between 1% and 10%, and some advocate drops every 2–3 hours for several days [19].

Alkalis are ionic salts that dissolve in water to form base solutions (pH greater than 7). In general, these agents cause more damage than acids due to extensive penetration of body tissues. The corrosive damage by liquefactive necrosis results in consumption of cell membranes and release of proteolytic enzymes, enhancing further injury. Permanent visual loss frequently results from agents with pH > 11, and tissue damage continues until the offending agents are consumed. Penetration into the anterior chamber can be rapid (<15 seconds), and damage to limbal stem cells frequently results in permanent corneal injury and opacification. These progenitor cells function to replace corneal epithelial cells and form a barrier to encroachment by conjunctival epithelium. In addition, secondary glaucoma can result from damage to the trabecular meshwork and scarring contraction of the anterior globe [20]. Advances in treatment options, including amniotic membrane transplantation (AMT), autologous limbal stem cell transplantation (ALT), with or without penetrating keratoprosthesis (PKP), continue to show promise in restoring vision, but results are highly variable [21, 22].

Anterior structures of the eye often suffer catastrophic damage to alkali burns. Despite advances in surgical techniques to restore anterior media transparency, damage to posterior structures is not easily appreciated. Postoperative glaucomatous changes can result in optic nerve damage. Monitoring has proved particularly challenging, with no reliable way of checking intraocular pressure (IOP) to date. Some surgeons will place a tube shunt at the time of keratoprosthesis placement in anticipation of this problem [22]. Even in the setting of normal IOP, premature vision loss is noted. Cade et al. studied the effects of anti-tumor necrosis factor alpha (TNF-a) antibodies on inflammatory cytokines with alkali-induced corneal burns in mice. Besides expected corneal injury, histopathology revealed retinal damage with apoptosis to the RGC within 24 hours and a second wave at 1-week post injury. A single dose of anti-TNF-a antibodies demonstrated a marked reduction in inflammatory cytokines, as well as a reduction in corneal neovascularization [23]. Further investigation in these areas is needed to better delineate these complex injury mechanisms.

It cannot be overstated that once a chemical exposure to the eye is suspected, nothing should delay immediate and copious irrigation with any neutral solution available (e.g., water, milk, iced tea, and saline solution). Following pH neutralization and screening for possible open globe injuries, further evaluation may proceed for extent of injury and quantification of visual impairment.

There are several classification schemes for ocular chemical injuries, including Hughes, Thoft, Roper-Hall (Table 14.1), and Dua grading systems. Regardless of which system is used, careful attention to the extent of corneal, limbal, and conjunctival damage is paramount to accurate grading and treatment planning. The degree of limbal ischemia (number of clock hours) and depth of corneal injury are vital prognostic factors, as well as any evidence of increased IOP.
Table 14.1

Roper-Hall classification of ocular chemical injuries

 

Clinical findings

 

Grade

Cornea

Conjunctiva limbus

Prognosis

I

Corneal epithelial damage

No limbal ischemia

Good

II

Corneal haze, iris details visible

<1/3 limbal ischemia

Good

III

Total epithelial loss, stromal haze, and iris details obscured

1/3–1/2 limbal ischemia

Guarded

IV

Cornea opaque, iris, and pupil obscured

>1/2 limbal ischemia

Poor

Adapted from Roper-Hall [201]

Grade 2 injuries display only focal limbal ischemia and mild corneal haze but may develop neovascularization (scarring) at the site of stem cell loss. Grade 3 injuries show ischemia of most of the limbus with significant corneal haze, limiting visualization of anterior chamber structures. Often the corneal epithelium undergoes encroachment by conjunctival epithelium with a significant decrease in visual acuity usually requiring surgical intervention.

Grade 4 injuries represent near or total loss of limbal stem cells and destruction of proximal conjunctival epithelium. The cornea is completely porcelainized. Return of vision may not be possible without aggressive surgical management.

In patients with severe corneal injury (Roper-Hall IV), the Dua system (Table 14.2) provides further subclassification of severe injuries (IV–VI) to more accurately predict outcomes and help guide interventions [24].
Table 14.2

Dua classification of ocular chemical injuries

Grade

Clinical findings

Conjunctival involvement

Prognosis

I

0 clock hours of limbal involvement

0%

Very good

II

<3 clock hours of limbal involvement

<30%

Good

III

Between 3 and 6 clock hours of limbal involvement

30–50%

Good

IV

Between 6 and 9 clock hours of limbal involvement

50–75%

Good to guarded

V

Between 9 and 12 clock hours of limbal involvement

75–100%

Guarded to poor

VI

Total limbus involved

Total conjunctival involvement

Very poor

Adapted from Dua et al. [25]

Early re-epithelialization is the most important determinant of ultimate visual function. Corneal epithelial regeneration serves to protect against proteolytic enzymes contained within the tear film. These enzymes are in contact with exposed stromal tissues that are susceptible to further damage and, if unchecked, may lead to corneal perforation.

The inflammatory response to chemical injury begins immediately and can hinder organized re-epithelialization. Regimented use of corticosteroids and immune modulators is essential in the acute phase of healing to limit these processes. Changes in inflammation, corneal clarity, and IOP should be monitored closely (daily) as indicators of response to interventions and ultimate prognosis.

Long-acting cycloplegics should be used for comfort along with oral pain medications. High-dose vitamin C is protective against both UV-based and chemical-induced inflammatory changes with acute corneal injury [25, 26, 27]. Broad-spectrum antibiotics are indicated as well as a tetracycline derivative (doxycycline) for both antimicrobial and anti-inflammatory effects.

Enzenauer et al. demonstrated the synergistic effects of silibinin, doxycycline, and dexamethasone in reducing inflammation-mediated vesicant-induced ocular injuries [28]. These injuries induce inflammatory changes in the epithelium; apoptotic cell death; and increased expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and matrix metalloproteinase-9 (MMP-9) in cultured rabbit eye corneas. Doxycycline has the ability to inhibit MMPs, and dexamethasone effectively reduces VEGF levels. The combination of these agents together with silibinin effectively reduced all injury-associated endpoints including cell death, micro bullae formation, neovascularization, MMP-9 and COX-2 levels, and epithelial thinning.

The inflammatory response in the first week after injury (acute phase) determines transition to chronic inflammation, stromal repair, and scar tissue formation. Ideally, at this point, corneal re-epithelialization is complete, and steroids are tapered. Ongoing inflammation in the setting of persistent corneal defects usually requires cautious extension of steroids, given the increased risk of perforation if used beyond 21 days [29]. Due to these limitations, failure of significant re-epithelialization within 10–14 days (early healing phase) post injury should prompt consideration of surgical intervention.

Beyond 3 weeks (late healing phase), maintenance of normal stromal function, close monitoring of IOP, and continued cornea care with topical lubricants and tear substitutes are vital. Loss of corneal sensation and damage to mucin-producing cells lead to inadequate corneal tear film production. Surgical evaluation is indicated for any persistent epithelial defects, and tarsorrhaphy may be indicated [30].

Ocular surface irritation or injury is typically measured by Draize testing, which has been the standard process for over 50 years. Chemist and Doctor of Pharmacology, John Henry Draize was recruited by the US Army in 1935 to investigate the effects of mustard gas and other chemical agents. Testing involves instillation of a fixed amount of liquid or solid xenobiotic into the conjunctival sac of one eye and closure of the eyelids for 1 second. Both the treated and untreated eyes are closely evaluated over the next several days. Changes to the cornea, conjunctiva, and lens are noted on a standard scale with a maximum score of 110. Scale weighting favors corneal injuries (maximum 80), as they have significant impact on visual function. A similar test is used to quantify xenobiotic-induced skin irritation.

The Draize test has been criticized for inter-observer variability, limited application of animal response to human eyes, and causing unnecessary cruelty to animals. Draize testing, developed for humanitarian purposes and highly regulated by federal agencies, has been modified over the years to reduce the number of animals needed for testing and amount/concentration of xenobiotics used. Alternate tests, including hen’s egg chorioallantoic membrane, human epidermal keratinocytes, and in vitro human corneal cell cultures, have been studied. To date, no single alternative test has accuracy equivalent to Draize testing; however, a combination of analyses may prove comparable [31, 32, 33, 34]. This is not surprising given our limited understanding of injury mechanisms from xenobiotic-induced ocular injuries.

Organic solvents are ubiquitous in modern society. These carbon-based xenobiotics are extremely useful in their ability to dissolve a plethora of materials and are widely used in paints, varnishes, lacquers, adhesives, glues, and degreasing/cleaning agents. They are also used in the production of dyes, polymers, plastics, textiles, printing inks, agricultural products, and pharmaceutical products. Accidental eye exposures frequently cause damage to lipophilic structures, including the corneal epithelium. Most of these agents do not have extremes from physiologic pH, however, they should be treated rapidly as with any acid or alkali injury. Organic solvents rapidly pass through cellular membranes, disrupting cell membrane functions and vital homeostasis mechanisms [35]. Even solvents common to ophthalmic medications, such as dimethyl sulfoxide (DMSO), used as a vehicle for topical application of pharmaceuticals, can cause corneal cellular injury at low doses [36]. Treatment priorities include copious irrigation until adequate decontamination, followed by evaluation for corneal injury. Typically, these injuries heal well without permanent dysfunction or visual impairment.

Similar to solvents, surfactants are common compounds that have the ability to emulsify or reduce surface tension between the interfaces of two surfaces. They contain both hydrophobic groups and hydrophilic groups and thus have the ability to mix both water-soluble and water-insoluble agents. Surfactants are frequently used as detergents, dispersal agents, and foaming agents. Their lipophilic terminus allows for rapid penetration through cellular tissues, and the hydrophilic portion allows for concentration in water-soluble tissues (corneal stroma). The hydrophilic terminus may be strongly ionic (and highly reactive) in solution. Typically, cationic agents are more damaging than anionic solutions. Benzalkonium chloride, a cationic detergent, is one of the most commonly used preservatives in topical preparations. At low concentrations (<0.01%), its surfactant qualities dissolve the lipid phase of the tear film, increasing drug penetration or delivery. At higher concentrations, it exerts direct cellular toxicity via damaging cytoplasmic membranes and cytoplasmic organelles and impeding metabolic cellular function [37].

Personal Protective Equipment (PPE)

All providers should be familiar with the classification and general use of personal protective equipment (PPE). This equipment is designed to protect providers from illness or injury resulting from contact with chemical, radiological, or biologic hazards. Selection of protective equipment is made specific to a given threat response. In scenarios with exposure to unknown agents, a minimum use of class B protection is recommended. No single PPE ensemble can protect the wearer from all hazards.

Appendix B of the HAZWOPER standard defines the OSHA/EPA Protection Levels A, B, and C as follows:
  • Level A—To be selected where the hazards are unknown or unquantifiable or when the greatest level of skin, respiratory, and eye protection is required.

  • Level B—The highest level of respiratory protection is necessary, but a lesser level of skin protection is needed.

  • Level C—The concentration(s) and type(s) of airborne substances is known, and the criteria for using air-purifying respirators are met.

These are general descriptions of protection level only and do not guarantee immunity from CBRN-specific hazards. The HAZWOPER standard itself states that the generic descriptions of the equipment do not fully address the performance of PPE in relationship to specific needs [38].

Specific NIOSH-approved equipment appropriate to each level is as follows:

Level A protection should be worn when the highest level of respiratory, skin, eye, and mucous membrane protection is needed. A typical Level A ensemble includes the following:
  • Positive pressure (pressure demand), self-contained breathing apparatus (SCBA) or positive-pressure supplied air respirator with escape SCBA

  • Fully encapsulating chemical protective suit

  • Gloves, inner and outer, chemical resistant

  • Boots, chemical resistant, steel toe, and shank (depending on suit boot construction, worn over or under suit boot)

Level B protection should be selected when the highest level of respiratory protection is needed, but a lesser level of skin and eye protection is needed. Level B protection is the minimum level recommended on initial site entries until the hazards have been further identified and defined by monitoring, sampling, and other reliable methods of analysis and equipment corresponding with those findings utilized. A typical Level B ensemble includes the following:
  • Positive-pressure (pressure-demand), self-contained breathing apparatus or positive-pressure supplied air respirator with escape SCBA

  • Chemical-resistant clothing (overalls and long-sleeved jacket, coveralls, hooded two-piece chemical splash suit, disposable chemical-resistant coveralls)

  • Gloves, inner and outer, chemical resistant

  • Boots, outer, chemical resistant, steel toe, and shank

Level C protection should be selected when the type of airborne substance is known, concentration measured, criteria for using air-purifying respirators met, and skin and eye exposure is unlikely. Periodic monitoring of the air must be performed. A typical Level C ensemble includes the following:
  • Full-face or half-mask, air-purifying respirator

  • Chemical-resistant clothing (one-piece coverall, hooded two-piece chemical splash suit, chemical-resistant hood and apron, disposable chemical-resistant coveralls)

  • Gloves, inner and outer, chemical resistant

  • Boots, steel toe and shank, chemical resistant

Level D protection is primarily a work uniform and is used for nuisance contamination only. It requires only coveralls and safety shoes/boots. Other PPE is based on the situation (types of gloves). It should not be worn on any site where respiratory or skin hazards exist (Chemical Hazards Emergency Medical Management, DHHS; http://chemm.nlm.nih.gov).

In addition, the National Fire Protection Association (NFPA) has defined protective equipment standards for response to CBRNE terrorist incidents. There are three categories of protective ensemble depending on the hazard type (vapors, liquids, and particulates) and the airborne contaminant level. Selection is based on thorough risk assessment in accordance to OSHA/HAZWOPER regulations:
  • Class 2 ensembles are intended for use at terrorism incidents involving vapor or liquid chemical or particulate hazards where the concentrations are at or above IDLH level requiring the use of CBRN compliant self-contained breathing apparatus (SCBA).

  • Class 3 ensembles are intended for use at terrorism incidents involving low levels of vapor or liquid chemical or particulate hazards where the concentrations are below IDLH, permitting the use of a CBRN compliant air-purifying respirators (APR) or power air-purifying respirator (PAPR).

  • Class 4 ensembles are intended for use at terrorism incidents involving biological or radiological particulate hazards where the concentrations are below IDLH levels permitting the use of CBRN compliant APR or PAPR. The ensembles are not tested for protection against chemical vapor or liquid permeability, gas-tightness, or liquid integrity [38].

Decontamination

Decontamination is accomplished by either physically removing or chemically neutralizing a toxic substance. In order to minimize ongoing injury from exposure to chemical agents, a systematic stepwise approach to decontamination should be familiar to all healthcare providers. For the purpose of our discussion, healthcare “providers” will include all personnel, from first responders and field medics to nurses and emergency/trauma physicians.

The first priority in all exposure scenarios is to avoid secondary contamination or exposure to providers. This is accomplished by appropriate use of personal protective equipment (PPE) by all providers. Effective decontamination is time dependent; however, until the specific chemical agent(s) is known, the highest level of protection (level A or B PPE) is recommended. Decontamination should occur prior to patient transport to a civilian or combat support hospital (CSH); however, this is not always possible. Regardless of use, it is vital to maintain separation of clean and “dirty” or contaminated areas and resources (i.e., vehicles and medical equipment).

In mass casualty events, staging areas need to be established between the exposure area(s) or hot zone and medical treatment areas. These include key areas such as decontamination and triage to effectively assess and treat large numbers of victims. The exact location and access of these areas involve many factors including, but not limited to, the specific exposure agent(s), number of potential victims, wind direction and weather conditions, presence of local shelter, evacuation routes, geography, and local resources.

The second priority is timely decontamination of victims. This is particularly true with skin exposures to liquid chemicals. Rapid decontamination will help minimize adverse health effects and, in turn, utilize less medical resources. If contaminated, carefully remove clothing with attention to possible injuries. If necessary, clothing may be cut and rolled away from the patient in such a fashion as to avoid further skin contact. Clothing should be double bagged in plastic to avoid further exposure and labeled for potential forensic analysis.

General recommendations for skin decontamination include copious irrigation with soap and water. Avoid contamination of unexposed areas, with particular attention to the face, eyes, and urogenital areas or open wounds. Be aware of contaminated water runoff in addition to what may collect in the patient’s socks and shoes. Moisture may enhance dermal absorption of certain chemical agents such as mustards. In this setting, the skin should be dusted with Fuller’s earth or Canadian Reactive Skin Decontaminant Lotion (RSDL) prior to thorough washing with soap and water [39].

With regard to chemical warfare (CW) agents, chemical decontamination can be much more effective than simple irrigation with water. Chemical decontamination either binds or converts toxic CW agents into innocuous products. Dry formulations that contain Fuller’s earth include PDK-1,2 and M-291 kits that are available for decontamination of skin as well as equipment. Diluted hypochlorite (0.5%) solution (one-part household bleach with ten parts water) is effective against mustards and V-nerve agents but not G-agents [40, 41]. Ready-to-use chemical formulations such as DS2 are commercially available. The active ingredient is ethylene glycol monomethylether, which hydrolyzes CW agents into nontoxic products. Other kits available include the M258A1, M280 (American), and C8 (German), which contain variable concentrations of sodium hydroxide or calcium hypochlorite. Ideal characteristics of decontamination agents are water-solubility, harmless to humans, stable for long-term storage and rapidly effective against most potential contaminates.

Chemical exposures to the eye require immediate irrigation to help minimize vision-threatening injuries. Whether secondary to occupational accident or on the battlefield, the key is prompt recognition and intervention. Most exposures occur far from a hospital setting, making prehospital treatment crucial in the severity and potential long-term disability from such injuries. Copious irrigation with tap water or isotonic saline has long been the standard of treatment for chemical eye exposures. Animal studies have shown no significant benefit of isotonic fluid irrigation compared to sterile water [42]. More recent studies demonstrate better outcomes with tap water irrigation of alkali burns, which may be largely due to immediate irrigation at the scene of the injury [43]. Since time from injury to decontamination is critical, prehospital irrigation is often dictated by what is readily available. Standard recommendations include a minimum of 15–20 minutes of irrigation for mild exposures, including dilute acids. This includes exploration and examination of all adnexa for gross contaminants. Continue complete ocular decontamination, including thorough cleansing of fornixes until normalization of tear film pH (7.4–7.6) and symptomatic improvement. More severe exposures including alkali burns often require extensive irrigation for several hours.

Recent studies have looked at using various buffering solutions for irrigation to improve injury outcomes. Diphoterine rinsing solution (DRS) is a polyvalent, hypertonic, neutral pH, amphoteric, water-soluble compound, which has the capacity to bind both acids and bases, oxidizing agents, and solvents [44, 45]. Animal studies looking at corneal injury, IOP elevation, and systemic oxidative stress from exposure to nitrogen mustard found DRS superior to isotonic saline irrigation [46]. In addition to mechanical decontamination, amphoteric compounds function as chelators, binding a variety of xenobiotics and radio nucleotides. Also, its hypertonic properties impede chemical tissue penetration and remove a portion of toxicants within the cornea [44]. Merle et al. (2005) looking at the efficacy of DRS for human ocular alkali burns showed faster corneal healing times with DRS. Skin decontamination studies to mustard agents have shown DRS was more effective than soap and water or isotonic saline [47]. While DRS is currently awaiting FDA approval, alternative agents include the borate-buffered balanced saline solution (Cederroth Eye Wash). Animal studies with NaOH-induced corneal burns showed significant improvement in anterior chamber pH with Cederroth versus saline solution regardless of irrigation rates [48].

Further development in these areas may provide reconstitution of dry products by medics in the field, supplying superior decontamination solutions without compromising team mobility. If buffered solutions are not available, many authors would recommend irrigation with tap water.

Patient Evaluation

Following rapid survey and stabilization of airway, breathing, and circulation, the patient should undergo immediate irrigation of the eyes prior to any detailed ocular evaluation in the setting of suspected chemical exposure. As mentioned before, the priority should be flushing the eye with what is readily available rather than delay decontamination. Alkali injuries can penetrate the cornea and anterior chamber in seconds to minutes. Ideal eye rinses include buffered solutions particular to the chemical exposure (if known) but seldom are these readily available to the first responder. Tap water is usually available, but any neutral solution is acceptable, including milk or iced tea.

Key historical elements include the chemical name(s) and concentration, time from exposure, mode of exposure (i.e., splash, projectile, and propellant), the presence of eyewear, and vision status prior to injury.

Beyond isolated exposures from accidental or occupational injuries, be aware of other symptoms particularly cough, wheezing or respiratory difficulties, nausea and vomiting, dizziness, muscle weakness, or fasciculation that may represent an impending CW attack. Clearly, management of life-threatening injuries takes priority over a detailed ophthalmologic evaluation per ATLS/AHLS protocols. Maintain proper isolation and decontamination precautions with appropriate use of PPE and notify EMS or command of suspected CW agent(s).

Continue irrigation for a minimum of 15–20 minutes and administer topical anesthetics if available following the initial irrigation phase. Remove contact lenses if visually present. Runoff irrigation fluid should be kept from cross-contaminating other nonexposed areas. Allow 3–5 minutes prior to assessment or reassessment of tear film pH. This is more than enough time to conduct a brief field evaluation of the adnexa, anterior, and posterior structures of the eye.

With a pen light, the eyes and adnexa are thoroughly examined for gross contaminants, particular matter, or chemical concretions. This includes mandatory eversion of upper and lower lids. Any significant findings should prompt removal of particles or resumption of irrigation. Examine external surfaces for skin burns or tissue loss, which may lead to corneal damage from incomplete lid closure. The corneal surface and anterior chamber can be seen with the naked eye and tangential lighting. Healthy corneal epithelial cells have a reflective luster or shine. In direct examination of the iris, note any gray areas of stromal opacification or loss of clarity. Corneal opacification, epithelial defects, and limbal ischemia should be noted. The presence and amount of blanching at the corneal-conjunctival border reflects limbal ischemia and has prognostic value (see chemical injuries). Slit lamp examination with mydriatics provides a more detailed assessment of these structures, including the lens, but would not be appropriate prior to completion of irrigation decontamination. Evaluate direct and consensual pupillary light reflexes, and note any differences in baseline diameter, asymmetry, and sluggish movement. The presence of normal reflexes does not reflect the absence of retinal injury or damage to the visual cortex that lies outside this pathway.

Any suspicion of penetrating injury requires eye shielding and immediate triage to CSH or forward hospital for further management. Consider withholding mydriatics in patients with suspicion of head injury, as these agents will render pupillary reflexes nonfunctional. Avoid alpha agonists such as phenylephrine due to its vasoconstriction effects and the potential to enhance pre-existing ischemic injury [49].

Evaluate ocular movements, and note the presence of nystagmus, disconjugate movement, diplopia, and lid positions (both open relaxed and closed). In the absence of formal tonometry, a “field assessment” of IOP can be difficult [50]. Some authors mention tactile feedback by gentle fingertip pressure over a closed lid, in addition to light shadow test across the iris, but neither are essential to early assessments. Assess pH prior to evaluation of visual acuity. Continue irrigation cycles with pH reassessment not more often than once every 15–20 minutes to not interfere with the efficacy of decontamination. Irrigation endpoints include absence of gross contaminates and normalization of tear film pH (7.3–8.0).

The importance of visual acuity assessment cannot be overstated. Visual acuity is the single most important prognostic factor after eye injury. Each eye should be assessed independently. In the absence of a Snellen chart, have the patient read print at a recorded distance. Assess for gross visual field defects in all four quadrants of each eye. If print cannot be read, have the patient count fingers at progressively shortened distances until the patient can do this reliably “counts three fingers at 4 feet.” If finger counting is not possible, check for detection of hand movements and, finally, localization of light perception if necessary [51]. In the absence of significant anterior chamber injury, intact visual acuity and visual fields confirm function of both the posterior bulb structures and visual cortex.

Once in a controlled setting or acute care facility, the patient may undergo a complete ophthalmologic exam, including formal dilated slit lamp examination, fluorescein staining, and direct or indirect funduscopic assessment.

The presence of significant defects or visual impairment may reflect underlying chemical injury, systemic toxicology, or CNS dysfunction and injury. Accurate assessment and recognition of injury patterns greatly impact medical outcomes and long-term disability [52]. Providers need to practice these assessment skills and decontamination protocols such that they can be performed efficiently and under potential duress.

Vision Testing

Following injury, in-depth assessment of vision can be accomplished via a variety of neuro−/electro-physiologic procedures. The most commonly employed tests are visual-evoked potentials (VEP), electroretinography (ERG), and electrooculogram (EOG).

VEPs are a form of sensory-evoked potential (SEP), which is simply an electrical signal from the CNS in response to the presentation of a stimulus. There exist various types of SEPs, including auditory-evoked potentials and somatosensory-evoked potentials (peripheral nerves), to assess competence of their respective neural pathways.

Using transducers, these electrical signals are graphically recorded as response amplitude and frequency. Repetitive signals demonstrate a constant pattern referred to as steady-state evoked potentials (SSEP). These measurements are specific to a particular stimulus (e.g., high-frequency versus low-frequency light flicker will demonstrate different amplitude response patterns). Simultaneous stimulation involves multiple SSEP recordings from different scalp locations, which allows for spatial analysis brain stimulation. Sweep technique plots response amplitudes against size of visual stimulus and frequently employs a changing checkboard pattern several times per second. This technique is useful in measuring visual development and contrast sensitivity in the first years of life [53]. In evoked potential feedback, the luminal strength of the visual stimulus is automatically adjusted to maintain constant response amplitude. Then the color or wavelength is changed, and a plot of luminance stimulus versus wavelength provides a graphical measure of spectral sensitivity of the visual system [54].

VEPs were first reported by Adrian and Matthews in 1934, who discovered changes in occipital lead electroencephalograms (EEG) under visual stimulation with light. Later, specific nomenclature was developed, and the recording of maximal amplitudes along the calcarine fissure (primary visual cortex) was discovered.

Electroretinography (ERG) measures retinal electrical responses to light stimulus with electrodes placed on or near the cornea. Light stimulus in reference to background lighting will demonstrate specific function of rods and cones (e.g., response from light stimulus in a dark room will measure rod function, whereas stimulus under daylight background will be more representative of cone function). Bright light will generate a biphasic wave with an initial negative deflection (a wave), which represents photoreceptor response. The trailing wave (b wave) reflects retinal bipolar cells and Muller cell function. From animal studies in these areas, a standard set of ERG protocols has been developed for use in the clinical assessment of human patients [55]. VEP and ERGs are valuable tools when suspecting xenobiotic-induced retinal or macular pathology because they can demonstrate dysfunction when clinical symptoms are subtle and injury is still reversible. The EPA has published guidelines on the use of EP testing in the context of toxicological studies [56].

Electroocculograms (EOG) measure standing electrical potentials between the front (cornea) and back (retina) of the eye. Unlike ERGs, they do not measure response to temporal visual stimuli but are mainly used to measure eye movements. Metabolic activity in the RPE generates light-sensitive and light-insensitive potentials. In this setting, EOGs can be used to evaluate healthy functioning of the RPE by comparing peak resting potentials during light and dark adaptations.

Beyond the diagnostic capabilities of tertiary referral centers, the keen provider should be aware of potential xenobiotic exposures in patients experiencing trouble with color discrimination, abrupt changes in night vision, dark adaptation, or contrast differentiation. Kollner’s rule is a term used in ophthalmology that pertains to the progressive nature of color vision loss that is secondary to eye disease. This rule states that outer retinal diseases and media changes result in predominant blue-yellow color defects, while diseases of the inner retina, optic nerve, and visual pathway will result in more red-green defects [57, 58].

Color and contrast changes often are the first symptoms in isolated toxin-induced retinopathies. Systemic xenobiotic exposures most likely will target the outer retina or RPE due to its proximity to the choriocapillaris blood supply. Other xenobiotics such as methanol easily penetrate the retina, CNS, and optic nerve, causing delayed toxicity via by-products of metabolism. Color vision testing has been used to rapidly screen occupational and environmentally exposed populations. A number of standard colorimetric tests exist, including the Farnsworth-Munson 100 Hue (FM-100) test and a simplified 15 chip version (Farnsworth D15) panel. Test subjects are required to arrange the color chips in a sequential chromatic order. Those individuals with color perception deficits will be unable to place in the correct order. Whether drinking water contaminated with heavy metals to methanol-adulterated alcoholic drinks, attention to the early symptoms of visual dysfunction may be nothing less than vision saving.

Increased intraocular pressure (IOP) is a frequent complication of severe chemical injury to the eye, often secondary to scarring of the trabecular meshwork and formation of posterior synechia. Vigilant reassessment of IOP via tonometry and ultrasound bio microscopy is often necessary to avoid potential secondary injuries.

Chemical Warfare Agents

Chemical warfare (CW) agents have been in use for centuries, but it was not until after the industrialization of Western Europe in the mid-nineteenth century that allowed for the mass production and accelerated development of warfare agents. In April of 1915, the devastating use of chlorine gas by German forces in Belgium marked the beginning of the modern chemical weapons era. This led to the development and use of other agents including sulfur mustards and phosgene. These agents, used by both axis and allied forces during World War I, were responsible for an estimated 100,000 deaths and excess of 1 million casualties (U.S. War Department Feb 1924, Amended Office of the Secretary of Defense on 7 Nov 1957).

The Lieber Code of 1863, which was signed by President Abraham Lincoln, provided instructions for the civilized conduct of Union soldiers during wartime. In essence, it was the first written recital of the customary laws of war and includes provisions on military jurisdiction, martial law, and the treatment of spies, deserters, and prisoners of war [59]. It also forbade the use of poisons. The Hague Conventions of 1899 and 1907 were the first multilateral treaties, which further defined the laws of war and created the first binding international court for compulsory arbitration. In the aftermath of World War I, the Geneva Protocol (1928) to the Hague Conventions banned the use of all forms of chemical and biological warfare. Despite their limited use, active research in CW agents continued. The Chemical Weapons Convention (1997) is an international arms control treaty with comprehensive bans on the development, production, and use of CW agents and provides destruction timelines for existing stockpiles.

Despite these international treaties, the recent use of CW agents in the Iraq-Iran War (1982–1988), Kurdistan rebellion (1988), and the Syrian Civil War (2013) underscores the ongoing need for vigilance in military training and healthcare provider education in these areas (Table 14.3).
Table 14.3

Standard Iraqi chemical agents in 1991

Name

Agent type

Comments

CS

Riot control

Low-toxicity agent for harassment and deception

Cyclosarin (GF)

Nerve

Deployed and stored in GB/GF mix

Sarin (GB)

Nerve

Deployed and stored in GB/GF mix. Some degraded Iran-Iraq war-era GB-only munitions found at Al Muthanna

Sulfur mustard (H, HD)a

Blister

Most prevalent agent in munitions and bulk storage containers

VX

Nerve

Quantities unknown but probably small when compared to other standard agents

aH is a common symbol for mustard gas. HD is variously used to designate distilled or otherwise highly pure sulfur mustard. Iraqi mustard was not distilled but was often greater than 90% pure

In general, CW agents are classified according to their physiologic effects. These categories include vesicants or blister agents, nerve agents, choking or pulmonary agents, blood agents, and riot-control agents. Volatility is important to note, as this impacts whether the agent is classified as persistent or nonpersistent. Less volatile agents like sulfur mustard and VX tend to persist in a given exposure area, whereas more volatile agents like chlorine, hydrogen cyanide, and phosgene evaporate and disperse quickly.

Vesicant or Blister Agents

In chemical warfare, sulfur mustard (HD) or “mustard gas” is the prototypic vesicant or blister agent [67]. It can exist as an oily liquid or vapor and colorless to yellow-brown in color and sometimes smells of garlic, onion, or mustard. A vapor hazard only above body temperatures, it is heavier than air and typically accumulates in low-lying areas. In cold climates, it may persist in these areas for several days. It is more effective in warmer climates and in higher humidity weather but will usually dissipate within 24–48 hours. At temperatures above 300 F, decomposition occurs with the release of toxic fumes including sulfur oxide and hydrochloric acid [60]. It causes severe delayed burns to the skin, eyes, and respiratory tract. Sulfur mustard can be absorbed into the body by inhalation, ingestion, and dermal contact. The median incapacitating dose is 100–200 mg-min/m3 and results in moderate-to-severe injuries [61]. Death is typically via inhalation injury.

Sulfur mustard is lipophilic and rapidly penetrates dermal surfaces including the cornea, often resulting in severe keratoconjunctivitis. Skin irritation, pain, and blistering are often delayed for several hours. The severity of symptoms depends on environmental conditions and the degree of exposure. Ocular findings include lacrimation, painful blepharospasm, and severe corneal and conjunctival edema similar to UV keratitis. The use of sulfur mustard during the Iraq-Iran War demonstrated that even with mild exposures, up to 90% of exposed experienced visual disability and were unable to return to combat duty for nearly 1 week [62, 63].

Sulfur mustard is a highly reactive alkylating agent that reacts with sulfhydryl, carbonyl, and amino groups. This causes denaturing of cellular proteins and inhibits DNA replication [64, 65]. In severe cases, pulmonary injury is complicated by septicemia and bone marrow suppression. Similar to chemical burns, significant exposures result in corneal defects and limbal ischemia on exam. IOP may be elevated. Severe cases result in prolonged keratitis, with recurrent corneal ulceration, scarring, and impaired visual function.

Depending on the severity of exposure, the majority of individuals with corneal injuries heal without sequela. Moderate or severe exposures can develop a chronic keratopathy, which can be delayed for several years [66]. Traditional surgical interventions have had mixed results, and the benefits from anti-inflammatory medications are temporary. This suggests an ongoing underlying mechanism to this condition [73]. Animal studies have shown an injury-dose response to sulfur mustard with corneal endothelial cell injury, abnormal morphology, epithelial bullae, and thickened Descemet membrane [68]. These findings suggest ongoing endothelial failure as a potential mechanism for chronic anterior keratopathies.

Other studies have attempted to characterize the temporal development of delayed keratopathy following sulfur mustard exposure. Chronically injured corneas were noted to have increased matrix metalloproteinase (MMP) activity, poor re-innervation, and limbal damage consistent with limbal epithelial stem cell deficiency (LSCD) [69]. Investigation of anti-inflammatory agents (NSAIDS), MMP inhibitors (doxycycline), neurotropic factors, and amniotic membrane transplantation have shown variable benefit. These interventions blunt the acute injury phase and delay the onset of chronic injury patterns. Further research is needed to better elucidate these mechanisms and to better match patients with specific interventions.

Limbal stem cell transplantation is effective in select patients. Unfortunately, severe injuries (Dua V–VI) associated with near-total limbal stem cell loss have variable success, even in the setting of aggressive surgical interventions. Traditional limbus tissue grafts are heterogeneous cell populations, which contain variable amounts of limbal stem cells (LSC). Recent work with autologous limbal cell grafts has yielded promising results for the treatment of LSCD [70]. Frank recently discovered ABCB5 as a novel molecular marker for mammalian LSC. ABCB5 monoclonal antibody-based purification yielded purified LSC grafts that were able to fully restore the cornea upon grafting to LSC-deficient mice [71].

The use of N-acetyl L-cysteine (NAC) to increase glutathione levels may provide benefit in preventing or reducing toxicity related to exposure to chemical irritants (particularly sulfur mustard) [72, 73, 74, 75].

Treatment includes appropriate triage and immediate decontamination, which may be difficult due to significant latency with onset of symptoms. Sulfur mustard may persist on clothing for several days. After removal of clothing, exposed areas should be dusted with Fuller’s earth or reactive skin decontaminant lotion (RSDL), followed by soap and copious water irrigation [39]. Ocular irrigation with buffered solutions, such as DRS, if available, otherwise use any neutral solution available (e.g., water, milk, and iced tea; see decontamination).

Although there are no specific antidotes for systemic mustard toxicity, there are several interventions under investigation, including N-acetyl cysteine (NAC), sodium thiosulfate [76], and amifostine [77].

Like sulfur mustard, nitrogen mustards are powerful blister agents with cytotoxic effects. Nitrogen mustard gas (HN2) was stockpiled by several nations during World War II, but it was never used in combat. Production and use is strongly restricted as are all schedule 1 substances within the Chemical Weapons Convention (Organization for the Prohibition of Chemical Weapons; http://www.opcw.org).

Nitrogen mustards have the same toxicity as sulfur mustards. Rapid elimination of chloride group(s) leads to the formation of a highly reactive aziridine (nitrogen) or sulfonium (sulfur) cyclic group that readily causes alkylating injury to DNA.

Due to their known cytotoxic effects, nitrogen mustards were studied for the treatment of lymphomas at Yale in 1942. These studies demonstrated how nitrogen mustard caused temporary regression of lymphomas in mice. It was also found that reactivity of the ethyleneimmonium ring with thiosulfate provided a potential antidote to nitrogen mustard’s cytotoxic effects [72]. Thus began the modern age of chemotherapy.

Several related chemotherapeutic agents have since been developed, including ifosfamide, cyclophosphamide, chlorambucil, and melphalan. The original nitrogen mustard (Bis-2-chloroethyl methylamine or mustine) is no longer in use due to its toxicity.

Lewisite (agent L) (Fig. 14.4) was first synthesized in 1904 by Julius Arthur Nieuwland and later purified by US chemist Winford Lee Lewis (1919). Lewisite (dichloro[2-chlorovinyl]arsine) is an organoarsenic compound. In its pure form, it is colorless and odorless, (like mustards). Impurities in mass production frequently yield a yellow-brown oily liquid (similar to mustard), and a smell described as freshly cut grass or geraniums.
Fig. 14.4

Lewisite (agent L). Lewisite, World War II Gas Identification Posters, ca. 1941–1945, U.S. Army, National Museum of Health and Medicine, http://nmhm.washingtondc.museum/collections/archives/agalleries/ww2/lewisite.jpg

Lewisite is heavier than mustard and poorly soluble in water. Lewisite may be mixed with sulfur mustard to lower the freezing point of sulfur mustard and increase its effectiveness at lower temperatures [78]. In addition to its potent vesicant effects causing severe pulmonary injury, it also has systemic effects including refractory hypotension and hepatic injury. Cellular toxicity is secondary to the reaction of arsenite ions with thiol groups of biologically active proteins involved in energy (ATP) production [79].

Unlike mustard agents, the irritant effects of lewisite are immediate. Exposure causes rapid onset of eye and skin irritant effects followed by pulmonary injury and finally systemic toxicity. Lewisite is highly lipid soluble and deeply penetrates dermal tissues. Toxicity of lewisite is many times than that of mustard agents but due to the rapid onset of irritant effects at relatively low concentrations, most exposed individuals take immediate protective action, limiting further contact [80].

Ocular effects include pain, blepharospasm, edema, and chemosis within the first minute of exposure. Severity of corneal injury is concentration (dose) dependent. Corneal irritation occurs at concentrations as low as 0.1 mg-min/m3, whereas injury occurs at doses nearly ten times higher. Permanent ocular damage occurs at 15 mg-min/m3, which is nearly 1 minute at olfactory (geraniums) detection (14 mg min/m3) threshold [80].

Compared to mustard agents, lewisite penetrates tissues with greater efficiency. Miosis and uveitis are demonstrated shortly following higher dose exposures, suggesting rapid corneal penetration, with injury to the corneal endothelial cells (CEC) and possibly posterior eye structures as well [81]. Although effective treatment is time critical, lewisite-induced injury can be mediated by the administration of 2,3-dimercaptopropanol (BAL). BAL is a useful chelator for many heavy metals and has multiple thiol groups that form stable bonds with arsenic in lewisite.

BAL itself is toxic with a narrow therapeutic range. Most patients receiving therapeutic doses of BAL intramuscularly will experience a transient increase in pulse and blood pressure.

Unfortunately, BAL is poorly water soluble, and no specific ocular formulation exists. In the rabbit cornea model, a 5% BAL compounded topical ointment or solution applied within 2 minutes of lewisite exposure prevented the development of a significant reaction [82]. Less toxic derivatives DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (d,l-2,3-dimercapto-1-propanesulfonic acid) are available for oral or parenteral administration. These newer agents and their chelates are hydrophilic, and they do not redistribute the toxic metals into the brain [83]. The toxicity of these antidotes is relatively low and include mild neutropenia and transaminitis [84].

Regardless of specific vesicant exposure, aggressive use of decontamination solutions, anti-inflammatory agents, and aforementioned immune modulators are necessary to help minimize the development of chronic inflammation, delayed keratopathy, and recurrent corneal ulceration. These interventions will also translate into better surgical outcomes for those patients requiring delayed keratoplasty, corneal transplantation, or limbal stem cell transplantation.

Choking Agents

First used in WWI, chlorine gas is a powerful pulmonary irritant or choking agent. Airway and pulmonary effects from CW agents are largely related to dose or length of exposure, which is affected by water solubility. Highly water-soluble agents cause immediate mucosal and upper airway irritation, allowing victims to take protective action, potentially limiting further injury. Poorly water-soluble agents like phosgene often cause delayed pulmonary toxicity from prolonged exposure times. Chlorine has intermediate water solubility and thus has the capacity to cause both upper airway irritation as well as pulmonary injury from prolonged low concentration exposures.

Significant exposures rapidly result in dermal, eye, and pulmonary irritant effects with morbidity largely due to pulmonary injury. Like mustards, it is heavier than air and may collect in low-lying areas. Chlorine is highly corrosive, and its toxic effects result from reaction with water to form hypochlorous and hydrochloric acid. In addition to causing direct cellular injury, these by-products lead to the production of free radicals that cause further damage to cellular proteins, pulmonary surfactant, and enzyme systems [85, 86, 87].

Clinical effects are dose dependent with mild irritation of mucosal membranes at 1–3 parts per million (PPM), onset of pulmonary effects at 15–20 ppm, and fatalities over 200 ppm [88]. Severe pulmonary exposure results in pulmonary edema and ARDS (acute respiratory distress syndrome). Dermal contact results in irritation and potential blister formation. Ocular effects include chemosis and conjunctivitis, with higher concentrations rapidly causing corneal epithelial defects [88].

Unlike most vesicants, chlorine-related casualties do not represent a significant contamination risk to rescue workers. Standard decontamination should include removal of clothing and copious irrigation for any dermal or eye symptoms. There is no specific antidote for chlorine exposures. Following decontamination, mainstay treatments include parenteral steroids and inhaled beta-agonists for respiratory complications [89, 90]. A small case series demonstrated benefit with inhaled sodium bicarbonate (3.75%) nebulizer without adverse effects [91].

Chlorine has many uses, ranging from household cleaning agent and disinfectant to water treatment and bleaching agents of wood pulp in pulp mills. Annual US industrial production exceeds 10 million metric tons (US Census Bureau 2009). Most US production is limited to less than a dozen states, requiring regular transport of large quantities to metropolitan areas [92].

Fatalities have resulted from both domestic accidents and terrorist attacks abroad. In January of 2005, a railroad accident in Graniteville, SC led to the release of nearly 60 tons of chlorine gas, resulting in nine fatalities and over 500 visits to local emergency departments for related symptoms [93]. Between January and June of 2007, insurgents in Iraq conducted 15 separate attacks using improvised (usually tanker truck) chlorine bombs that were responsible for over 100 fatalities and countless injured [94]. Clearly, this agent remains a viable threat for terrorist attacks both here in the United States and abroad. Although case fatality rates for those surviving to hospital evaluation are low, the sheer number of potential patients seeking medical care may rapidly overwhelm local and regional medical resources.

Carbonyl dichloride or phosgene (COCl2) is a colorless gas well known for its use as a chemical weapon during World War I. Like chlorine, phosgene is heavier than air and will collect in low-lying terrain. It is used today as a chemical reagent in the production of other organic compounds and pharmaceuticals. The majority of phosgene is used in the production of isocyanates (e.g., toluene diisocyanate and methylene diphenyl diisocyanate), which are used in the production of polyurethanes. Toxicity from exposure to methyl isocyanate is clinically indistinguishable to that of phosgene. Because of these large-scale industrial uses, it is classified as a schedule 3 chemical under the Chemical Weapons Convention [2].

Unlike chlorine gas, phosgene (Fig. 14.5) is poorly water soluble and therefore reaches the pulmonary alveolus without significant upper airway symptoms or irritant warning. Phosgene is a highly reactive acylator, reacting with nucleophilic moieties at its site of predominant contact (alveolus) [95]. Clinical effects include cough, dyspnea, hypotension, vomiting, and dermal irritation [96]. Death is secondary to pulmonary edema and acute lung injury (ALI). Phosgene was responsible for the majority of chemical deaths during WWI. It is not clear whether phosgene-induced ALI is secondary to cardiogenic dysregulation or direct pulmonary injury. Histopathology of the lungs reveals exposure-dependent edema and a progressive bronchiolar inflammatory response, with infiltration of polymorphonuclear cells and lymphocytes [97]. Recent animal studies seem to favor cardiogenic dysfunction and demonstrated the inefficacy of anti-inflammatory agents post exposure [98, 99, 100]. Some authors recommend that NAC and bronchodilators should be given in all cases that have respiratory symptoms, with an additional benefit potentially from corticosteroids [101].
Fig. 14.5

Phosgene. Phosgene, World War II Gas Identification Posters, ca. 1941–1945, U.S. Army, National Museum of Health and Medicine, http://www.medicalmuseum.mil/assets/images/galleries/world_war_II/phosgene.jpg

Olfactory detection described as “freshly mown hay” or “cut green corn” occurs at 1–2 ppm but without immediate symptoms. Toxicity of phosgene is enhanced by its lack of water solubility. Unlike chlorine, low-level gas concentrations may go unnoticed and result in significant morbidity due to a higher cumulative exposure. The same 1–2 ppm exposure after several hours of latency leads to significant dermal irritation and pulmonary edema [102]. The lethal dose of phosgene in humans is nearly 500 ppm/min. Exposure to 5 ppm for 100 minutes is equally as fatal as exposure to 50 ppm for 10 minutes [103].

Although pulmonary injury dominates medical management with significant exposures, ocular symptoms in these cases often include lachrymation and conjunctivitis. Corneal epithelial defects may result in delayed keratopathy, but permanent eye injuries are rarely reported in the literature. Unlike lewisite, phosgene’s irritating quality can be mild and delayed, which may result in exposure for prolonged periods [104]. Dose-dependent exposure determines time of symptom onset and degree of injury. Unfortunately, this usually results in significant exposure by the time of moderate symptom onset [105].

This has led to the development of chemical sensors, which combine with phosgene to initiate intramolecular cyclization and convert nonfluorescent molecules to highly fluorescent products with detection limits as low as 1 nM [106]. Residual vapor detection (RVD) kits, which utilize silica impregnated with colorimetric chemicals, are also effective for phosgene detection, in addition to several other CW agents.

Nerve Agents

Nerve agents are phosphorus-containing organic chemicals or organophosphates (OP) that bind to acetylcholinesterase, a key enzyme that regulates neurotransmission by metabolizing acetylcholine within the synapse.

Originally developed as an insecticide, tabun (GA) was first synthesized in 1936 by German scientist Dr. Gerhard Schrader. Recognizing the extreme toxicity of this agent, other agents were developed under the Nazi regime including sarin (GB) in 1938 and soman (GD) in 1944. Cyclosarin (GF) was later developed in 1949. These agents, known as “G-series” nerve agents because of the initial development by German scientists who first synthesized them, are classified as weapons of mass destruction by the United Nations.

After WWII, further development of these agents led to the discovery of even more toxic pesticides. Diethyl S-[2-(diethylamino)ethyl] phosphorothioate (Amiton) was marketed as a highly effective pesticide by Imperial Chemical Industries, a British chemical company. It was later withdrawn from commercial use due to its extreme toxicity but not before recognition by the British government. This led to the development of a new class of nerve agents known as “V-series” agents. Unlike G series agents, V agents are persistent with a consistency similar to oil, making cross-contamination to health care providers problematic.

Further development of insecticides with strict regulatory guidance has led to drastically improved public safety. Created by the United Nations, an international classification system (Globally Harmonized System of Classification and Labeling of Chemicals or GHS) was developed to assign consistent criteria for classification and labeling at a global level (Globally Harmonized System of Classification and Labelling of Chemical (GHS) -2nd ed. United Nations, 2012).

OP toxicity is secondary to inhibition of acetylcholinesterase (AChE) causing accumulation of excess acetylcholine neurotransmitter in the nicotinic and muscarinic synapses. Excess stimulation of these receptors leads to a cholinergic toxidrome (see Fig. 14.6). Muscarinic receptor overstimulation causes miosis, lachrymation, salivation, diarrhea, loss of bladder control, and potentially lethal bradycardia, bronchorrhea, and bronchoconstriction (aka “killer B’s”). Excess nicotinic effects include transient mydriasis, tachycardia, muscle spasm, and seizures, progressing to paralysis and coma. Weakness often starts peripherally and progresses to respiratory muscle paralysis with both early (<4 hours) and late (>24 hours) respiratory failure [107]. Symptom onset may be delayed with highly lipophilic compounds such as chlorpyrifos and diazinon [108].
Fig. 14.6

Cholinergic Toxidrome. (Modified from Cholinesterase Inhibitors, ATSDR, Oct 2007, http://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=5)

Clinically, these agents do not cause ocular toxicity per se but are important to mention because of their ocular effects including miosis, decreased vision, and eye pain. The Tokyo subway sarin attack on 20 March 1995 left 12 dead and over 5000 people complaining of acute illness. Of the 627 patients who presented to local emergency departments, over 90% displayed miosis, and nearly half complained of decreased or blurred vision and eye pain [109]. Unlike G agents, exposure to VX may cause little or no initial ocular symptoms. Initial symptoms may also be affected by route of exposure (e.g., inhalation of G agents versus more common dermal absorption of VX) (Fig. 14.7).
Fig. 14.7

Organophosphate aging and pralidoxime (2-PAM). (Modified from CDG Case Studies in Environmental Medicine. http://www.atsdr.cdc.gov/csem/csem.asp?csem=11&po=23)

Inhibited (or phosphonylated) AChE may spontaneously reactivate, and they reactivate more quickly in the presence of an oxime drug (e.g., 2 PAM), or become irreversibly bound to the OP, a process known as “aging” (involves dealkylation, dearylation, and deamidation). Irreversible inhibition or aging is associated with high mortality rates, and timing varies between different agents. Soman is perhaps the one of the most potent nerve agents with an average aging time of less than 5 minutes (Table 14.4) [110].
Table 14.4

Irreversible inhibition or aging associated with high mortality rates and timing varies between different agents

Agent

LCt50 (lethal concentration mg-min/m3)

Aging half-life

Tabun (GA)

400

<40 h

Sarin (GB)

100

<12 h

Soman (GD)

50

minutes

VX

10

<55 h

Adapted from Ivarsson et al. [202]

The focus of treatment is prudent use of atropine to avoid morbidity from the muscarinic “killer B’s” and pralidoxime to regenerate AChE prior to potential aging. This is in concert with thorough decontamination to avoid ongoing exposure to both patient and healthcare providers.

The adult atropine dosing is 1–3 mg intravenously (child: 0.05 mg/kg IV), with repeated doubling of dosage every 3–5 minutes as needed until drying of pulmonary secretions [111]. Children may be more vulnerable than adults with more pronounced CNS effects, and they have a larger surface area to body size, faster minute ventilation, and faster metabolic rates [112, 113]. Once control of secretions (clear lungs) is achieved, maintain with an infusion of 10–20% of the loading dose every hour, monitoring for evidence of atropine toxicity (e.g., delirium and hyperthermia) and titrate accordingly. Large doses are often required and may be needed for days depending on severity.

Treat nicotinic symptoms (fasciculations, muscle weakness, respiratory depression, coma, and seizures) with pralidoxime in addition to atropine. This is most effective if given within 24 hours of exposure but is dependent on the specific agents. Not all agents undergo aging. Administer for 24 hours after cholinergic manifestations have resolved. WHO recommendations include an initial bolus of least 30 mg/kg followed by an infusion of more than 8 mg/kg/h or 1–2 g of pralidoxime infused over 15 minutes (child: 50 mg/kg max 2 g/dose) [114]. This is followed by an infusion of 500 mg/h (child: 20 mg/kg/h max 500 mg/h). Avoid depolarizing neuromuscular agents such as succinylcholine for rapid sequence intubation, as they might have prolonged action times.

Incapacitating Agents

3-Quinuclidinyl benzilate (BZ) or “buzz” is an anticholinergic glycolate similar to atropine and scopolamine. These agents antagonize muscarinic cholinergic receptors in both the peripheral and central nervous systems. BZ was discovered by a Swiss pharmaceutical company in the 1950s, looking to develop an antispasmodic agent for gastrointestinal complaints [115]. Its development as a military weapon was highly prioritized shortly thereafter. Over 50 tons were produced for the US Army between 1963 and 1964 (“A Plan to Destroy an Old Weapon”, Chemical Weekly, 1982;13–14). Aerosolized dissemination was done using thermal generators of either 3 × 50-lb canisters (M16) or a 750-lb bomb cluster (M43) [116].

BZ is odorless, nonirritating, and persistent. The ICt50 (incapacitating concentration in 50% of exposed individuals) would vary based on activity, but for mild exertion, it is approximately 100 mg-min/m3 [117]. With respect to other hallucinogens like weaponized LSD, BZ has a superior safety index, with approximately a 100-fold difference between LCt50 and ICt50. Inhalational exposure leads to fluctuating delirium with behavioral lability, dry flushed skin, and obvious mydriasis (dilated pupils). Of note, mydriasis from anticholinergic toxicity can usually be differentiated from sympathomimetic agents (e.g., amphetamines and cocaine), as the latter will constrict slightly with light reflex testing. This is not possible with anticholinergics because the pupillary constriction mechanism relies on cholinergic function and is effectively “paralyzed” under these conditions. Other symptoms include drying of secretions and constipation (opposite to nerve agent effects). Use of the Mark 1 antidote kit (atropine) could worsen symptoms, but CNS effects would most likely only be manifest after multiple doses.

After much testing, the use of BZ was eventually abandoned by the US military due to several reasons. Live dispersal would manifest as a white cloud obvious to targeted personnel. Also, the rate and duration of action are highly variable, with only half of effected individuals showing symptoms at 5 hours. Unlike nerve agents, effective inhalational delivery could be largely subverted by breathing through several layers of folded clothing, and BZ was relatively expensive to produce. Designed to be used in very specific scenarios as a means for nonlethal incapacitation, the majority of those affected required restraint to prevent self-injury with duration of action of more than 36 hours [117].

Specific antidote therapy is aimed at increasing levels of postsynaptic acetylcholine. The antidote of choice is carbamate anticholinesterase physostigmine, which, unlike pyridostigmine, is able to penetrate the CNS and reverse the central, as well as peripheral neuronal effects of BZ. Adult dosing is 1–2 mg IM or slow IV push (<1 mg/min). Rapid administration may lead to dangerous bradycardia and arrhythmias. Administration of physostigmine is clinically more effective if given beyond 4 hours following BZ exposure [118]. The successful use of antidote does not shorten the clinical course of BZ exposure (upwards of 96 hours), and given the short duration of physostigmine (60 minutes), frequent re-dosing is required (start at 2 mg/h and titrate to effect).

Although the United States considered BZ obsolete in 1977, the Soviets and Iraq were reported to continue development of BZ known as “agent 78” and “agent 15,” respectively. Recent alleged reports of use of these agents include the Syria and Gouta attacks.

Fentanyl is a powerful synthetic opioid, which has been developed for use as an incapacitating agent by both the United States and former Soviet Union. In weaponized aerosol form, primary clinical effects include pin-point pupils (miosis), CNS depression, and respiratory depression within seconds to minutes of exposure. Fentanyl is approximately 100 times more potent than morphine and heroin. Ultrapotent analogs include alfentanil, sulfentanil, and carfentanil. Much controversy surrounds the suspect use of this or related agents (3-methyl fentanyl or kolokol-1) by Russian Spetsnaz in the 2002 Moscow theater hostage crisis. Over 130 of 850 hostages died from exposure to an unconfirmed chemical agent that was introduced through the theater’s ventilation system prior to breach. There are unconfirmed reports that a handful of hostages were revived by the use of naloxone by EMS personnel. Fentanyl can be absorbed via inhalation, ingestion, or dermal contact.

Naloxone is an opioid receptor antagonist and can reverse the effects of fentanyl within 1–3 minutes following intravenous administration (0.4–2 mg doses). Maximum effect is within 5 minutes and the duration of action is nearly 1 hour. Doses may be repeated until desired effect.

Following animal testing, the United States abandoned further development of aerosolized fentanyl (including related analogs) as an effective incapacitating agent primarily due to its unacceptably low safety index.

Riot Control Agents

Riot control agents (RCAs) are designed for immediate incapacitation of individuals while minimizing harmful or permanent effects. Historically, these agents have been used for centuries (e.g., Japanese use of pepper dust blown in the face of enemies). RCAs are considered harassing agents and nonlethal and designed to produce temporary disability. Most of these agents are solids at room temperature, soluble in organic solvents, and typically dispersed as aerosols. They all cause rapid onset of lachrymation, eye pain, and ocular and dermal irritation. The United States excludes these agents from the Geneva Convention on chemical weapons; however, their use during wartime is restricted to defensive use and only with written approval from the President (Gerald Ford 8 Apr 1975, Executive Order 11850 “Renunciation of Certain Uses in War of Chemical Herbicides and Riot Control Agents”, National Archives; Joseph Benkert 27 Sept 2006, “U.S. Policy and Practice with Respect to the Use of Riot Control Agents by the U.S. Armed Forces”, Senate Committee on Armed Services).

Chloroacetophenone (CN) was invented by German chemist Carl Graebe in the later part of the nineteenth century. It was later developed by the British and United States during WWI as a very stable and very effective lachrymator. Post WWI, it became the primary RCA of choice until gradual replacement by chlorobenzylidene malononitrile (CS) in the 1950s. Both agents act through alkylation of intracellular sulfhydryl groups on enzymatic processes. Injury is limited due to rapid regeneration of these enzymes and breakdown of the parent compounds.

Clinical effects include intense eye pain and rapid onset of lacrimation, conjunctivitis, copious rhinorrhea, salivation, pharyngeal irritation, cough, and dyspnea. These agents have excellent safety profiles. Animal studies demonstrate CN inhalation median lethal concentration-times (LCt50) between 7000 and 9000 mg-min/m3. At these levels, autopsy revealed pulmonary edema, alveolar hemorrhage, tracheitis, and bronchopneumonia [119].

Rare deaths have been associated with indiscriminate use of these agents. A single CN grenade (128 g) was thrown into a room (27 m3) where an assailant had barricaded himself from police [120]. He remained in the room for approximately 30 minutes, after which he was found comatose and in pulmonary edema. He was rapidly transported to a local hospital and died 12 hours later. Estimated exposure was more than 140,000 mg-min/m3, which is approximately ten times estimated LCt50 for humans. A handful of similar case reports all involve individuals confined to relatively small, enclosed spaces. High levels of CN can cause corneal and conjunctival injury with loss of corneal epithelium [16]. Other considerations include proximity and injury from the dispersal device itself.

No permanent eye injuries have been described with exposure to the recommended harassing or “field concentration” doses of CN. Sensitization to prior exposures is a theoretical concern and has been reported in animal studies with CN and other RCAs [121].

O-chlorobenzylidene malononitrile (CS), also 2-chlorobenzalmalononitrile, is the key component in tear gas and the most widely used RCA in US law enforcement and military operations today. CS has a half-life of less than 15 minutes, making it ideal as a temporary incapacitant. The US military developed variants of CS including CS1, CS2, and CSX. These agents have increased shelf life, resist degradation, and can be used over water terrain.

Clinical effects are similar, although CS is superior to CN as a more potent lachrymator with reduced toxicity. Animal studies on CS inhalational toxicity demonstrate LCt50 (mg-min/m3) between 35,000 (guinea pig) and 70,000 (rat) [119, 122]. Following exposure, symptoms include immediate conjunctivitis with burning pain, blepharospasm, and profuse lacrimation with photophobia. Conjunctivitis and erythema of the eyelids may persist for an hour. CS is much less likely than CN to produce long-term ocular effects including corneal scarring or delayed keratopathy [123, 124]. Animal studies of direct ocular exposure to CS solutions did not produce permanent damage, and all tissues were normal within 1 week [125].

Exposure symptoms include burning or stinging sensation in the nose, mouth, and throat with excessive rhinorrhea and salivation. Some individual experience pronounced coughing, dyspnea, tightness of the chest, skin irritation, and vomiting. These effects usually resolve within 10–15 minutes after cessation of exposure with the exception of ocular irritation, which usually last up to 1 hour. CS is less tolerated by individuals under exertion or in higher ambient temperatures [126].

CS is commonly used to simulate CW agents in training scenarios for military and law enforcement (LE). Heated dispersion of CS canisters is frequently employed for mask confidence training; however, within enclosed spaces, this was found to produce several semi-volatile air contaminants [127]. The metabolic effects of CS exposure and its metabolites are well known. Current studies are looking at the products of pyrolysis from the heated dispersion of CS. GC/MS of decomposition products demonstrates a loss of cyanide from the CS molecule, and air samplings reveal the presence of both HCl and HCN in high-temperature CS dispersion [128]. Currently, the use of CS capsules is the only approved method for enclosed-space mask confidence training.

Oleoresin Capsicum (OC) or “pepper spray” is a mixture of pepper plant extracts (paprika, chili peppers, and jalapeno) from the Capsicum genus, including Capsicum annuum and Capsicum frutescens. The active ingredients in pepper sprays are capsaicinoids (vanilloid family) and include several different individual chemicals (capsaicin, norhydrocapsaicin, dihydrocapsaicin, and homocapsaicin).

OC concentrations may vary from 0.1% to 3% of CRC (Capsaicinoid Related Content), but manufacturers do not specify amounts of individual capsaicinoids; thus, it is difficult to make comparisons of relative strengths with different brands. Most LE agencies use a CRC between 1% and 2%, and the EPA mandates pepper sprays marketed as “bear deterrents” must contain at least 1% but not more than 2% CRC [129]. Another measure, the Scoville scale is an empirical measurement of spicy foods as reported in Scoville heat units (SHU). Testing involves exact dry weight measurements of extracted capsaicinoids sampled by trained tasters to detect the heat in a dilution sample, which is rated in multiples of 100 SHU [130, 131]. Pepper spray products demonstrate variability in the capsaicinoid concentrations, between different manufacturers, as well as from different product lots of the same manufacturer, and are not standardized for capsaicinoid content even though they may be classified by SHU [132].

Synthetic capsaicin analogues, such as nonivamide (pelargonic acid vanillylamide or PAVA), has similar effects and is more heat stable than capsaicin [133, 134]. In addition to its use as a RCA, nonivamide is used in food flavorings and spice blends, as well as a cheaper pharmaceutical alternative to capsaicin in therapeutic liniments.

OC is widely used by the US government and LE agencies. Like CS and CN, it is a highly effective dermal and upper respiratory irritant. Primary physiologic effects include intense ocular and dermal irritation with pain, blepharospasm, and excessive lachrymation. Ocular exposure causes involuntary closure of the eyes and temporary visual impairment for approximately 15 minutes. Visual acuity normally returns within 5–10 minutes following decontamination, although individuals frequently experience pain for up to 30 minutes [135]. The LD50 of OC is route dependent. Human LD50 for dermal exposure is estimated at 500 mg/kg, whereas oral is approximately 200 mg/kg, inhaled is 2 mg/kg, and intravenous is 0.5 mg/kg [136]. Rats fed capsaicin 50 mg/kg per day for 60 days developed no significant untoward effects [137, 138].

Physiologic effects are secondary to capsaicin binding to sensory receptors TRPV1 (transient receptor potential vanilloid receptor 1). TRPV1 functions in the detection and regulation of body temperature, as well as provides sensation of thermal pain (nociception). Capsaicin-induced bronchospasm, mucosal edema, and neurogenic inflammation are mediated by TRPV1, increased release of substance P and neurokinin A [139, 140].

Dosage varies based on delivery device, but the most commonly used carrier is isopropyl alcohol [141]. This may complicate ocular injuries when used at close range. Although OC use in LE is common and generally considered very safe, direct exposure to high concentrations can lead to permanent injury. Rare human case reports site epithelial necrosis, limbal ischemia, and ultimate permanent peripheral field defects due to conjunctivalization following direct spray exposure to OC [142]. Animal studies have shown keratitis and neurotrophic injury following systemic exposure to capsaicin [143]. Children may be particularly sensitive to long-term injury. A case report of OC exposure in a toddler demonstrated conjunctival proliferation and scarring at the limbus despite topical corticosteroid treatment [144]. It is suspected that OC exposure may release neuropeptides which induce inflammation separate from traditional immune-mediated mechanisms. This results in neurogenic inflammation and loss of blink reflex, which can last for several days and increases risk of severe corneal injury [145].

Dibenzoxazepine (CR) was developed for use by the British military in the early 1960s. It is the latest of the “C” series RCAs and the most potent incapacitator of the group. Similar but more powerful than CS, CR causes immediate incapacitation with intense blepharospasm, temporary functional blindness, painful skin irritation (exacerbated in moist areas), and coughing with dyspnea [145]. Attempts at decontamination with water often worsen dermal pain and these affected areas can remain sensitized for days. Avoid cross-contamination and decontaminate with soap and water as with other “C” agents [146].

CR is a solid at room temperature and very stable. Dispersal is usually by particle emulsion in propylene glycol and release from heated canisters. As a vapor, CR is heavier than air and hydrolyzes slowly in water, and thus will persist in low lying areas.

Animal toxicology studies reveal that CR is less toxic than CN and CS [147]. Respiratory effects include dyspnea with diminished FEV for 20 minutes after CR inhalational exposure [148]. Animals exposed to aerosol doses of 80,000 to 160,000 mg-min/m3 revealed alveolar hemorrhage and edema only on microscopic lung examination [149]. Intense dermatologic effects typically last for 30 minutes, followed by gradual diminution over several hours [147].

Clinical ocular effects include intense lachrymation and conjunctivitis lasting less than 1 hour. Animal studies with corneal exposures to both CR aerosol and solution (in polyethylene glycol) up to 17,000 mg-min/m3 produced mild injection and dose-related corneal edema which cleared over several days without any permanent effects [150].

Chloropicrin (PS) or nitrochloroform was first discovered in 1848 by Scottish chemist John Stenhouse. The name chloropicrin comes from his use of a chlorinating agent applied to picric acid. Among his many discoveries, he is probably best known for his description of the absorbent properties of wood charcoal to disinfect and deodorize, which led to his invention of charcoal air-filters and charcoal respirators [151].

PS is colorless, poorly water soluble, and volatile at ambient temperatures. Although used as a harassing agent in WWI, it might be better thought of as a pulmonary or choking agent. Current formulation is by the reaction of nitromethane with sodium hypochlorite, and it is used today as a highly regulated broad-spectrum fungicide and insecticide [152].

Due to its dermal and respiratory irritant effects, WWI German forces used concentrated PS gas as a tear agent against allied forces. Although not as toxic as phosgene or the vesicants of WWI, exposure would provoke vomiting, causing soldiers to remove their masks, exposing them to more CW agents.

Unlike phosgene, PS is immediately irritating to the nose, eyes, lungs, and skin at 1–2 PPM [153]. Victims report an unpleasant taste followed by nausea, vomiting, and headache. PS can also be absorbed systemically via inhalation, ingestion, and dermal contact. PS is a volatile aliphatic nitrate that causes direct cellular injury at the site of dermal contact. Systemic effects in animal studies include methemoglobinemia and modification of free sulfhydryl groups [154]. It is not clear the exact mechanisms, whether related to the parent compound or secondary metabolites, but evidence indicates oxidative damage which may be reversed by antidotes such as NAC [155, 156]. Increasing exposure leads to pulmonary edema and death via early asphyxiation or delayed chemical pneumonia [157]. The estimated LCt50 for PS is 2000 mg-min/m3 or 300 PPM [158]. Much like the vesicants of WWI, direct skin exposure causes irritation and rash with blister formation [159].

Ocular irritation usually begins before odor threshold (<1 PPM), and includes lachrymation, blepharospasm, and conjunctivitis. These early warning symptoms usually prompt potential victims to seek protection from further exposure. Case reports of ocular exposure to liquid PS demonstrated severe corneal edema, chemosis and eventual perforation [160]. Specific animal data for ocular exposures are limited but reports demonstrate dose-dependent corneal injury patterns similar to mustard agents.

Adamsite (DM), or diphenylaminochloroarsine, was developed by German scientist Heinrich Otto Wieland in 1915, and later production was improved by Major Robert Adams at University of Illinois in 1918 [161].

DM is an odorless, yellow-green crystalline substance with low volatility (persistent) and poorly water soluble. It is usually dispersed by powder grenade or aerosolized in organic solvents. It was heavily stockpiled by the United States during WWII but not used until Vietnam. DM was often mixed with CN or CS and used by the US military during the Vietnam War as an effective means to deny enemy access of territory [162].

Clinical effects from DM exposure typically have a latency of 5–10 minutes. Gastrointestinal effects, including nausea, vomiting, and diarrhea, predominate over dermal and respiratory irritant effects. Delayed effects had the advantage of creating a significant exposure to most victims. Primate studies demonstrated rapid onset of symptoms including rhinorrhea, salivation, vomiting, lack of coordination, and dyspnea following inhalation exposures with estimated LCt50 between 12,000 and 14,000 mg-min/m3 [163]. These data correlate with human LCt50 estimates for exposure to highly purified DM. Human deaths have been reported following exposure to high DM concentrations within an enclosed space [164]. Postmortem examination revealed pulmonary edema and diffuse inflammation throughout the entire respiratory tract. ED50 (incapacitating dose) in human volunteers of DM ranged from 22 to 220 mg-min/m3. Animal studies on ocular toxicity revealed dose-dependent corneal injury from temporary conjunctivitis (0.2 mg) to corneal epithelial injury and partial limbal ischemia (0.5 mg) to complete corneal opacification (1.0–5.0 mg) [164].

Classified as a malodorant, “skunk” is marketed as a nonlethal means for crowd control. It is commonly used by Israel Defense Forces as an improvement over the use of RCAs or rubber bullets following increasing criticism of disproportionate use of force in conflicts with Palestinian protestors.

Produced by Odortec Ltd., this product is marketed as “safe to consume”, “100% eco-friendly”, and “poses no health hazard” [165]. Specific chemical ingredients are lacking, though production involves the fermentation of yeast with sodium bicarbonate and production of various amino acids. The MSDS reports prolonged contact may cause dermal, eye, and respiratory irritation [166]. The product is stable and nonvolatile, although its odor effects tend to persist for several days.

In contrast, natural skunk spray or skunk musk contain a mixture of several volatile sulfur-containing compounds including methylquinoline, quinolinemethanethiol, quinolinemethyl thioacetate, phenylethanethiol, butenyl disulfide, and methylbutyl disulfides identified by GC/MS [167]. The relative amounts of specific chemicals present are clearly species specific. Known to cause dermal irritation, weakness, malaise, vomiting, headache, and confusion in human exposures; cyanosis, pulmonary irritation; liver and kidney injury in animals, butanethiol or n-butyl mercaptan has threshold exposure limits set by the CDC of 0.5 ppm (27 mg-min/m3) [168].

There are animal case reports of methemoglobinemia with Heinz body formation following exposure to natural skunk musk, later confirmed by in vitro studies [169, 170]. These studies demonstrated a dose-dependent relationship of skunk musk to the level of resultant methemoglobin, supporting a theory of oxidative stress-induced hemolysis.

These agents could represent a potential terrorist chemical threat, but due to their relative safety and very low odor detection thresholds (<0.001 ppm) (National Center for Biotechnology Information, NIH; http://pubchem.ncbi.nlm.nih.gov), their risk relative to other agents is small.

Ultraviolet Light

The toxicodynamics of many chemicals is mediated via oxidative injury, but ultraviolet radiation (UV) is the most important oxidizing agent in regard to the eye. High-energy UV-C (100–280 nm) radiation is completely filtered by our atmosphere (Fig. 14.8). We are exposed to only a small portion of UV-B (280–314 nm) and most of UV-A (315–399 nm). A typical human retina functions at wavelengths from approximately 390–700 nm [171]. Both the cornea (UV-B) and lens (UV-C) absorb UV radiation, preventing transmission of nonvisible light to posterior ocular structures and the retina.
Fig. 14.8

High-energy UV-C radiation. Office of Air and Radiation (6205J); June 2010; EPA 430-F-10-025, The stratospheric ozone layer screens out much of the sun’s harmful UV rays, http://www.epa.gov/sunwise/doc/uvradiation.html

Our eyes are constantly exposed to UV-induced photo-oxidation, generating free radical oxygen species which cause both acute oxidative injury and cumulative effects over time. Enhanced protein binding, biotransformation reactions, and a plethora of free radical scavengers such as glutathione and superoxide dismutase are present in the eye to help compensate for these toxins.

Studies exploring corneal transmission of UV radiation as a function of position across the corneal surface show decreased transmission in the peripheral regions [172]. It is suspected that the effects of UV radiation are more pronounced in the posterior cornea (corneal endothelium), a single layer of cells that have little ability to proliferate in vivo. With maximum UV transmission in the central regions of the cornea, we would expect greater damage on cells through free radical oxidative injury. These mechanisms, in part, explain age-dependent injury patterns common to the central cornea.

Battlefield laser (light amplification by stimulated emission of radiation) injuries are increasing in frequency and deserve note. The use of powerful lasers for target identification and fire control is common on today’s battlefield. Important factors in determining severity of injury are (1) location of retinal injury, (2) power output of the laser, and (3) duration of exposure [173]. A moderate retinal lesion outside the macula may be sub-clinical, whereas a small lesion within the fovea may be visually devastating.

Biological injury is determined by the amount of energy per unit area over a given exposure time (watts-sec/cm3). Lasers are often classified by power output. Most ‘laser pointers’ in the United States are class 2 or 3a lasers (less than 5 mW output) [174, 175]. By contrast, class 3b (<500 mW) and class 4 (>500 mW) are typically used in occupational and military settings and capable of causing extensive retinal injury [176]. The retina is far more susceptible to laser injuries because the eye focuses light onto the retina with up to 10,000 times the irradiance present at the cornea [177]. Patients may present with cornea redness, pain, and irritation but any anterior structure injury is relatively minor and usually secondary to external rubbing or irritation. Spectral optical coherence tomography often demonstrates focal areas of retinal injury with inner and outer retinal segment disruption [178]. Patients may have “blind spots” in their visual field, but the presence and degree of impairment is often related to retinal lesion location in proximity to the fovea (central vision). Minor injuries usually recover over a period of weeks, but some patients develop chronic complications including progressive chorioretinal scarring, macular cyst/hole formation, epiretinal membrane formation, and CNV [179, 180, 181].

Definitive treatment of laser-induced retinal injuries is limited. There is support for systemic corticosteroids, antioxidants, and other anti-inflammatory agents. Intra-vitreal anti-vascular endothelial growth factors and steroid agents have been used to successfully treat radiation-induced macular edema and neovascular events secondary to radiation retinopathy in cancer patients, but visual outcomes in these patients remain variable [182, 183]. Future research will help evaluate the use of retinal-specific biomarkers for early detection of subtle or subclinical injuries.

Systemic Ocular Toxins

Beyond external exposures, systemic xenobiotics can impact vision via toxicity at many different sites within the eye. The proper function of each refractive segment of the eye is maintained by complex biochemical systems. These systems are vital both in the maintenance of tissue protein structure and metabolism, as well as detoxifying free radicals and other chemical stressors.

Many xenobiotics influence photo toxicity through the formation of stable ring structures which lead to free radical formation. Oxidation of thiol groups on lens proteins leads to cross-linking of polypeptide disulfide bonds and the accumulation of high molecular weight aggregates with enhanced light-scattering effects [184, 185]. Common examples include glucocorticoids which induce covalent modification of lens crystallins, followed by formation of water-insoluble aggregates or cataracts [186].

The retina is highly specialized and thus susceptible to xenobiotic mediated toxicity on many levels. Choriocapillaries with high flow rates allow diffusion of xenobiotics through loose junctions into the outer retina. Many xenobiotics are concentrated by melanin binding in the choroid and RPE [187]. Oxidative toxicity is often synergistic between specific xenobiotics and UV-induced injury. High cellular metabolism may enhance retinal toxicity through accelerated production of secondary toxic metabolites [188].

Retinal neurotoxicity from lead poisoning has been well studied. Exposures in the United States have declined dramatically since the removal of lead from gasoline, but this is not the case for individuals working with jet fuel or military members overseas. Ocular pathology includes optic neuritis manifesting as decreased visual acuity, diplopia, ophthalmoplegia, amblyopia, and scotomas with progression to blindness [189]. Optic nerve toxicity from lead mimics CNS toxicity reflected in global neurocognitive deficits [190]. Early scotomas may only be apparent under scotopic conditions or with early ERG screening [191]. Animal studies suggest interference with cellular calcium signaling may cause mitochondrial homeostasis dysfunction leading to apoptosis [192]. A similar mechanism is proposed with other heavy metals including arsenic, thallium, and cobalt [193, 194].

Methanol, a widely used solvent and fuel source, causes irreversible retinal and optic nerve dysfunction secondary to its metabolism to formic acid. Visual impairment usually begins 12–24 hours post ingestion [195]. Although the exact mechanism is not known, it is suspected that both local and systemic metabolism to formic acid (formate) disrupts mitochondrial oxidative energy production. This proposed mechanism for optic neuropathy is echoed in other xenobiotics including chloramphenicol, ethambutol, carbon monoxide and cyanide [196, 200]. Malnourished individuals with folate deficiencies and decreased tetrahydrofolate activity are particularly sensitive to these effects. There is no definitive treatment for methanol-induced optic neuritis, but some studies report good outcomes with intravenous methylprednisolone [197].

Toxicity from systemic exposure to organic solvents, usually inhaled or dermal, is well recognized but the mechanism is not well understood. Dose-dependent dyschromatopsia and scotomas are well described in factory workers suffering from chronic exposures [198, 199].

Summary

Ocular chemical exposures should always be treated as true vision-threatening emergencies. Rapid and thorough decontamination is the mainstay of treatment and may be nothing short of vision saving. Healthcare providers need to be familiar with treatments of both occupational and insurgent-related or battlefield chemical exposures. Although ocular blast and open globe mechanisms dominate battlefield eye injuries, this can be partially mitigated by more consistent use of eye protection.

The presence of multiple eye or dermal complaints in a given proximity should alert providers to the possibility of CW agents. Education of current potential CW threats and proper use of PPE is requisite to all soldiers and LE personnel. Diluted hypochlorite solution (0.5% bleach) may be effective in decontamination of intact skin exposed to mustard vesicants and V-nerve agents but should not be used as ocular irrigation solutions. Ready-to-use commercial chemical decontaminants are highly effective against most CW agents, and include both dry and liquid formulations. When in doubt, copious soap and water is usually effective.

Beyond decontamination, early recognition of eye injuries is essential to help minimize long-term complications including delayed keratopathy, recurrent corneal ulceration, and secondary glaucoma. With regard to irrigation, tap water is at least as effective if not superior to saline rinse. Specific irrigation solutions such as DRS (diphoterine rinsing solution) and borate-buffered Cederroth Eye Wash have shown superior efficacy to standard saline in the setting of alkali and mustard eye exposures in animals. If these agents are not readily available, any neutral solutions prehospital (e.g., milk and water) is preferred to avoid any delays in immediate decontamination. The effects of RCAs, under proper use, are temporary and largely self-limited.

Poor visual outcomes after acute corneal injuries are associated with ongoing inflammation beyond the early healing phase (10–14 days). Close follow-up (sometimes daily) is required to optimize outcomes. Current studies support the use of anti-inflammatory agents and immune modulators to aid in early healing, thereby minimizing sub-acute and chronic disease states that result in long-term visual disability. Ongoing early monitoring of IOP is essential to avoid secondary injury. Advances in surgical techniques including limbal stem cell and corneal transplantation have improved success rates in recent years. Discovery of injury-specific biochemical markers have expanded our understanding of these mechanisms.

Systemic exposure to xenobiotics frequently present with isolated neurologic or visual complaints. Healthcare providers should be aware of potential early symptoms including rapid changes in scotopic vision and dyschromatopsias. VEP and ERGs are valuable screening tools for suspected xenobiotic-induced retinal or macular injury in early or subclinical cases. When in doubt, early referral for comprehensive visual testing is recommended. Depending on exposure history, providers may refer patients to toxicology for further evaluation.

References

  1. 1.
    Weapons of war “poison gas” 2009. https://www.firstworldwar.com/weaponry/gas.htm.
  2. 2.
    OPCW: Report on the implementation of the convention on the prohibition of the development, production, stockpiling and use of chemical weapons and on their destruction. http://www.opcw.nl: OPCW; 2013.
  3. 3.
    Puangsricharern V, Tseng SC. Cytologic evidence of corneal diseases with limbal stem cell deficiency. Ophthalmology. 1995;102(10):1476–85.PubMedCrossRefGoogle Scholar
  4. 4.
    Laibson PR, Oconor J. Explosive tear gas injuries of the eye. Trans Am Acad Ophthalmol Otolaryngol. 1970;74(4):811–9.PubMedGoogle Scholar
  5. 5.
    Adler. In: Adler, editor. Adler’s physiology of the eye. 9th ed. St. Louis: Mosby-Year Book; 1992.Google Scholar
  6. 6.
    Sears. In: Sears, editor. Pharmacology of the eye: Springer-Verlag; 1984.Google Scholar
  7. 7.
    Eves P, Smith-Thomas L, Hedley S, Wagner M, Balafa C, Mac NS. A comparative study of the effect of pigment on drug toxicity in human choroidal melanocytes and retinal pigment epithelial cells. Pigment Cell Res. 1999;12(1):22–35.PubMedCrossRefGoogle Scholar
  8. 8.
    Potts. Toxic responses of the eye Casarett and Doull’s Toxicology: the basic science of poisons. 5th ed. New York: McGraw-Hill; 1996.Google Scholar
  9. 9.
    Goldsmith TH. Optimization, constraint, and history in the evolution of eyes. Q Rev Biol. 1990;65(3):281–322.PubMedCrossRefGoogle Scholar
  10. 10.
    King G, Hirst L, Holmes R. Human corneal and lens aldehyde dehydrogenases. Localization and function(s) of ocular ALDH1 and ALDH3 isozymes. Adv Exp Med Biol. 1999;463:189–98.PubMedCrossRefGoogle Scholar
  11. 11.
    Mader TH, Carroll RD, Slade CS, George RK, Ritchey JP, Neville SP. Ocular war injuries of the Iraqi Insurgency,January-September 2004. Ophthalmology. 2006;113(1):97–104.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    CDC/DHHS. Explosions and blast injuries, a primer for clinicians; 2008.Google Scholar
  13. 13.
    Arya SK, Malhotra S, Dhir SP, Sood S. Ocular fireworks injuries. Clinical features and visual outcome. Indian J Ophthalmol. 2001;49(3):189–90.PubMedGoogle Scholar
  14. 14.
    Sacu S, Segur-Eltz N, Stenng K, Zehetmayer M. Ocular firework injuries at New Year's eve. Ophthalmologica. 2002;216(1):55–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Jr HW. Mustard gas injuries to the eyes. Arch Ophthalmol. 1942;(27):582–601.Google Scholar
  16. 16.
    Leopold IH, Lieberman TW. Chemical injuries of the cornea. Fed Proc. 1971;30(1):92–5.PubMedGoogle Scholar
  17. 17.
    Hoffmann DH. Eye burns caused by tear gas. Br J Ophthalmol. 1967;51(4):265–8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Wang X, Zhang Y, Ni L, You C, Ye C, Jiang R, et al. A review of treatment strategies for hydrofluoric acid burns: current status and future prospects. Burns. 2014;40(8):1447–57.PubMedCrossRefGoogle Scholar
  19. 19.
    Trevino MA, Herrmann GH, Sprout WL. Treatment of severe hydrofluoric acid exposures. J Occup Med. 1983;25(12):861–3.PubMedCrossRefGoogle Scholar
  20. 20.
    Dohlman CH, Cade F, Pfister R. Chemical burns to the eye: paradigm shifts in treatment. Cornea. 2011;30(6):613–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Clare G, Suleman H, Bunce C, Dua H. Amniotic membrane transplantation for acute ocular burns. Cochrane Database Syst Rev. 2012;9:Cd009379.Google Scholar
  22. 22.
    Fish R, Davidson RS. Management of ocular thermal and chemical injuries, including amniotic membrane therapy. Curr Opin Ophthalmol. 2010;21(4):317–21.PubMedGoogle Scholar
  23. 23.
    Cade F, Paschalis EI, Regatieri CV, Vavvas DG, Dana R, Dohlman CH. Alkali burn to the eye: protection using TNF-alpha inhibition. Cornea. 2014;33(4):382–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Gupta N, Kalaivani M, Tandon R. Comparison of prognostic value of Roper Hall and Dua classification systems in acute ocular burns. Br J Ophthalmol. 2011;95(2):194–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. Br J Ophthalmol. 2001;85(11):1379–83.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Suh MH, Kwon JW, Wee WR, Han YK, Kim JH, Lee JH. Protective effect of ascorbic Acid against corneal damage by ultraviolet B irradiation: a pilot study. Cornea. 2008;27(8):916–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Bunker DJ, George RJ, Kleinschmidt A, Kumar RJ, Maitz P. Alkali-related ocular burns: a case series and review. J Burn Care Res. 2014;35(3):261–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Geffen N, Topaz M, Kredy-Farhan L, Barequet IS, Farzam N, Assia EI, et al. Phacoemulsification-induced injury in corneal endothelial cells mediated by apoptosis: in vitro model. J Cataract Refract Surg. 2008;34(12):2146–52.PubMedCrossRefGoogle Scholar
  29. 29.
    Tewari-Singh N, Jain AK, Inturi S, Ammar DA, Agarwal C, Tyagi P, et al. Silibinin, dexamethasone, and doxycycline as potential therapeutic agents for treating vesicant-inflicted ocular injuries. Toxicol Appl Pharmacol. 2012;264(1):23–31.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Donshik PC, Berman MB, Dohlman CH, Gage J, Rose J. Effect of topical corticosteroids on ulceration in alkali-burned corneas. Arch Ophthalmol. 1978;96(11):2117–20.CrossRefGoogle Scholar
  31. 31.
    Edward Trudo WR. Chapter 7 - Chemical Injuries of the Eye. Ophthalmic Care of the Combat Casualty Borden Institute, Office of the Surgeon General; 2003.Google Scholar
  32. 32.
    Spielmann H, Kalweit S, Liebsch M, Wirnsberger T, Gerner I, Bertram-Neis E, et al. Validation study of alternatives to the Draize eye irritation test in Germany: cytotoxicity testing and HET-CAM test with 136 industrial chemicals. Toxicol In Vitro. 1993;7(4):505–10.PubMedCrossRefGoogle Scholar
  33. 33.
    Moldenhauer F. Using in vitro prediction models instead of the rabbit eye irritation test to classify and label new chemicals: a post hoc data analysis of the international EC/HO validation study. Altern Lab Anim. 2003;31(1):31–46.PubMedCrossRefGoogle Scholar
  34. 34.
    Doucet O, Lanvin M, Thillou C, Linossier C, Pupat C, Merlin B, et al. Reconstituted human corneal epithelium: a new alternative to the Draize eye test for the assessment of the eye irritation potential of chemicals and cosmetic products. Toxicol In Vitro. 2006;20(4):499–512.PubMedCrossRefGoogle Scholar
  35. 35.
    Ikarashi Y, Tsuchiya T, Nakamura A. Comparison of Three In Vitro Assays to Determine the Ocular Toxicity of Detergent, Oil, and Organic Solvents. Cutan Ocul Toxicol. 1993;12(1):15–24.CrossRefGoogle Scholar
  36. 36.
    Sikkema J, de Bont JA, Poolman B. Mechanisms of membrane toxicity of hydrocarbons. Microbiol Rev. 1995;59(2):201–22.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Galvao J, Davis B, Tilley M, Normando E, Duchen MR, Cordeiro MF. Unexpected low-dose toxicity of the universal solvent DMSO. FASEB J. 2014;28(3):1317–30.PubMedCrossRefGoogle Scholar
  38. 38.
    Lapalus P, Ettaiche M, Fredj-Reygrobellet D, Jambou D, Elena PP. Cytotoxicity studies in ophthalmology. Lens Eye Toxic Res. 1990;7(3–4):231–42.PubMedGoogle Scholar
  39. 39.
    DHHS/CDC/NIOSH. Guidance on Emergency Responder Personal Protective Equipment (PPE) for Response to CBRN Terrorism Incidents.: DHHS/CDC/NIOSH; 2008.Google Scholar
  40. 40.
    Taysse L, Daulon S, Delamanche S, Bellier B, Breton P. Skin decontamination of mustards and organophosphates: comparative efficiency of RSDL and Fuller's earth in domestic swine. Hum Exp Toxicol. 2007;26(2):135–41.PubMedCrossRefGoogle Scholar
  41. 41.
    Trapp. The detoxification and natural degradation of chemical warfare agents: Stockholm International Peace Research Institute; 1985.Google Scholar
  42. 42.
    Braue EH Jr, Smith KH, Doxzon BF, Lumpkin HL, Clarkson ED. Efficacy studies of Reactive Skin Decontamination Lotion, M291 Skin Decontamination Kit, 0.5% bleach, 1% soapy water, and Skin Exposure Reduction Paste Against Chemical Warfare Agents, part 2: guinea pigs challenged with soman. Cutan Ocul Toxicol. 2011;30(1):29–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Kompa S, Redbrake C, Hilgers C, Wustemeyer H, Schrage N, Remky A. Effect of different irrigating solutions on aqueous humour pH changes, intraocular pressure and histological findings after induced alkali burns. Acta Ophthalmol Scand. 2005;83(4):467–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Chau JP, Lee DT, Lo SH. A systematic review of methods of eye irrigation for adults and children with ocular chemical burns. Worldviews Evid Based Nurs. 2012;9(3):129–38.PubMedCrossRefGoogle Scholar
  45. 45.
    Hall AH, Blomet J, Mathieu L. Diphoterine for emergent eye/skin chemical splash decontamination: a review. Vet Hum Toxicol. 2002;44(4):228–31.PubMedGoogle Scholar
  46. 46.
    Schrage NF, Struck HG, Gerard M. Recommendations for acute treatment for chemical and thermal burns of eyes and lids. Ophthalmologe. 2011;108(10):916–20.PubMedCrossRefGoogle Scholar
  47. 47.
    Goldich Y, Barkana Y, Zadok D, Avni I, Berenshtein E, Rosner M, et al. Use of amphoteric rinsing solution for treatment of ocular tissues exposed to nitrogen mustard. Acta Ophthalmol. 2013;91(1):e35–40.PubMedCrossRefGoogle Scholar
  48. 48.
    Gerasimo PBJ, Mathieu L, Hall AH. Diphoterine decontamination of 14C-sulfur mustard contaminated human skin fragments in vitro. Toxicologist. 2000;(54):152.Google Scholar
  49. 49.
    Rihawi S, Frentz M, Reim M, Schrage NF. Rinsing with isotonic saline solution for eye burns should be avoided. Burns. 2008;34(7):1027–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Pless M, Friberg TR. Topical phenylephrine may result in worsening of visual loss when used to dilate pupils in patients with vaso-occlusive disease of the optic nerve. Semin Ophthalmol. 2003;18(4):218–21.PubMedCrossRefGoogle Scholar
  51. 51.
    He M, Huang W, Friedman DS, Wu C, Zheng Y, Foster PJ. Slit lamp-simulated oblique flashlight test in the detection of narrow angles in Chinese eyes: the Liwan eye study. Invest Ophthalmol Vis Sci. 2007;48(12):5459–63.PubMedCrossRefGoogle Scholar
  52. 52.
    Levinson. In: Levinson, editor. Clinical methods: the history, physical, and laboratory examinations. 3rd ed: Reed Publishing; 1990.Google Scholar
  53. 53.
    Blice JP. Ocular injuries, triage, and management in maxillofacial trauma. Atlas Oral Maxillofac Surg Clin North Am. 2013;21(1):97–103.PubMedCrossRefGoogle Scholar
  54. 54.
    Norcia AM, Tyler CW, Allen D. Electrophysiological assessment of contrast sensitivity in human infants. Am J Optom Physiol Optic. 1986;63(1):12–5.CrossRefGoogle Scholar
  55. 55.
    Regan D. Electrical responses evoked from the human brain. Sci Am. 1979;241(6):134–46.PubMedCrossRefGoogle Scholar
  56. 56.
    Marmor MF. An updated standard for clinical electroretinography. Arch Ophthalmol. 1995;113(11):1375–6.PubMedCrossRefGoogle Scholar
  57. 57.
    EPA. EPA: Health effect test guidelines. Neurophysiology: Sensory Evoked Potentials.: EPA; 1998.Google Scholar
  58. 58.
    Kollner. Die Störungen des Farbensinners. ihre klinische Bedeutung und ihre Diagnose. Karger; 1912.Google Scholar
  59. 59.
    Schwartz. Visual perception: a clinical orientation; 2004.Google Scholar
  60. 60.
    Department UW. U.S. War Department, General Orders No. 100, Adjutant General’s Office, Washington, April 24. The War of the Rebellion: A Compilation of the Official Records of the Union and Confederate Armies. Washington DC: U.S. Government Printing Office; 1863. p. 1880–901.Google Scholar
  61. 61.
    CDC/NIOSH. Sulfur Mustard, CAS #: 505–60-2; RTECS #: WQ0900000; UN #: 2810. CDC/NIOSH; 2011.Google Scholar
  62. 62.
    Army US. Potential Military Chemical/Biological Agents and Compounds. US Army Field Manual 3–9, US Navy Publication P-467, US Air Force Manual 355–71990. p. 20,32.Google Scholar
  63. 63.
    Vidan A, Luria S, Eisenkraft A, Hourvitz A. Ocular injuries following sulfur mustard exposure: clinical characteristics and treatment. Isr Med Assoc J. 2002;4(7):577–8.PubMedGoogle Scholar
  64. 64.
    Graham JSSB. Historical perspective on effects and treatment of sulfur mustard injuries. Chem Biol Interact. 2013;206(3):512–22.PubMedCrossRefGoogle Scholar
  65. 65.
    Grant W. In: Grant W, editor. Toxicology of the eye : effects on the eyes and visual system from chemicals, drugs, metals and minerals, plants, toxins and venoms. Springfield: Thomas; 1986.Google Scholar
  66. 66.
    Shulman LN. The biology of alkylating-agent cellular injury. Hematol Oncol Clin North Am. 1993;7(2):325–35.PubMedCrossRefGoogle Scholar
  67. 67.
    Papirmeister B, Feister AJ, Robinson I, Ford RD (1991). Medical Defense Against Mustard Gas: Toxic Mechanisms and Pharmacological Implications. Boca Raton: CRC Press; 1991.Google Scholar
  68. 68.
    Javadi MA, Yazdani S, Kanavi MR, Mohammadpour M, Baradaran-Rafiee A, Jafarinasab MR, et al. Long-term outcomes of penetrating keratoplasty in chronic and delayed mustard gas keratitis. Cornea. 2007;26(9):1074–8.PubMedCrossRefGoogle Scholar
  69. 69.
    McNutt P, Tuznik K, Nelson M, Adkins A, Lyman M, Glotfelty E, et al. Structural, morphological, and functional correlates of corneal endothelial toxicity following corneal exposure to sulfur mustard vapor. Invest Ophthalmol Vis Sci. 2013;54(10):6735–44.PubMedCrossRefGoogle Scholar
  70. 70.
    Kadar T, Dachir S, Cohen L, Sahar R, Fishbine E, Cohen M, et al. Ocular injuries following sulfur mustard exposure--pathological mechanism and potential therapy. Toxicology. 2009;263(1):59–69.PubMedCrossRefGoogle Scholar
  71. 71.
    Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med. 2010;363(2):147–55.PubMedCrossRefGoogle Scholar
  72. 72.
    Frank MH, Frank NY. Restoring the cornea from limbal stem cells. Regen Med. 2015;10(1):1–4.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gilman A. The initial clinical trial of nitrogen mustard. Am J Surg. 1963;105:574–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Atkins KB, Lodhi IJ, Hurley LL, Hinshaw DB. N-acetylcysteine and endothelial cell injury by sulfur mustard. J Appl Toxicol. 2000;20(Suppl 1):S125–8.PubMedGoogle Scholar
  75. 75.
    Shohrati M, Karimzadeh I, Saburi A, Khalili H, Ghanei M. The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review. Inhal Toxicol. 2014;26(9):507–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Jugg B, Fairhall S, Smith A, Rutter S, Mann T, Perrott R, et al. N-acetyl-L-cysteine protects against inhaled sulfur mustard poisoning in the large swine. Clin Toxicol (Phila). 2013;51(4):216–24.CrossRefGoogle Scholar
  77. 77.
    Devereaux A, Amundson DE, Parrish JS, Lazarus AA. Vesicants and nerve agents in chemical warfare. Decontamination and treatment strategies for a changed world. Postgrad Med. 2002;112(4):90–6; quiz 4.PubMedCrossRefGoogle Scholar
  78. 78.
    Vijayaraghavan R, Kumar P, Joshi U, Raza SK, Lakshmana Rao PV, Malhotra RC, et al. Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity. Toxicology. 2001;163(2–3):83–91.PubMedCrossRefGoogle Scholar
  79. 79.
    Sidell FRUJ, Smith WJ. Part I: Medical aspects of chemical and biological warfare. In: Zajtchuk B, editor. Textbook of military medicine. Falls Church: Office of the Surgeon General, Dept of the Army; 1997. p. 197–228.Google Scholar
  80. 80.
    Gupta RC. Handbook of toxicology of chemical warfare agents: Academic Press; 2009.Google Scholar
  81. 81.
    Gates MWJ, Zapp JA. In: Committee NDR, editor. Arsenicals: chemical warfare agents and related chemical problems. Washington, D.C; 1946.Google Scholar
  82. 82.
    IOM. Institute of Medicine Committee on the Survey of the Health. Effects of mustard gas and lewisite. In: Pechura CM, Rall DP, editors. Veterans at Risk: the health effects of mustard gas and lewisite. Washington, DC: National Academies Press (US) Copyright 1993 by the National Academy of Sciences. All rights reserved; 1993.Google Scholar
  83. 83.
    Hughes WF Jr. Clinical uses of 2,3-dimercaptopropanol (BAL); the treatment of lewisite burns of the eye with BAL. J Clin Invest. 1946;25(4):541–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Aaseth J, Skaug MA, Cao Y, Andersen O. Chelation in metal intoxication-Principles and paradigms. J Trace Elem Med Biol. 2015;31:260–6.PubMedCrossRefGoogle Scholar
  85. 85.
    Andersen O. Principles and recent developments in chelation treatment of metal intoxication. Chem Rev. 1999;99(9):2683–710.PubMedCrossRefGoogle Scholar
  86. 86.
    Evans RB. Chlorine: state of the art. Lung. 2005;183(3):151–67.PubMedCrossRefGoogle Scholar
  87. 87.
    Massa CB, Scott P, Abramova E, Gardner C, Laskin DL, Gow AJ. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction. Toxicol Appl Pharmacol. 2014;278(1):53–64.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Bismuth C, Borron SW, Baud FJ, Barriot P. Chemical weapons: documented use and compounds on the horizon. Toxicol Lett. 2004;149(1–3):11–8.PubMedCrossRefGoogle Scholar
  89. 89.
    CDC/ATSDR. Medical Management Guidelines for Chlorine, CAS# 7782-50-5, UN# 1017. In: DHHS/CDC/ATSDR, editor.: CDC/ATSDR; 2014.Google Scholar
  90. 90.
    Wang J, Winskog C, Edston E, Walther SM. Inhaled and intravenous corticosteroids both attenuate chlorine gas-induced lung injury in pigs. Acta Anaesthesiol Scand. 2005;49(2):183–90.PubMedCrossRefGoogle Scholar
  91. 91.
    Gunnarsson M, Walther SM, Seidal T, Lennquist S. Effects of inhalation of corticosteroids immediately after experimental chlorine gas lung injury. J Trauma. 2000;48(1):101–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Vinsel PJ. Treatment of acute chlorine gas inhalation with nebulized sodium bicarbonate. J Emerg Med. 1990;8(3):327–9.PubMedCrossRefGoogle Scholar
  93. 93.
    CalEPA. Air Toxics Hot Spots Program Risk Assessment Guidelines: Part III. In: Assessment OoEHH, editor. Technical Support Document for the Determination of Noncancerous Chronic Reference Exposure Levels. SRP Draft. Berkeley: California Environmental Protection Agency; 1999.Google Scholar
  94. 94.
    Van Sickle D, Wenck MA, Belflower A, Drociuk D, Ferdinands J, Holguin F, et al. Acute health effects after exposure to chlorine gas released after a train derailment. Am J Emerg Med. 2009;27(1):1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Jones R, Wills B, Kang C. Chlorine gas: an evolving hazardous material threat and unconventional weapon. West J Emerg Med. 2010;11(2):151–6.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Luo S, Trubel H, Wang C, Pauluhn J. Phosgene- and chlorine-induced acute lung injury in rats: comparison of cardiopulmonary function and biomarkers in exhaled breath. Toxicology. 2014;326:109–18.PubMedCrossRefGoogle Scholar
  97. 97.
    CDC/DHHS. Phosgene: Emergency Preparedness and Response.: CDC/DHHS; 2013.Google Scholar
  98. 98.
    Jugg B, Jenner J, Rice P. The effect of perfluoroisobutene and phosgene on rat lavage fluid surfactant phospholipids. Hum Exp Toxicol. 1999;18(11):659–68.PubMedCrossRefGoogle Scholar
  99. 99.
    Li W, Liu F, Wang C, Truebel H, Pauluhn J. Novel insights into phosgene-induced acute lung injury in rats: role of dysregulated cardiopulmonary reflexes and nitric oxide in lung edema pathogenesis. Toxicol Sci. 2013;131(2):612–28.PubMedCrossRefGoogle Scholar
  100. 100.
    Pauluhn J, Hai CX. Attempts to counteract phosgene-induced acute lung injury by instant high-dose aerosol exposure to hexamethylenetetramine, cysteine or glutathione. Inhal Toxicol. 2011;23(1):58–64.PubMedCrossRefGoogle Scholar
  101. 101.
    Li W, Rosenbruch M, Pauluhn J. Effect of PEEP on phosgene-induced lung edema: pilot study on dogs using protective ventilation strategies. Exp Toxicol Pathol. 2015;67(2):109–16.PubMedCrossRefGoogle Scholar
  102. 102.
    Vaish AK, Consul S, Agrawal A, Chaudhary SC, Gutch M, Jain N, et al. Accidental phosgene gas exposure: A review with background study of 10 cases. J Emerg Trauma Shock. 2013;6(4):271–5.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Thomas C. In: Grant W, editor. Toxicology of the eye. 2nd ed; 1974.Google Scholar
  104. 104.
    Hygienists ACoGI, editor Documentation of the TLV's and BEI's with Other World Wide Occupational Exposure Values. American Conference of Governmental Industrial Hygienists 2006. Cincinnati, OH.Google Scholar
  105. 105.
    CDC/ATSDR. Medical Management Guidelines for Phosgene (COCl2), CAS# 75–44-5, UN# 1076. CDC/ATSDR; 2014.Google Scholar
  106. 106.
    Diller WF. Early diagnosis of phosgene overexposure. Toxicol Ind Health. 1985;1(2):73–80.PubMedCrossRefGoogle Scholar
  107. 107.
    Kundu P, Hwang KC. Rational design of fluorescent phosgene sensors. Anal Chem. 2012;84(10):4594–7.PubMedCrossRefGoogle Scholar
  108. 108.
    Hulse EJ, Davies JO, Simpson AJ, Sciuto AM, Eddleston M. Respiratory complications of organophosphorus nerve agent and insecticide poisoning. Implications for respiratory and critical care. Am J Respir Crit Care Med. 2014;190(12):1342–54.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Quistad GB, Sparks SE, Casida JE. Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides. Toxicol Appl Pharmacol. 2001;173(1):48–55.PubMedCrossRefGoogle Scholar
  110. 110.
    Okumura T, Hisaoka T, Naito T, Isonuma H, Okumura S, Miura K, et al. Acute and chronic effects of sarin exposure from the Tokyo subway incident. Environ Toxicol Pharmacol. 2005;19(3):447–50.PubMedCrossRefGoogle Scholar
  111. 111.
    Chandar NB, Ganguly B. A first principles investigation of aging processes in soman conjugated AChE. Chem Biol Interact. 2013;204(3):185–90.PubMedCrossRefGoogle Scholar
  112. 112.
    Foltin G, Tunik M, Curran J, Marshall L, Bove J, van Amerongen R, et al. Pediatric nerve agent poisoning: medical and operational considerations for emergency medical services in a large American city. Pediatr Emerg Care. 2006;22(4):239–44.PubMedCrossRefGoogle Scholar
  113. 113.
    AAP. Chemical-biological terrorism and its impact on children: a subject review. American Academy of Pediatrics. Committee on Environmental Health and Committee on Infectious Diseases. Pediatrics. 2000;105(3 Pt 1):662–70.Google Scholar
  114. 114.
    Chung S, Shannon M. Hospital planning for acts of terrorism and other public health emergencies involving children. Arch Dis Child. 2005;90(12):1300–7.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Eddleston M, Roberts D, Buckley N. Management of severe organophosphorus pesticide poisoning. Crit Care. 2002;6(3):259.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Sternbach LHaSK. Antispasmodics: (1)Bicyclic basic alcohols, (2)Esters of basic bicyclic alcohols. J Am Chem Soc. 1952;74.Google Scholar
  117. 117.
    Corps USAC. Joint CB Technical Data Source Book: Volume II Riot Control and Incapacitating Agents, Part Three: Agent BZ. Fort Douglas, Utah; 1972.Google Scholar
  118. 118.
    Rosenblatt D, Dacre J, Shiotsuka R, Rowlett C. Problem definition studies on the potential environmental pollutants VIII. Chemistry and toxicology of BZ (3-Quinuclidinyl Benzinlate), TR 7710. In: Army U, editor. Fort Detrick: US Army Medical Bioengineering Research and Development Laboratory; 1977.Google Scholar
  119. 119.
    US Army BI. Chapter 5: incapacitating agents. In: Medical management of chemical casualties handbook: US Army, Borden Institute.Google Scholar
  120. 120.
    Ballantyne B, Swanston DW. The comparative acute mammalian toxicity of 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS). Arch Toxicol. 1978;40(2):75–95.PubMedCrossRefGoogle Scholar
  121. 121.
    Chapman AJ, White C. Death resulting from lacrimatory agents. J Forensic Sci. 1978;23(3):527–30.PubMedCrossRefGoogle Scholar
  122. 122.
    Rothberg S. Skin sensitization potential of the riot control agents BBC, DM, CN and CS in guinea pigs. Mil Med. 1970;135(7):552–6.PubMedCrossRefGoogle Scholar
  123. 123.
    Ballantyne B, Callaway S. Inhalation toxicology and pathology of animals exposed to o-chlorobenzylidene malononitrile (CS). Med Sci Law. 1972;12(1):43–65.PubMedCrossRefGoogle Scholar
  124. 124.
    Gaskins JR, Hehir RM, McCaulley DF, Ligon EW Jr. Lacrimating agents (CS and CN) in rats and rabbits. Acute effects on mouth, eyes, and skin. Arch Environ Health. 1972;24(6):449–54.PubMedCrossRefGoogle Scholar
  125. 125.
    Rengstorff RH, Mershon MM. CS in trioctyl phosphate: effects on human eyes. Mil Med. 1971;136(2):152–3.PubMedCrossRefGoogle Scholar
  126. 126.
    Ballantyne B, Gazzard MF, Swanston DW, Williams P. The ophthalmic toxicology of o-chlorobenzylidene malononitrile (CS). Arch Toxicol. 1974;32(3):149–68.PubMedCrossRefGoogle Scholar
  127. 127.
    Beswick FW, Holland P, Kemp KH. Acute effects of exposure to orthochlorobenzylidene malononitrile (CS) and the development of tolerance. Br J Ind Med. 1972;29(3):298–306.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Kluchinsky TA Jr, Sheely MV, Savage PB, Smith PA. Formation of 2-chlorobenzylidenemalononitrile (CS riot control agent) thermal degradation products at elevated temperatures. J Chromatogr A. 2002;952(1–2):205–13.PubMedCrossRefGoogle Scholar
  129. 129.
    Kluchinsky TA Jr, Savage PB, Fitz R, Smith PA. Liberation of hydrogen cyanide and hydrogen chloride during high-temperature dispersion of CS riot control agent. AIHA J (Fairfax, Va). 2002;63(4):493–6.CrossRefGoogle Scholar
  130. 130.
    EPA. The Environmental Protection Agency’s (EPA) List of Registered Bear Deterrents containing capsaicin (regulated under FIFRA). EPA; 1996.Google Scholar
  131. 131.
    Peter KV. In: Peter KV, editor. Handbook of herbs and spices: Woodhead Publishing; 2012.Google Scholar
  132. 132.
    Tainter D, Grenis A, Norwat R. Spices and seasonings (A Food Technology Handbook). Second edition. Food Serv Technol. 2001;1:181. https://doi.org/10.1046/j.1471-5740.2001.d01-1.x.CrossRefGoogle Scholar
  133. 133.
    Reilly CA, Crouch DJ, Yost GS. Quantitative analysis of capsaicinoids in fresh peppers, oleoresin capsicum and pepper spray products. J Forensic Sci. 2001;46(3):502–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Weiser T, Roufogalis B, Chrubasik S. Comparison of the effects of pelargonic acid vanillylamide and capsaicin on human vanilloid receptors. Phytother Res. 2013;27(7):1048–53.PubMedCrossRefGoogle Scholar
  135. 135.
    Kozukue N, Han JS, Kozukue E, Lee SJ, Kim JA, Lee KR, et al. Analysis of eight capsaicinoids in peppers and pepper-containing foods by high-performance liquid chromatography and liquid chromatography-mass spectrometry. J Agric Food Chem. 2005;53(23):9172–81.PubMedCrossRefGoogle Scholar
  136. 136.
    Steffee CH, Lantz PE, Flannagan LM, Thompson RL, Jason DR. Oleoresin capsicum (pepper) spray and “in-custody deaths”. Am J Forensic Med Pathol. 1995;16(3):185–92.PubMedCrossRefGoogle Scholar
  137. 137.
    Gosselin RE, Hodge HC, Smith RP, Gleason MN. Clinical toxicology of commercial products. 4th ed. Baltimore: Williams and Wilkins; 1976.Google Scholar
  138. 138.
    Monsereenusorn Y. Subchronic toxicity studies of capsaicin and capsicum in rats. Res Commun Chem Pathol Pharmacol. 1983;41(1):95–110.PubMedGoogle Scholar
  139. 139.
    toxicology Ijo. Final report on the safety assessment of capsicum annuum extract, capsicum annuum fruit extract, capsicum annuum resin, capsicum annuum fruit powder, capsicum frutescens fruit, capsicum frutescens fruit extract, capsicum frutescens resin, and capsaicin. Int J Toxicol. 2007;26(Suppl 1):3–106.Google Scholar
  140. 140.
    Hazari MS, Rowan WH, Winsett DW, Ledbetter AD, Haykal-Coates N, Watkinson WP, et al. Potentiation of pulmonary reflex response to capsaicin 24h following whole-body acrolein exposure is mediated by TRPV1. Respir Physiol Neurobiol. 2008;160(2):160–71.PubMedCrossRefGoogle Scholar
  141. 141.
    E T-H. Cough reduction using capsaicin. Respir Med. 2015;109(1):27–37.CrossRefGoogle Scholar
  142. 142.
    Tuorinsky SD. Medical aspects of chemical warfare.: Office of the Surgeon General, Department of the Army. Washington, D.C: Borden Institute (U.S.) Government Printing Office; 2008.Google Scholar
  143. 143.
    Voegeli S, Baenninger PB. Severe chemical burn to the eye after pepper spray attack. Klin Monbl Augenheilkd. 2014;231(4):327–8.PubMedCrossRefGoogle Scholar
  144. 144.
    Fujita S, Shimizu T, Izumi K, Fukuda T, Sameshima M, Ohba N. Capsaicin-induced neuroparalytic keratitis-like corneal changes in the mouse. Exp Eye Res. 1984;38(2):165–75.PubMedCrossRefGoogle Scholar
  145. 145.
    Gerber S, Frueh BE, Tappeiner C. Conjunctival proliferation after a mild pepper spray injury in a young child. Cornea. 2011;30(9):1042–4.PubMedCrossRefGoogle Scholar
  146. 146.
    Olajos EJ, Salem H. Riot control agents: pharmacology, toxicology, biochemistry and chemistry. J Appl Toxicol. 2001;21(5):355–91.PubMedCrossRefGoogle Scholar
  147. 147.
    Ballantyne B, Beswick FW, Thomas DP. The presentation and management of individuals contaminated with solutions of dibenzoxazepine (CR). Med Sci Law. 1973;13(4):265–8.PubMedCrossRefGoogle Scholar
  148. 148.
    Ballantyne B, Swanston DW. The irritant effects of dilute solutions of dibenzoxazepine (CR) on the eye and tongue. Acta Pharmacol Toxicol. 1974;35(5):412–23.CrossRefGoogle Scholar
  149. 149.
    Ashton I, Cotes JE, Holland P, Johnson GR, Legg SJ, Saunders MJ, et al. Acute effect of dibenz b.f.--1:4 oxazepine aerosol upon the lung function of healthy young men [proceedings]. J Physiol. 1978;275:85.CrossRefGoogle Scholar
  150. 150.
    Colgrave HF, Brown RF, Cox RA. Ultrastructure of rat lungs following exposure to aerosols of dibenzoxazepine (CR). Br J Exp Pathol. 1979;60(2):130–41.PubMedPubMedCentralGoogle Scholar
  151. 151.
    Ballantyne B, Gazzard MF, Swanston DW, Williams P. The comparative ophthalmic toxicology of 1-chloroacetophenone (CN) and dibenz(b.f)-1:4-oxazepine(CR). Arch Toxicol. 1975;34(3):183–201.PubMedCrossRefGoogle Scholar
  152. 152.
    Stenhouse J, editor. On the economical applications of Charcoal to sanitary purposes, notices of the proceedings at the meetings of the Members of the Royal Institution of Great Britain; 1855.Google Scholar
  153. 153.
    EPA. RED Fact Sheet: Chloropicrin. US EPA: EPA; 2008.Google Scholar
  154. 154.
    CDC/NIOSH. CHLOROPICRIN (PS) : Lung Damaging Agent; CAS #: 76–06-2; RTECS #: PB6300000; UN #: 1580. CDC/NIOSH; 2014.Google Scholar
  155. 155.
    Sparks SE, Quistad GB, Casida JE. Chloropicrin: reactions with biological thiols and metabolism in mice. Chem Res Toxicol. 1997;10(9):1001–7.PubMedCrossRefGoogle Scholar
  156. 156.
    Pesonen M, Hakkinen M, Rilla K, Juvonen R, Kuitunen T, Pasanen M, et al. Chloropicrin-induced toxic responses in human lung epithelial cells. Toxicol Lett. 2014;226(2):236–44.PubMedCrossRefGoogle Scholar
  157. 157.
    Pesonen M, Pasanen M, Loikkanen J, Naukkarinen A, Hemmila M, Seulanto H, et al. Chloropicrin induces endoplasmic reticulum stress in human retinal pigment epithelial cells. Toxicol Lett. 2012;211(3):239–45.PubMedCrossRefGoogle Scholar
  158. 158.
    OEHHA C. Acute RELs and toxicity summaries using the previous version of the Hot Spots Risk Assessment Guidelines: CA OEHHA; 1999.Google Scholar
  159. 159.
    DHHS/NIOSH. NIOSH Pocket Guide to Chemical Hazards, National Institute for Occupational Safety and Health (NIOSH) Education and Information Division: DHHS/NIOSH; 2015.Google Scholar
  160. 160.
    CDC. Brief report: exposure to tear gas from a theft-deterrent device on a safe--Wisconsin, December 2003. MMWR Morb Mortal Wkly Rep. 2004;53(8):176–7.Google Scholar
  161. 161.
    Zasshi ONeaNNI. Case Report: Chloropicrin Eye Exposure. Japan Assoc Rural Med, Toxnet. 1980;29(3).Google Scholar
  162. 162.
    Prentiss A. Chemicals in war; a treatise on chemical warfare. New York/London: McGraw-Hill Book Company; 1937.Google Scholar
  163. 163.
    Hersh SM. Chemical and biological warfare: America's hidden arsenal: Doubleday; 1969.Google Scholar
  164. 164.
    McNamara BPOE, Weimer JT, Ballard TA. Toxicology of riot control chemicals - CS, CN and DM, EDGEWOOD ARSENAL ABERDEEN PROVING GROUND; Apr 1965-Jul 1968. 1968.Google Scholar
  165. 165.
    Owens M. Toxicology of DM, DEPARTMENT OF THE ARMY EDGEWOOD ARSENAL, Oct 1967. Maryland: Edgewood Arsenal; 1967.Google Scholar
  166. 166.
    Ltd O. http://www.skunk-skunk.com/121755/The-Product Aviezer 121/1 99860 Israel.
  167. 167.
  168. 168.
    Wennig R, Schneider S, Meys F. GC/MS based identification of skunk spray maliciously deployed as “biological weapon” to harm civilians. J Chromatogr B Analyt Technol Biomed Life Sci. 2010;878(17–18):1433–6.PubMedCrossRefGoogle Scholar
  169. 169.
    CDC/NIOSH. NIOSH Guide to Chemical Hazards: N-butyl Mercaptan.: CDC/NIOSH; 2015.Google Scholar
  170. 170.
    Fierro BR, Agnew DW, Duncan AE, Lehner AF, Scott MA. Skunk musk causes methemoglobin and Heinz body formation in vitro. Vet Clin Pathol. 2013;42(3):291–300.PubMedCrossRefGoogle Scholar
  171. 171.
    Zaks KL, Tan EO, Thrall MA. Heinz body anemia in a dog that had been sprayed with skunk musk. J Am Vet Med Assoc. 2005;226(9):1516–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Starr C. Biology: concepts and applications. Belmont: Thomson Brooks/Cole; 2006.Google Scholar
  173. 173.
    Doutch JJ, Quantock AJ, Joyce NC, Meek KM. Ultraviolet light transmission through the human corneal stroma is reduced in the periphery. Biophys J. 2012;102(6):1258–64.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Barkana Y, Belkin M. Laser eye injuries. Surv Ophthalmol. 2000;44(6):459–78.PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Marshall J. The safety of laser pointers: myths and realities. Br J Ophthalmol. 1998;82(11):1335–8.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Lamotte J, Fife J, Lee A, Hemenger R. The power output of laser pointers: do they exceed federal standards? Optom Vis Sci. 2001;78(7):525–8.PubMedCrossRefGoogle Scholar
  177. 177.
    Boosten K, Van Ginderdeuren R, Spileers W, Stalmans I, Wirix M, Van Calster J, et al. Laser-induced retinal injury following a recreational laser show: two case reports and a clinicopathological study. Bull Soc Belge Ophtalmol. 2011;317:11–6.Google Scholar
  178. 178.
    Albert DM. In: Albert DM, editor. Principles and practice of ophthalmology. 3rd ed: Saunders; 2008.Google Scholar
  179. 179.
    Giani A, Thanos A, Roh MI, Connolly E, Trichonas G, Kim I, et al. In vivo evaluation of laser-induced choroidal neovascularization using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(6):3880–7.PubMedCrossRefGoogle Scholar
  180. 180.
    Owens SL, Bunce C, Brannon AJ, Wormald R, Bird AC. Prophylactic laser treatment appears to promote choroidal neovascularisation in high-risk ARM: results of an interim analysis. Eye (Lond). 2003;17(5):623–7.CrossRefGoogle Scholar
  181. 181.
    Montezuma SR, Vavvas D, Miller JW. Review of the ocular angiogenesis animal models. Semin Ophthalmol. 2009;24(2):52–61.PubMedCrossRefGoogle Scholar
  182. 182.
    Nakajima T, Hirata M, Shearer TR, Azuma M. Mechanism for laser-induced neovascularization in rat choroid: accumulation of integrin alpha chain-positive cells and their ligands. Mol Vis. 2014;20:864–71.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Reichstein D. Current treatments and preventive strategies for radiation retinopathy. Curr Opin Ophthalmol. 2015;26(3):157–66.PubMedCrossRefGoogle Scholar
  184. 184.
    Aslam SA, Davies WI, Singh MS, Charbel Issa P, Barnard AR, Scott RA, et al. Cone photoreceptor neuroprotection conferred by CNTF in a novel in vivo model of battlefield retinal laser injury. Invest Ophthalmol Vis Sci. 2013;54(8):5456–65.PubMedCrossRefGoogle Scholar
  185. 185.
    Lou MF. Redox regulation in the lens. Prog Retin Eye Res. 2003;22(5):657–82.PubMedCrossRefGoogle Scholar
  186. 186.
    Raghavachari N, Qiao F, Lou MF. Does glutathione-S-transferase dethiolate lens protein-thiol mixed disulfides?-A comparative study with thioltransferase. Exp Eye Res. 1999;68(6):715–24.PubMedCrossRefGoogle Scholar
  187. 187.
    Wang L, Zhao WC, Yin XL, Ge JY, Bu ZG, Ge HY, et al. Lens proteomics: analysis of rat crystallins when lenses are exposed to dexamethasone. Mol BioSyst. 2012;8(3):888–901.PubMedCrossRefGoogle Scholar
  188. 188.
    Dayhaw-Barker P. Retinal pigment epithelium melanin and ocular toxicity. Int J Toxicol. 2002;21(6):451–4.PubMedCrossRefGoogle Scholar
  189. 189.
    Metry KJ, Neale JR, Doll MA, Howarth AL, States JC, McGregor WG, et al. Effect of rapid human N-acetyltransferase 2 haplotype on DNA damage and mutagenesis induced by 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx). Mutat Res. 2010;684(1–2):66–73.PubMedCrossRefGoogle Scholar
  190. 190.
    Brown DV. Reaction of the rabbit retinal pigment ipithelium to systemic lead poisoning. Trans Am Ophthalmol Soc. 1974;72:404–47.PubMedPubMedCentralGoogle Scholar
  191. 191.
    You Y, Gupta VK, Li JC, Klistorner A, Graham SL. Optic neuropathies: characteristic features and mechanisms of retinal ganglion cell loss. Rev Neurosci. 2013;24(3):301–21.PubMedCrossRefGoogle Scholar
  192. 192.
    Ruther K, Foerster J, Berndt S, Schroeter J. Chloroquine/hydroxychloroquine: variability of retinotoxic cumulative doses. Ophthalmologe. 2007;104(10):875–9.PubMedCrossRefGoogle Scholar
  193. 193.
    Yang P, Baciu P, Kerrigan BC, Etheridge M, Sung E, Toimil BA, et al. Retinal pigment epithelial cell death by the alternative complement cascade: role of membrane regulatory proteins, calcium, PKC, and oxidative stress. Invest Ophthalmol Vis Sci. 2014;55(5):3012–21.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Bahiga LM, Kotb NA, El-Dessoukey EA. Neurological syndromes produced by some toxic metals encountered industrially or environmentally. Z Ernahrungswiss. 1978;17(2):84–8.PubMedCrossRefGoogle Scholar
  195. 195.
    Apel W, Stark D, Stark A, O'Hagan S, Ling J. Cobalt-chromium toxic retinopathy case study. Doc Ophthalmol. 2013;126(1):69–78.PubMedCrossRefGoogle Scholar
  196. 196.
    Sanaei-Zadeh H, Zamani N, Shadnia S. Outcomes of visual disturbances after methanol poisoning. Clin Toxicol (Phila). 2011;49(2):102–7.CrossRefGoogle Scholar
  197. 197.
    Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002;40(6):573–84.PubMedCrossRefGoogle Scholar
  198. 198.
    Shah S, Pandey V, Thakore N, Mehta I. Study of 63 cases of methyl alcohol poisoning (hooch tragedy in Ahmedabad). J Assoc Physicians India. 2012;60:34–6.PubMedGoogle Scholar
  199. 199.
    Mergler D, Blain L. Assessing color vision loss among solvent-exposed workers. Am J Ind Med. 1987;12(2):195–203.PubMedCrossRefGoogle Scholar
  200. 200.
    Cavalleri A, Gobba F, Nicali E, Fiocchi V. Dose-related color vision impairment in toluene-exposed workers. Arch Environ Health. 2000;55(6):399–404.PubMedCrossRefGoogle Scholar
  201. 201.
    Roper-Hall MJ. Thermal and chemical burns. Trans Ophthalmol Soc U K. 1965;85:631–53.PubMedGoogle Scholar
  202. 202.
    Ivarsson U, Nilsson H, Santesson J, editors. A FOA briefing book on chemical weapons: threat, effects, and protection. Umeå: National Defence Research Establishment; 1992.Google Scholar
  203. 203.
    Kayama M, Kurokawa MS, Ueno H, Suzuki N. Recent advances in corneal regeneration and possible application of embryonic stem cell-derived corneal epithelial cells. Clin Ophthalmol. 2007;1(4):373–82.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Derek L. Eisnor
    • 1
  • Brent W. Morgan
    • 2
  1. 1.Grady Memorial Hospital, Emory University, Department of ToxicologyAtlantaUSA
  2. 2.Grady Memorial Hospital, Emory University, Department of Emergency MedicineAtlantaUSA

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