cbrn protection (managing the threat of chemical, biological, radioactive and nuclear weapons) ||...
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67
Part IICBRN Characteristics – Is There Something Inimitable?
copyright by Jörg Pippirs, http://www.artesartwork.de
CBRN Protection: Managing the Threat of Chemical, Biological, Radioactive and Nuclear Weapons,First Edition. Edited by A. Richardt, B. Hulseweh, B. Niemeyer, and F. Sabath.© 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.
68 CBRN Characteristics – Is There Something Inimitable?
69
3Chemical Agents – Small Molecules with Deadly PropertiesHans-Jurgen Altmann, Silke Oelze, and Bernd Niemeyer
Over the centuries, toxic substances have been used in assaults to poison enemiesand to gain advantage without the fear of retaliation. With breakthrough in naturalscience the utilization of toxic substances in open battleground reached a first climaxduring World War I. Today, thousands of poisonous substances are known but onlya few are considered to be suitable for chemical warfare. About 70 different chem-icals have been stockpiled or even applied as chemical warfare agents during thetwentieth century. Chosen for different tactic or strategic reasons, research into toxiccompounds reached a peak during the cold war. It seems obvious that the same gen-eral principles are responsible for the mode of action of these chemicals in the body.
3.1Are Special Properties Required for Chemical Warfare Agents?
Our understanding of chemical compounds that can be employed as chemical war-fare agents is vital for the ability of military forces and first responders to cope withthe possible threat due to the usage of these compounds by enemy forces or terror-ists. Thus, this chapter gives the reader basic information about the classification,different types, their mechanisms of action, and hints to additional literature.
One of the most important questions we have to answer properly is: What arethe chemical, physical, and biological properties of a chemical substance that leadto it being considered as a possible chemical warfare agent? What we can state isthat chemicals have to fulfill several characteristics to make them considered aschemical warfare agents. Important properties are summarized and discussed. InFigure 3.1 important aspects for potential chemical warfare agents are summarized.In Table 3.1 we discuss these properties.
To give an impression of the toxicity of different chemical warfare agents weshould be aware that only a small single droplet of VX (ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate) is enough for devastating effectson a single person. The necessary amount of different nerve agents and sulfur lostfor a lethality via skin contact is visualized in Figure 3.2 The toxicity levels for variouschemicals warfare agents for inhalation versus skin contact are given in Table 3.2.
CBRN Protection: Managing the Threat of Chemical, Biological, Radioactive and Nuclear Weapons,First Edition. Edited by A. Richardt, B. Hulseweh, B. Niemeyer, and F. Sabath.© 2013 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2013 by Wiley-VCH Verlag GmbH & Co. KGaA.
70 3 Chemical Agents – Small Molecules with Deadly Properties
Toxicity
Miscibility
Stability againstdecontamination
Mechanisms ofaction
Environmentalstability
Main importantproperties for
chemical warfareagents
Route of entry
Figure 3.1 Main important issues of chemicals considered as chemical warfare agents.
Table 3.1 Main important properties for potential chemical warfare agents.
Property Description
Toxicity Substance must be able to act rapidly or delayed in small concentrations,producing damage or lethal effects on man and animals. Its inherentproperties should be tailorable to maximum effects on personnel
Route of entry For humans, a compound should have different routes of entry, such asskin penetration, assimilation on moist tissues, and absorption throughthe gastrointestinal tract
Mechanism ofaction
Effects via different organs and on various biochemical systems. Forexample, failure of organs and interference with special enzymes
Stability againstdecontamination
Matter should be resistant against common decontamination agents andprocedures to complicate decontamination for the parties affected
Stability Chemicals must be stable or capable of being stabilized by additivesduring the period between production and use. It should also be stableunder the environmental conditions of application
Miscibility Chemicals should be miscible with solvents and/or thickeners [e.g.,poly(methyl methacrylate)s, chlorinated rubbers, waxes, etc.] as well asother compounds present in the ammunition
Substances used as chemical warfare agents normally are liquids or solids.However, some of the substances are fairly volatile and so the gas concentrationafter dissemination may become poisonous very rapidly due to high toxicity andhigh vapor pressures. Both solid substances and liquids can also be dispersedinto the air as aerosols, which are small particles or droplets sprayed into the airbut which behave like gases and can penetrate the body through the respiratory
3.2 How can we Classify Chemical Warfare Agents? 71
SomanVX
SarinSulfur-
mustard
LD50 (mg kg−1)
Figure 3.2 Comparison of the amount of indicated chemical warfare agent, applying skincontact effecting an LD50-toxicity.
Table 3.2 Toxic levels for humans of several toxic compounds during inhalation and skincontact, projected from animal experiments in the early twentieth century (various sources).The values can differ due to the different experimental conditions.
Inhalation, LCt50 Skin contact, LD50
(mg min–1m–3) (mg kg–1)
VX 50 0.14Soman 70 0.7Sarin 100 24Sulfur mustard 1500 100Phosgene 3000 –HCN 11000 –
tract just like a gas. Therefore, the physical conditions, defining the compound’saggregate state at different seasons have to be considered in the discussion aboutthe utilization of substances as possible chemical warfare agents. An illustrationof the degree of vapourization of a solid/liquid agent in the four different seasonsof the moderate climate zones is presented in the upper route of Figure 3.3. Inthe lower sketch the intensity of the darkness of the background colour reflects animproved gasification. Additionally the lengths of the radiating lines off the griddedrectangle, which stands for the hazardous substance also visualize the degree of asubstance in the gas phase.
3.2How can we Classify Chemical Warfare Agents?
Chemicals can be sorted in different ways. To classify chemical warfare agents wewill use the most widespread criteria:
72 3 Chemical Agents – Small Molecules with Deadly Properties
Winter Spring Summer Autumn
Figure 3.3 Aggregate states of chemicalwarfare agents as well as of other chemi-cals; the length of the radiating lines as wellas the darkness of the gray colored back-ground in the bottom sketches represent
the intensity of gasification of substancestransferred into the gas phase, depend-ing on the season. The top line of pic-tures depicts the corresponding season(winter–spring–summer–autumn).
• A physicochemical behavior (natural scientific points),• B route of entry into the body (protective measures),• C organs to be affected (personal concern),• D physiological effects on human (medical orientated),• E identification according to the NATO Code (military background and disposal).
warfare agents according the above presented characterstics A to E. This clas-sification automatically gives the interested reader hints for effective protectivemeasures against the threat of chemical warfare agents.
3.2.1A: Physicochemical Behavior
This criterion is based on physicochemical data of the relevant substances. Thecompounds can be divided into:
• volatile substances that mainly contaminate the air as they vaporize rapidly,especially when the temperature rises (short-term effect);
• persistent substances with low volatilities, which therefore mainly contaminatesurfaces with a long-term effect.
• Volatility: is the tendency of a solid or liquid substance to evaporate.
The volatility of a substance is directly related to its vapor pressure. In turn,the vapor pressure depends on the temperature. Increasing of the temperature
3.2 How can we Classify Chemical Warfare Agents? 73
I II
LCP
a
GTP
S
Pressure (P)
Temperature (T)
S : SolidL : LiquidG : Gas
TP : Triple PointCP : Critical Point
Figure 3.4 Schematic representation of aphase (pressure–temperature) diagram ofa pure substance.
(e.g., as the sun shines or the change from winter to summer time or othergeographical conditions) increases the vapor pressure and consequently heightensthe volatility. In this way a compound that formerly was characterized as ‘‘lowvolatile’’ generates a higher vapor pressure, and consequently may contaminateand effect in another way. A long-term effective substance may change into mediumor short-term effectiveness with rising temperature, due to different environmentalconditions. Another parameter affecting volatility is the integration of additives.The (common) application of thickeners reduces the vapor pressure.
General information of the degree of volatility can be found from the phasediagram. In a temperature–pressure diagram (Figure 3.4), on the ordinate thepressure of a system containing a pure substance is indicated against the relevanttemperature given at the abscissa.
The following areas or selected indicators are marked:
• S Solid state of substances: At sufficiently low temperature all compounds aresolid (S), at medium and elevated pressure. On increasing the temperature wepass the melting curve (‘‘solidus’’ line, indicated as I or II in Figure 3.4) into theliquid region L (follow line a leftward).
• L Liquid phase: Liquid phase L is present at characteristic temperatures andpressures for a given chemical. For most pure compounds the solidus linebehaves like line II. Exceptions (line I) are detected for, for example, water, wherewe find a negatively inclined solidus line. This is connected with the phrase‘‘anomaly of water.’’ Most other substances show a descending of solid matter inits liquid phase.
• G Gaseous phase: Increasing the temperature still further (along line a) wereach the bubble point, which is situated at the bubble point line, reflecting theequilibrium of the gaseous and liquid phase. Going on further we enter thegaseous region G. This bubble point line starts from the triple point (TP) andends at the critical point (CP). A direct phase transfer of solid substances intothe gas phase can be realized by sublimation (line to left of and below the TP).Impressive examples are mothballs and also the diminishing of snow in wintertimes during longer periods of sunny days and temperatures constantly below0 ◦C. Each phase transfer is related to an energy uptake (in the direction from leftto right along line a) and vice versa.
74 3 Chemical Agents – Small Molecules with Deadly Properties
• TP: Under this exceptional condition [e.g., for water TTP = 273.16 K (0.01 ◦C)and pTP = 611.66 Pa (around 6 mbar)] all three phases S, L, G are present at once.Under no other condition all three phases can be detected.
• CP: A compound behaves in a special way under the conditions above the criticalpoint. For water these data are TCP = 647.1 K and pCP = 22.1 MPa (221 bar)[1–3].
3.2.2B: Route of Entry into the Body
Naturally, the routes into the body are most important in terms of protectionmeasures to be applied. Consequently, the technical development of protectivematerial, activities to be taken during exposure, and, finally, the decontaminationare often guided by them. The most important entry points of chemical warfareagents into the human body are the eyes, nose, mouth, and skin (Figure 3.5). Theydiffer according to the amount and the mechanism of uptake of the biological,radiological, and nuclear warfare agents.
Entry via the eyes and mouth is preferred for gaseous and aerosol matter. Aerosolsconsist of small particulates such as small particles of liquid or solids. Additionallycontaminated food, including beverages like water, infiltrates via the mouth intothe gastrointestinal tract [4]. The entry of aerosols and gases through the nose issimilar, as described in Section 4.4 – via breathing and inhalation. The skin can beaffected by all of the mentioned aggregate states of chemical agents. Preferentially,poorly volatile chemicals, like thickened, sedentary chemical agents with low vaporpressure, such as S-Lost, bear on humans via the skin, the body’s largest organ.Another mechanism of permeation is by direct contact of these compounds withunprotected parts of the body, enabling penetration and spreading of the hazardouseffect.
Lung agents
Blood agents
Skin agents
Psycho-chemical agentsNerve agents
Eye irritating agents
Nose and throatirritating agents
Figure 3.5 Routes of entry of chemical warfare agents into the human body and the or-gans affected.
3.2 How can we Classify Chemical Warfare Agents? 75
3.2.3C: Organs to be Affected
Several organs are affected by chemical warfare agents, which are intended toimpact on the soldier in combat and civilian personal in terroristic attacks [5].Besides these compounds a much greater number of chemicals exist that areapplied in industry and which sometimes also exhibit a hazardous influence onhealth. They are summarized as toxic industrial chemicals (TIC). In general, aTIC often has a ‘‘lower impact’’ on human health than chemical warfare agents.Occasionally, TIC substances are simultaneously used as chemical warfare agents,such as phosgene (COCl2), chlorine (Cl2), hydrogen cyanide (HCN), and others. Wefocus here on chemical warfare agents, while considering TIC to be also dangerousin the same scenarios.
The two main differences between these compounds are the possible lethaland non-lethal effects, as seen from Figure 3.6, which illustrates major classes ofchemical warfare agents.
The major level of discrimination is the various organs to be affected, and theeffects of these substances, which can be ascertained in the third line of Figure 3.6.Direct contact with ‘‘vesicants’’ leads to blisters on the skin’s surface [6]. ‘‘Bloodagents’’ directly attack the ability of blood to transport oxygen (O2) into, and carbondioxide (CO2) out of, cells [7]. ‘‘Lachrymators’’ are materials, that irritate the eyesto tears and finally to blindness [8]. Substances leading to vomiting are called‘‘sternutators,’’ which consequently affect the intestinal tract [9]. A lethal influenceon the nervous system is conducted by ‘‘nerve agents’’ [e.g., tabun (GA), sarin (GB),soman (GD), cyclosarin (GF), and VX] [7]. They are the most effective substances
Chemical warfare agents
Severe affected organs with possible lethal effects
Vesi-cants
Bloodagents
Lachrymat-ors
Sternuta-tors
DA, DC,DM
DL, CP,PS, CN,
CS
AC, CK,AsH3,CO
HD, LHN
GA, GB,GD, GF,
VX
BZ,LSD
Nervous systemagents
Non-lethal
Figure 3.6 Division of chemical warfare agents into their effects on different humanorgans.
76 3 Chemical Agents – Small Molecules with Deadly Properties
Table 3.3 NATO code for the most common, ‘‘pure’’ chemical warfare agents.
Common name(s) NATO code
Mustard gas, yperite, sulfur mustard, S-lost, bis(2-chloroethyl) sulfide HDSesquimustard, sesquiyperite QOxygen mustard, Oxol-lost, bis(2-chloroethylthioethyl) ether TNitrogen mustard, bis(2-chloroethyl)ethylamine, NH-lost HN1Nitrogen mustard, bis(2-chloroethyl)methylamine, N-lost HN2Nitrogen mustard, tris(2-chloroethyl)amine, TBA HN3Phenyldichloroarsine PDEthyldichloroarsine EDLewisite LHydrogen cyanide, prussic acid, HCN ACCyanogen chloride CKCarbon monoxide COω-Chloroacetophenone, ‘‘tear gas’’ CNo-Chlorobenzylidene-malononitrile CSAdamsite DMDiphenylchloroarsine, Clark I DADiphenylcyanoarsine, Clark II DCTabun, O-ethyl-N,N-dimethylphosphoramide cyanide GASarin, O-isopropyl(methyl)phosphono fluoride GBSoman, O-pinacolyl(methyl)phosphonyl fluoride GDVX, ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl)(methyl)phosphinate VXChlorine CLPhosgene PGDiphosgene, trichloromethyl chloroformate DPChloropicrine PS3-Quinuclidinyl benzilate BZ
in relation to the concentration needed for effectuation on humans. ‘‘Non-lethal’’compounds may exhibit psychogenic effects, which negatively influence a soldier’sability for combat. Adequate low concentrations even of ‘‘lethal’’ substances resultin major physiological damage, although the patient may survive.
The last line of Figure 3.6 lists relevant compounds of the chemical classesaccording to the so-called ‘‘NATO code’’ (see Table 3.3). The different classes ofsubstances as well as selected chemicals are described according this classificationin Section 3.3.
3.2.4D: Physiological Effects on Humans
Two main groups are defined, namely, those substances that are lethal andthose that are incapacitating (non-lethal). This kind of classification is relevantfor analysis and medication after exposure. A profound description of medical
3.2 How can we Classify Chemical Warfare Agents? 77
IncapacitatingDose (ICt50)
Dose forMiosis (MCt50)
Median of theIncapacitatingDose (ID50)
Median of theLethal Dose
(LD50)
Agent's Influenceon Humans
Lethal Dose(LCt50)
Figure 3.7 Data that indicate an agent’s influence on humans.
diagnoses and medication of various chemical warfare agents is necessary formedical countermeasures [10]. The detrimental effects of chemical substances ingeneral are characterized by the toxicity of the compound. Some characteristic dataprovide information on the agent’s effect on humans (Figure 3.7).
ICt50 gives the median incapacitating dose (ct product) of a chemical agent,agent vapor, or aerosol that affects 50% of applied persons.
LCt50 represents the median lethal dose of the chemical warfare agent (asagent vapor or aerosol) for which 50% of contacted persons die.
LD50 is the median of the lethal dose of chemical warfare agents.MCt50 stands for the median dose for miosis.ID50 is the median of the incapacitating dose for 50% of the affected
population.
Vapor toxicity is expressed as LCt50, ICt50, and MCt50 and reported in terms ofmg min m−3, whereas the LD50 represents toxicity via percutaneous absorption,and it is reported in terms of milligrams. The terms LCt50, ICt50, and MCt50 arethe lethal concentration × time, incapacitating concentration × time, and miosisconcentration × time, respectively, for 50% of the population. LD50 representsthe dose that causes lethality to 50% of the population. All values except MCt50
values are related to a ‘‘standard man’’ with a body weight of 75 kg and in soundcondition. For the different chemical warfare agents these data will be reportedseparately.
78 3 Chemical Agents – Small Molecules with Deadly Properties
3.2.5E: Identification According to the NATO Code
Most chemical warfare agents are assigned a ‘‘NATO weapon designation’’ inaddition to, or in place of, a common name (Table 3.3).
Another important point we have to address is the possibility of mixing purechemical warfare agents with additives. The behavior and effects of ‘‘pure’’ sub-stances are significantly altered by additives. This can lead to an increase in viscosity,which is adjusted to the desired grade. The resultant increased persistency andability to stick to surfaces can complicate decontamination tremendously.
3.3Properties of Chemical Warfare Agents
We will discuss the different agents of the above ordered groups. The structure ofthe presentation will be:
• general comments on the structural characteristic of the compounds in thegroup, chemical nomination on, and their physicochemical properties;
• toxic action of these substances, recognition of being affected, and the effect ofthese compounds in the human body.
3.3.1Blister Agents (Vesicants)
This group consists of two different subgroups: the ‘‘alkylating agents’’ and the‘‘arsenicals,’’ which will be discussed separately. We start with the alkylating agents[4, 10].
The alkylating agents are divided into three different sub-classes, the sulfur,nitrogen, and oxygen Losts. The close chemical relation of these substances can beseen from the general structure of the nitrogen Losts, where the ligand R1 variesfrom an amino-ethyl, -methyl, and -ethyl-chloride group (Figure 3.8).
All of these agents consist of two or more chloro-alkyl groups, which provide,together with the more central positioned sulfur, nitrogen, and oxygen atom,respectively, chemically reactive leaving groups that exhibit, finally, their damagingimpact (Figure 3.9).
N R1
Cl
ClFigure 3.8 Generalized structure of nitrogen mustard,R1 = C2H5(HN1), CH3(HN2), and C2H4Cl (HN3).
3.3 Properties of Chemical Warfare Agents 79
SClCl
SSCl
Cl
SSClCl O
Mustard, Mustard gas, S-Lost, Yperite (HD)
2,2-Dichloro diethylsulfide
Sesquimustard, Sesquiyperite (Q)1,2-Bis-(2-chloro-ethylthio)-ethane
Oxygen mustard, Oxol-Lost, (T)Bis-(2-chloro-ethylthioethyl)-ether
NH-Lost, Nitrogen mustard, EBA (HN1)Bis-(2-chloro ethyl) ethyl amine
N-Lost, Nitrogen mustard, EBA, N-methyl-Lost, MAB (HN2)Bis-(2-chloroethyl)methylamine
Stickstoff-yperit, TBA, Nitrogen mustard (HN3)Tris-(2chloroethyl) amine
NCH3
Cl
Cl
N CH3
Cl
Cl
NCl
Cl
Cl
Figure 3.9 Nomination and molecular ge-ometries of blister agents of the alkylatingagents. The molecular geometries have beenoptimized based on molecular mechanicsforce field (MMFF) and DFT (density func-tional theory) calculations (hybrid density
functional B3LYP/6-31G*, RMS gradient of0.001), using the molecular modeling pro-gram Spartan ’04 (Wavefunction, Inc. Irvine,CA). The molecules are represented in aball-stick model enclosed by the calculatedelectron density (IsoVal = 0.03) [11].
The most well-known example of a blistering agent is 2,2-dichlorodiethyl sulfide,also-called (sulfur) mustard, or mustard gas, abbreviated with HD the NATO code forthe technical product. It is a colorless and odorless liquid. Owing to decompositionproducts, the technical product smells like mustard or garlic. It is a strongvesicant. It is often thickened, which finally results in a pale yellow solid material.Additional information on structure, chemical reactions, and decontamination ofmustard can be drawn from the literature [4, 5, 10]. A close relative of sulfurmustard is sesquimustard (Q). HN1, HN2, and HN3 are all called nitrogen mustard,although they differ in chemical structure (Figure 3.8) and, consequently, in theirphysicochemical as well as in their toxicological behavior.
80 3 Chemical Agents – Small Molecules with Deadly Properties
Color is an important physicochemical property for the recognition of substancesif suspicious substances are found and to be disposed. Mustards range fromcolorless to pale yellow (mustard gas) as well as to dark yellow for nitrogenmustard. They can be either odorless or smell like garlic or mustard (sulfurmustard) or fish (nitrogen mustard). Both types are persistent, even in soil and seawater (sulfur mustard in its thickened form). Nitrogen mustard vaporized into theair degrades to some degree within hours. As seen from the relative vapor density(in relation to air density) all vapors of blister agents are heavier than air and thusfill rooms from the bottom upwards.
Sulfur, oxygen, and HN3 mustard agents have low vapor pressures (Tables 3.4and 3.5), based on their high boiling points. To increase the tendency of thesesubstances to remain in one place, and in this way their long-term damagingeffect, the boiling point is increased, resulting in a reduction of vaporization, bymixing with thickeners or with other chemical warfare agents providing this effect.Mixtures of H and Q are known as HQ-mixtures. Thus their intended impact isaimed more at the direct action of solid or liquid substances on the body than viathe gaseous phase. We can see from Tables 3.4 and 3.5 that their solubility in wateris generally low, and that they are liquid under standard conditions (20 ◦C and 1bar air pressure).
Alkylating blister agents (e.g., mustard gas) cause little or no pain at the timetissue is exposed. This clinical symptom-free period of several hours may benot recognized by the patient and potentially spread the agent on the skin andelsewhere. As their name implies, these substances cause the formation of painfulblisters and large bullae on the skin up to 24 h after exposure dependent onthe penetrated dose. These blisters hurt, weep, coalesce, and always irritate, thusreducing the combatant’s awareness.
Systemic effects after extensive exposure include bone marrow depression with adrop in the white blood cell count and gastrointestinal tract damage. Blister agents
Table 3.4 Physicochemical characterization of blister agents of the S- and O-mustards.
Property HD T Q(distilled mustard) (oxygen-mustard) (sesqui-mustard)
Formula (C2H4Cl)2S (ClC2H4SC2H4)2O (ClC2H4S)2C2H4
Molecular weight (g mol–1) 159.1 263.3 219.2Relative vapor densitya 5.4 9.08 (calculated) Not availableLiquid density (g cm–3) 1.27 (25 ◦C) 1.231 (20 ◦C) 1.229Boiling point (◦C) 217 174 (267 Pa)
(decomp. above 170)328.7
Melting point (◦C) 14 10 –Vapor pressure (Pa) 0.07 (20 ◦C) 2.9 × 10–5 (25 ◦C) 0.048 (25 ◦C)Volatility (mg m–3) 610 (20 ◦C) 2.4 (25 ◦C) 0.4 (25 ◦C)Solubility in water (%) 0.06–0.08 (20 ◦C) Practically insoluble 0.03 (20 ◦C)
aRelative to air.
3.3 Properties of Chemical Warfare Agents 81
Table 3.5 Physicochemical characterization of blister agents of the nitrogen mustards.
Property HN1 HN2 HN3(nitrogen-mustard) (nitrogen-mustard) (nitrogen-mustard)
Formula C6H13Cl2N C5H11Cl2N C6H12Cl3NMolecular weight (g mol–1) 170.1 156.1 204.5Relative vapor densitya 5.9 5.4 7.1Liquid density (g cm–3) 1.09 (25 ◦C) 1.15 (20 ◦C) 1.24 (25 ◦C)Boiling point (◦C) 194 (1013 hPa),
(decomp. above120 ◦C)
75 (1333 Pa) 230–235 (1013 hPa)(decomp.;dimerization above50 ◦C)
Melting point (◦C) –34 –65 to −60 –Vapor pressure (Pa) 21.3 (20 ◦C) 38.7 (20 ◦C) –4Volatility (mg m–3) 1520 (20 ◦C) 2500–2600 70–76Solubility in water (%) Sparingly soluble 1.2 (20 ◦C) 0.008–0.016 (20 ◦C)
aRelative to air.
of the mustard group act as alkylating agents that covalently bind to DNA andconsequently damage our basic biological information source, as the transcriptionmechanism of the DNA is disrupted. Their action on cell components results ininhibition of cellular division (mitosis) with decreased tissue respiration, finallyleading to cell death. For this purpose some of the substances have found uses aschemotherapeutic agents in the treatment of cancer.
Owing to the immunosuppressive effects of mustards the risk of superinfectionis significantly enhanced. Wound healing is dramatically impaired because ofDNA damaged stem cells and altered protein synthesis. Thus, hospitalization ofwounded patients lasts weeks to months depending on the burnt surface. Besidethe skin, other areas of the body surface may also be affected. Eye, throat, lungtissue, and mucous membranes can be damaged. Pseudo-membrane formationin the bronchial tract may be life threatening due to airway obstruction. Alkylatingblister agents (nitrogen and sulfur mustards) are carcinogenic and mutagenic andcan alter membrane proteins, leading to altered signal transduction within thetissue as well as metabolic dysfunction as demonstrated in Figure 3.10 [6].
The median incapacitating dose (ICt50) ranges from 50 mg min m−3 for oxygenmustard and sesquimustard to up to 1500 mg min m−3 for sulfur mustard(Table 3.6).
NH-mustard (HN1) is less persistent and has similar blistering potency than sul-fur mustard. HN3 is more persistent and is equal to sulfur mustard in its blisteringpotential. Its properties and toxicity are also similar to the other mentioned agents(Table 3.7). Eye irritation and skin erythema occur sooner than with sulfur mustardupon exposure to nitrogen mustard, and eye lesions appear to be more severe. Thesubstances are known carcinogens and can cause cancer even years after exposure.
82 3 Chemical Agents – Small Molecules with Deadly Properties
CH2 CH2 Cl
CH2 CH2 ClS +S
CH2 CH2 OH
CH2 CH2 OHS
Sulfur mustard
H2O Glutathione DNA RNA Membraneproteins
Proteins / enzymes
Thiodiglycol
Decreasedcellular defense
DNAdamage
Altered proteinsynthesis
Altered signaltransduction
Alkylation offunctional groups
CH2
CH2
CH2 CH2 Cl
Reactive intermediate "sulfonium cation"
Cancer Impaired wound healing Metabolic dysfunction
Figure 3.10 Effects of sulfur mustard on DNA, RNA, and proteins.
Table 3.6 Toxicity data of blister agents of the sulfur mustard and sesquimustard.
Variable Sulfur mustard Sesquimustard
Value (mg min m–3) Application Value (mg min m–3) Application
LD50 4000–7000 mg Liquid on skin 200 mg Liquid aerosol on skinLCt50 750–1500 Vapor 200 VaporICt5 50 Vapor – –ICt50 100–1500 Vapor 50 Vapor
Table 3.7 Toxicity data of blister agents: Nitrogen mustard.
Variable Value (mg min m–3) Substance Application
ICt50 200 HN1 VaporLCt50 1500 HN1 VaporICt50 100 HN2 VaporLCt50 3000 HN2 VaporICt50 200 HN3 VaporLCt50 1500 HN3 VaporLD50 7000–14 000 mg HN3 Liquid on skin
The third important mustard variation is oxygen mustard, which is approximatelythree to four times more toxic to the skin than sulfur mustard and is used incombination with sulfur mustard as HT-mixtures. Oxygen mustard is an oilycolorless liquid. Some sources state a garlic-like odor [8].
3.3 Properties of Chemical Warfare Agents 83
3.3.2Arsenicals
Organic substances containing arsenic derivatives from arsenic(III) chloride, whichitself is toxic to humans and very toxic to aqueous organisms with a long-termeffect. This class of chemicals can be subdivided into arsenics and lewisites warfareagents – both are chloroarsines. We begin with the arsenics.
Phenyldichloroarsine (PD) and ethyldichloroarsine (ED) are the actual warfareagents of this subgroup. The older matter, which has been overcome at present,is methyldichloroarsine (MD). Figure 3.11 summarizes their names and structuralproperties.
The lewisite group consists of lewisite types I–III (called L1 to L3 in the NATOcode), which differ in the degree of substitution of chloro groups of arsenic(III)
Cl ClAs
Cl
Pfiffikus, Sternite, DJ (PD)Phenyldichloro-arsine
Dick, Ethyl-Dick (ED)Ethyldichloro-arsine
Methyl-Dick, Medicus (MD)Methyldichloro-arsine
Lewisite III (L3)Tris(2-chlorovinyl)arsine
Lewisite II (L2)Bis(2-chlorovinyl)chloroarsine
Lewisite I (L1)2-Chlorovinyl(dichloro)arsine
As
ClCl
Cl
As⋅Cl
Cl
Cl
As
Cl
ClAs CH3
Cl
Cl
As
CH3Cl
Cl
Figure 3.11 Nomination and molecu-lar geometries of blister agents (arsenicand lewisite group). The molecular ge-ometries have been optimized basedon MMFF and DFT calculations (hybriddensity functional B3LYP/6-31G*, RMS
gradient of 0.001), using the molecularmodeling program Spartan ’04 (Wave-function, Inc. Irvine, CA). The moleculesare represented in a ball-stick model en-closed by the calculated electron density(IsoVal = 0.03) [11].
84 3 Chemical Agents – Small Molecules with Deadly Properties
chloride by chlorovinyl substitutes (Figure 3.11). L1, an organic dichloroarsine, isthe most common lewisite, which provides a high volatility and decomposes inaqueous media. Lewisites are colorless, odorless oily liquids when purified, butwhen produced with impurities or containing decomposition products they have ageranium-like smell.
As liquids, they can easily penetrate rubber, plastics, leather, and most fabricsand remain more dangerous as liquids than as vapor. Liquids with a high vaporpressure generally undergo constant evaporation and thus these substances arenon-persistent. They react with water in such a manner that they lose theirvolatility and their blistering potency due to rapid hydrolysis (Table 3.8). Littleis known about their stability in the natural environment. Phenyldichloroarsine,ethyldichloroarsine, and MD can be mixed with sulfur mustard similarly tolewisite–mustard mixtures. The arsenicals act as freezing point depressors forsulfur Lost and cause immediate action when contamination occurs. Mixtures of Land HD are known as HL-mixtures.
The toxic properties of arsenicals (Table 3.9) result in similar irritant effects tothose from other blister agents. Contact with arsenics as well as lewisites results ineffects on the skin (usually the first effect), eyes [with rapid damage from temporaryto permanent blindness if immediate (<1 min) decontamination does not occur],and respiratory system, and also the stomach and intestines (main organs affected).
Lewisite acts first as a vesicant (since first contact is usually through dermalexposure). Within 5 min of dermal exposure a gray area of dead epithelium maydevelop, similar to that seen with corrosive burns. Skin penetration can result fromcontact with either liquid or vapor. Lewisite consecutively behaves as pulmonaryirritant and finally as a systemic poison. It can cause violent sneezing and severepain. It acts stepwise and leads to diarrhea, restlessness, hypothermia, weakness,acute lung injury, and respiratory distress syndrome, as well as hypotension,after severe inhalation, which finally may lead to shock and death. It differs inits clinical impact, which may even appear within seconds of exposure. Verysmall amounts (0.5 mL) can lead to systemic effects; as little as 2 mL can be
Table 3.8 Physicochemical characterization of the lewisite agent L1.
Property L1 (lewisite)
Formula C2H2AsCl3Molecular weight (g mol–1) 207.3Relative vapor densitya 7.1Liquid density (g cm–3) 1.89 (20 ◦C)Boiling point (◦C) 190Melting point (◦C) –18Vapor pressure (Pa) 0.39 (20 ◦C)Volatility (mg m–3) 4480 (20 ◦C)Solubility in water (%) 0.05 decomposes rapidly
aRelative to air.
3.3 Properties of Chemical Warfare Agents 85
Table 3.9 Toxicological data of blister agents (arsenic and lewisite groups).
Variable Value (mg min m–3) Substance Application
ICt50 5–10 ED VaporLCt50 3000–5000 ED VaporICt50 16–25 MD VaporLCt50 3000–5000 MD VaporICt50 16–20 PD VaporLCt50 1300–2600 PD VaporLD50 7000 mg L1 Liquid on skinICt50 200–300 L1 VaporLCt50 1200–1500 L1 VaporLD50 1500 mg L2 Liquid on skinICt50 – L2 –LCt50 1300 L2 VaporLD50 – L3 Lewisite III is expected to cause the
typical symptoms of arsenicpoisoning, such as damage to skin,nervous system, kidneys, and liver.Only a few data sets of toxicologicaldata are available
ICt50 – L3LCt50 – L3
fatal (Table 3.8, providing exemplarily data of Lewisite I). As few data on humanexposure are available, most information on its clinical effects is based on animalstudies.
Lewisites react with the thiol groups of proteins and thus interact with enzymesand finally interfere with the metabolism. Similar to Losts they also react with DNAby alkylation (Figure 3.10).
Recognition of being affected is through symptoms like itching and irritation,which may occur for about 24 h, with or without skin blistering. Dermal contactresults in immediate stinging and burning sensations and erythema within 30 min.Formations of sharply defined and painful blisters, which may occur 2–13 h afterexposure, with deep necrosis can be identified. In addition, a geranium-like odormay be detectable on the victim.
3.3.3Blood Agents
These chemicals act in the blood, its compounds, and at the cell surface in orderto reduce the body’s oxygen uptake, O2 utilization in cells, and the CO2 release(Figure 3.12) [6].
They can be classified within three main groups:
• cyanides• trihydrides• carbonyls.
86 3 Chemical Agents – Small Molecules with Deadly Properties
Locks ontohemoglobin (HB)
Nausea,vomiting, acidosis,
convulsions,unconsciousness,
death
Binding on
Cytochrome oxidase
Hemoglobin
C NH
HCN
Inhalation
Figure 3.12 Effects of cyanide withinthe body. After the hydrogen cyanide gas(HCN) is inhaled, the molecule locks ontohemoglobin, the oxygen-carrying moleculein red blood cells, and is then distributedvia the bloodstream to cells throughout the
body. In the cells it binds to a metabolic en-zyme called cytochrome oxidase and preventscells from using oxygen to produce energy.In this way cyanide effectively chemically as-phyxiates the body [12].
Some of these agents, which can be used as chemical warfare agents, are widelyapplied in the basic chemical industry. Hence these chemicals are widely availableand thus they can be employed in asymmetric warfare.
Important substances of blood agents include hydrogen cyanide (AC), cyanogenchloride (CK), arsine (SA), and carbon monoxide (CO) (Figure 3.13).
These substances exhibit a high vapor pressure due to their low boiling points.Thus they are normally very volatile and therefore have a low persistency. Solidsubstances (e.g., cyanogen bromide) transfer directly from the solid state into thegas phase by sublimation, unter typical meterological conditions. Thus inhalationis the usual route of entry into the human body. Other entries of blood agents areingestion, skin contact, or eye contact. Their solubility in water differs greatly, withthe consequence that initial uptake via the mucosa differs accordingly.
Hydrogen cyanide (AC) is a colorless gas, which smells like ‘‘bitter almond’’ butit may not be easily recognized. Hydrogen cyanide gas in the air is explosive atconcentrations over 5.6% (v/v), equivalent to 56 000 ppm (v/v); it is fully soluble inwater (Table 3.10). Cyanogen chloride (CK) is a colorless, volatile liquid with strongirritant, choking, and corrosive effects. Today the substance is widely employedas a test substance for filter canisters. Cyanogen bromide (CB) is a crystalline,sublimating compound that is corrosive to copper and copper alloys, aluminum,
3.3 Properties of Chemical Warfare Agents 87
N
N
Cl
Br
Arsine (SA)
Cyanogen Bromide (CB)
Cyanogen Chloride (CK)
HH
H
As
Iron Carbonyl Nickel Carbonyl
Hydrogen Cyanide (AC)
Carbon Monoxide (CO)
C− O+
HC N
H
H
HP
Phosphine
FeO
OO
O
O
Ni
O
O
O
O
Figure 3.13 Nomination and molecular ge-ometries of blood agents. The moleculargeometries have been optimized based onMMFF and DFT calculations (hybrid densityfunctional B3LYP/6-31G*, RMS gradient of
0.001), using the molecular modeling pro-gram Spartan ’04 (Wavefunction, Inc. Irvine,CA). The molecules are represented in aball-stick model enclosed by the calculatedelectron density (IsoVal = 0.03) [11].
and zinc. It has a pungent odor. Only pure, water-free cyanogen bromide is stablefor several months when stored in tight containers. Carbon monoxide (CO) iscolorless, odorless, and tasteless and does not irritate the respiration tract. Itis slightly lighter than air and hardly soluble in water and it is flammable. Itgenerates explosive mixtures in air. In the United States, the Occupational Safetyand Health Administration (OSHA) limits long-term workplace exposure levelsof carbon monoxide to 50 ppm [13]. The World Health Organization (WHO) alsohas guidelines for carbon monoxide [13]. In Germany the MAK-value (maximalconcentration on workplaces) for carbon monoxide is set to 35 mg m−3; both valuesreflect the hazardous effect of CO. The compound does not have the physical andchemical properties a chemical warfare agent usually has [7, 10]. Nevertheless ithas detrimental effects of poisoning and it can be generated through side reactions,and thus potentially utilized for asymmetric warfare, and terroristic attacks.
88 3 Chemical Agents – Small Molecules with Deadly Properties
Table 3.10 Physicochemical characterization of blood agents.
Property AC CK CB CO SA(hydrogen (cyanogen (cyanogen (carbon (arsine)cyanide) chloride) bromide) monoxide)
Formula HCN ClCN BrCN CO AsH3
Molecular weight (gmol–1)
27 61 106 28 78
Vapor density (gcm–3)
0.99 2.1 3.4 1.145(25 ◦C, 1bar)
1.640(−64 ◦C)
Liquid/solid density(g cm–3)
0.69a 1.18a 2.02b 0.814a
(−195 ◦C)1.34a
(20 ◦C)Boiling point (◦C) 25.7 12.8 61–62 –191.5 –55 to
−62.5Melting point (◦C) –13.3 –6.9 49–52 –205 –117Vapor pressure (Pa) 742 (25 ◦C) 1 000
(25 ◦C)85–90(20 ◦C)
Gas understandardconditions
1.47 × 106
(20 ◦C)
Volatility (mg m–3) 1 080000(25 ◦C)
2 600000(12.8 ◦C)
504(20 ◦C)
– 31 000(0 ◦C)
Solubility in water(%)
Completelysoluble
6–7 (20 ◦C) Limited,less thanCK
0.0026(20 ◦C)
0.07(20 ◦C)
aLiquid density.bSolid density.
Arsine is a very toxic compound, which acts mainly by inhalation. Ingestion isnot considered as potential route of exposure. Owing to its physical and chemicalproperties pure arsine is difficult to handle.
Blood Agents – Interference with the Oxygen Transport
Blood agents interfere with red blood cells’ ability to (i) transport oxygen (O2) inthe bloodstream to the cells and (ii) remove carbon dioxide (CO2) from the cellsinto the lungs. Furthermore, they may block both the uptake of oxygen by cellsinto the body and oxygen utilization (Figure 3.12). Consequently, exposureto blood agents results in systemic effects and especially affects those organsystems that are most sensitive to low oxygen levels. These are:
• central nervous system,• brain,• heart and blood vessels,• lungs.
3.3 Properties of Chemical Warfare Agents 89
This leads ultimately to insufficient oxygen exploitation and the unnaturalreturn transport of the oxygen in the venous blood. The symptoms of bloodagent poisoning may vary a great deal from agent to agent.
Cyanide intoxication results in inhibition of the enzyme Cytochrome C Oxidase,which acts in the aerobic energy generation process of higher developed creatures.We can gauge the poisoning potential of AC by considering the very low lethaldosage on oral uptake of 50–60 mg per ‘‘standard man’’ of 75 kg weight; the lethaldose for intravenous application is, as expected, significantly lower. Table 3.11shows the lethal concentration that leads to death within 30 Seconds. Peopleaffected by cyanides typically exhibit a light red color of the skin, which points toa high oxygen saturation of the venous blood stream, resulting from ‘‘inefficient’’oxygen exploitation in the cells. Another effect is that the people concerned sufferfrom suffocation – thus these agents are also called ‘‘asphyxiants.’’
The toxic effect of carbon monoxide arises from its tight binding to hemoglobin,which is 325 times stronger than that of oxygen. Thus a carbon monoxideconcentration of 0.1% in the breathing air deactivates around 50% of the redblood cells [14]. A carbon monoxide content of more than 2% leads to death within1–2 min [15]. The half-life of carbon monoxide elimination is in the range of2−6.5 h, depending on the amount of CO assimilated, the ventilation rate, and theoxygen concentration during ventilation. Carbon monoxide intoxication is indicatedby cherry-red colored mucosa, which may be absent or not well developed in casesof light contamination. An irreversible effect of blood agents is the destruction ofblood cells by arsine.
3.3.4Tear Agents (Lachrymators)
Tear agents, or lacrimators (from the Latin lacrima, meaning ‘‘a tear’’), commonlyreferred to as tear gas are a group of chemical agents with low toxicity. Their vaporscan produce a sharp, irritating pain in the eyes resulting in an abundant flow oftears. There is no permanent damage to the eyes and the effects wear off quickly.For a short period clear visibility is not possible. A protective mask will provide a
Table 3.11 Toxicity data of the blood agent hydrogen cyanide (AC).
Variable Value (mg) Application
LD50 50–60 OralLD50 1 IntravenousLD50 7500 Liquid on skinLD50 100 Liquid on skinLC50 0.5–2% Vapor on skin
90 3 Chemical Agents – Small Molecules with Deadly Properties
complete safeguard. Some of the newer tear agents can cause runny noses, severechest pains, nausea, and vomiting, too. These agents are also being employedagainst civil or prison riots by police and military to disperse crowds. Figure 3.14shows the chemical structure and names of two well-known agents.
High purity chloroacetophenone (CN) is a white crystalline solid reminiscent ofgranulated sugar or salt. The technical product has a gray-green color. It has anodor similar to apple blossoms. Chlorobenzylidene-malononitrile (CS) is used inagents mixed with different additives and/or solvents to vary the persistency, wayof dissemination, and rate of hydrolysis.
Tear agents exhibit high boiling points and melting points, resulting in verylow vapor pressure and thus significantly low volatility (Table 3.12). Dispersionis realized as a solution in organic solvents, such as chloroform, for example, asa 30% solution of CN. They are disseminated as aerosols or in spray form bymany police forces as an incapacitating agent to disperse civilian crowds, and tosuppress persons who are violently aggressive. CS is up to ten times more effectivethan CN.
CN causes tears, irritation of the eyes, and a burning sensation on the skin. Theprimary effects of CN on the eyes are tears and photophobia (sensitivity to light).The median ICt50 concentration is described in literature as 80 mg · min · m−3, the
O
Cl
ClN
N
A-Pulver, B2, CAF, CAP, C.N., CN- or "Tear gas", Grandite, HAF, W-, O-, Om-, Omega-Salt (CN)
2-Chloro-aceto-phenone
CB, K62, C55118, NCI, OCBM, Tear gas 3, F KF-11 (CS)o-Chlora-benzylidene-malondinitril
Figure 3.14 Nomination and moleculargeometries of tear agents. The moleculargeometries have been optimized based onMMFF and DFT calculations (hybrid densityfunctional B3LYP/6-31G*, RMS gradient of
0.001), using the molecular modeling pro-gram Spartan ’04 (Wavefunction, Inc. Irvine,CA). The molecules are represented in aball-stick model enclosed by the calculatedelectron density (IsoVal = 0.03) [11].
3.3 Properties of Chemical Warfare Agents 91
Table 3.12 Physicochemical characterization of tear agents.
Property CN CS
Formula C8H7ClO C10H5ClN2
Molecular weight (g mol–1) 155 189Relative vapor densitya 5.3 –Liquid density (g cm–3) 1.32 (solid) (20 ◦C) 1.04(20 ◦C)Boiling point (◦C) 249 310–315 (with decomposition)Melting point (◦C) 54 95–96Vapor pressure (Pa) 0.0041 (20 ◦C) 0.00034 (20 ◦C)Volatility (mg m–3) 34.3 (20 ◦C) 0.36 (20 ◦C)Solubility in water (g l–1) – 1–5 (16 ◦C)
aRelative to air.
Table 3.13 Toxicity data of tear agents.
Variable Value (mg min m–3) Substance Application
ICt50 80–100 CN AerosolLC50 7000–25 000 CN AerosolTC50 0.3–0.4 mg m–3 CN Aerosol/eye and respiratory tractICt50 20 CS AerosolLCt50 10 000–61 000 CS Pyrotechnically generated aerosolTC50 0.023 mg m–3 CS Aerosol
lethal dose of 50% of the probe animals (LCt50 mg · min · m−3) is reported to be3700 for rats, 73 500 for mice, and 35 000 for guinea pigs. The incapacitation doseof these chemicals is low, while at the same time the lethal dose is significantlyhigh for both compounds (Table 3.13). The newly introduced TC50 value is alsogiven in Table 3.13. It reflects the concentration required to produce a detectableirritation within 1 min for 50% of the population studied. This extremely low valueproves the effectiveness of the tear agents, if employed.
CS may create severe pulmonary damage. It can also severely damage heartand liver and there is a possibility that exposure could cause lethal effects. WhenCS is metabolized, cyanide can be detected in human tissue. According to theUnited States Army Center for Health Promotion and Preventive Medicine, CSemits ‘‘very toxic fumes’’ when heated to decomposition and can be an immediatedanger to life and health at specified concentrations. Persons exposed to CS even inlow concentrations should contact medical personal immediately due to reportedsevere traumatic injury and possible mutagenic effects [16].
Although described as a non-lethal weapon for crowd control, many studies haveraised doubts about this classification. Such an evaluation easily derives from the
92 3 Chemical Agents – Small Molecules with Deadly Properties
potential impacts cited from the literature above. The employment of tear agents isa widespread police doctrine. Domestic utilization of CS by police forces is legal inmany countries.
3.3.5Vomiting Agents (Sternutators)
The most widely known vomiting agents are organoarsenic substances(Figure 3.15). The main and intended effect on humans is the ‘‘mask breaking’’action. The victims feel sickness and are vomiting. At this point the victims areforced to unmask, thereby exposing themselves unprotected to the environment.Consequently, these substances were intended to be employed in combinationwith more hazardous compounds, like nerve agents, so that the unprotectedpersons might be attacked.
DA appears as colorless crystals, DC as a white solid, and DM as lightyellowish-to-greenish crystals dependent on purity. DA and DM are odorless, whileDC reportedly smells similar to garlic or bitter almonds. All three agents are insol-uble in water, and soluble in organic solvents, such as acetone, dichloromethane,ethanol or diethyl ether. They have extremely low vapor pressures (Table 3.14).Consequently, they are typically disseminated as aerosols, by spraying or addingthem [up to 50% (in solid state)] to pyrotechnic mixtures (like nitrocellulose,
Cl
NH
As
Cl
As
N
As
Adarnsite, Azin. G2.D.M., DM-Gas or DM-Toxic, P-15, R-15 (DM)10-Chloro-5,10-dihydro-phenarsazine, Diphenylamin-chlorarsine
Clark I, C1, Cl, DA-Gas, Sternite, No. 12, OW-6 (DA)
Chloro-diphenylarsine
Clark II, C2, C II, DC-Gas, CA, CDA, Sternite, G5, Red ("aka") (DC)
Diphenyl-cyanoarsine
Figure 3.15 Nomination and molecular ge-ometries of vomiting agents. The moleculargeometries have been optimized based onMMFF and DFT calculations (hybrid densityfunctional B3LYP/6-31G*, RMS gradient of
0.001), using the molecular modeling pro-gram Spartan ’04 (Wavefunction, Inc. Irvine,CA). The molecules are represented in aball-stick model enclosed by the calculatedelectron density (IsoVal = 0.03) [11].
3.3 Properties of Chemical Warfare Agents 93
Table 3.14 Physicochemical characterization of vomiting agents.
Property DM DA DC
Formula C12H9AsClN C12H10AsCl C12H10AsCNMolecular weight (g mol–1) 277.6 264.6 255.2Density (g cm–3) 1.65 1.42 1.45Boiling point (◦C) 410 (decomp.)
sublimes readily333 (decomp.) 377
Melting point (◦C) 195 38–45 31.5–35Vapor pressure (Pa) 2.67 × 10–11 (20 ◦C) 0.067 (20 ◦C) 0.027 (20 ◦C)Volatility (mg m–3) 0.02 0.3–0.68 (20 ◦C) 0.1–0.15 (20 ◦C)Solubility in water (%) Practically insoluble Practically
insolublePracticallyinsoluble
Table 3.15 Toxicity data of vomiting agents.
Variable Value (mg min m–3) Substance Application
LD 620 mg m–3 DM Aerosol (30 min inhalation)ICt50 2–150 DM AerosolLCt50 11 000–30 000 DM AerosolICt50 10–30 DC AerosolLCt50 10 000 DC AerosolLC 60 mg m–3 DA Vapor (30 min inhalation)ICt50 10–30 DA VaporLCt50 15 000 DA Vapor
or nitropenta). Thus, the primary route of absorption is through the respira-tory system. Exposure can also occur via ingestion, dermal absorption, or eyeimpact.
DM is now regarded as obsolete. But for some aggressors adamsite could still bein use, as stockpiles may be available.
The toxic effects of vomiting agents are similar to those caused by typical ‘‘riotcontrol agents’’ (e.g. CS). The action may vary, as seen for DM, which is slowerin onset and longer in duration, often lasting several hours. Five to ten minutesafter agent pick up, irritation of the eyes, lungs, and mucous membranes develop,followed by headache, nausea, and persistent vomiting. As shown in Table 3.15 theincapacitation dose of these chemicals is as low or even lower than that of the tearagents, while at the same time the lethal dose is significantly high, similar to thatof CN and CS (refer to Table 3.13). Vomiting agents are even more effective thantear agents while providing similar low fatal potential.
94 3 Chemical Agents – Small Molecules with Deadly Properties
3.3.6Nerve Agents
Nerve agents belong to the class of phosphorous-oxygens, containing variousorganic compounds (Figure 3.16). A more detailed classification allocates them intothe phosphono-group (Figure 3.17). Tabun is a phosphono-cyanide, while somanand sarin are phosphono fluorides, and VX is a member of the phosphono-thiolategroup, according to the ligands of the general chemical structure of these substances(Figure 3.16).
In terms of physicochemical behavior nerve agents show high boiling points,ranging from 150 to 300 ◦C, and low melting points down to less than −50 ◦C.Thus, although they are also called nerve ‘‘gases’’ these chemicals are liquid at
R2
R1
O
OX
P
Figure 3.16 General chemical structure of nerve agents;R1 and R2 reflect the hydrocarbon ligands, while X repre-sents the heteroatom function.
O N
N
CH3 CH3CH3
CH3H3C
H3C
CH3
CH3
CH3
CH3
O
Tabun (GA)
O
O
F
P
P
F
O
OP
OP
F
OH3C
H3C
O-Ethyl-N,N-dimethyl phosphoramide cyanide
Sarin (GB)O-Isopropyl(methyl)phosphono fluoride
Cyclo-Sarin (GF)Cyclohexyl(methyl)phosphono fluoride
VX (VX)Ethyl ({2-[bis(propan-2-yl)amino]ethyl}sulfanyl(methyl)phosphinate
Soman (GD)O-pinacolyl(methyl)phosphono fluoride
H3C
H3C
CH3
CH3
CH3
CH3
O P S
N
O
Figure 3.17 Nomination and molecular ge-ometries of nerve agents. The moleculargeometries have been optimized based onMMFF and DFT calculations (hybrid densityfunctional B3LYP/6-31G*, RMS gradient of
0.001), using the molecular modeling pro-gram Spartan ’04 (Wavefunction, Inc. Irvine,CA). The molecules are represented in aball-stick model enclosed by the calculatedelectron density (IsoVal = 0.03) [11].
3.3 Properties of Chemical Warfare Agents 95
Table 3.16 Physicochemical characterization of nerve agents.
Property Tabun Sarin Soman Cyclohexyl- VX(GA) (GB) (GD) sarin (GF)
Formula C5H11N2O2P C4H10FO2P C7H16FO2P C7H14FO2P C11H26NO2PSMolecular weight(g mol–1)
162 140 182 180 267
Density (g cm–3) 1.073 1.089 1.022 1.120 1.008Boiling point (◦C) 247 147 167 298 300Melting point (◦C) –50 –56 –42 <–30 –39Vapor pressure(Pa)
9 (24 ◦C) 387 (25 ◦C) 53.3 (25 ◦C) 6.67 (25 ◦C) 0.09 (25 ◦C)
Volatility (mg m–3) 600 (25 ◦C) 22 000 (25 ◦C) 3 900 (25 ◦C) 0.44 (25 ◦C) 0.01 (25 ◦C)Solubility in water(%)
10 (25 ◦C) ∞ 2 (25 ◦C) ∼2 3 (25 ◦C)
Table 3.17 Estimated toxicity data of nerve agents.
Variable Value (mg min m–3) Substance Application
LD50 4000 mg GA Contact on human skinLD50 1700 mg GBLD50 300 mg GDLD50 10 mg VXLCt50 200 GA InhalationLCt50 100 GBLCt50 100 GDLCt50 50 VX
room temperature. They provide a wide variety in volatility as well as solubility inwater, which might be of interest for the method of decontamination. The broadrange of vapor pressure classifies the different chemicals into more sedentary (e.g.,VX) and more volatile agents, such as sarin (GB) (Table 3.16).
The toxicity of nerve agents is the highest of all chemical warfare agents [10].Clinical effects of nerve agents depend on:
• the route of entry,• concentration of the agents,• time of exposure,• kind of agent.
Tabun (GA) has a much less effect than VX, which provides the most hazardouseffect. Table 3.17 summarizes the estimated toxic impact of nerve agents onhumans. Action from contact on skin is listed in the top half of the table, while theimpact from inhalation is shown in the lower half. Exposure to low concentrations
96 3 Chemical Agents – Small Molecules with Deadly Properties
of nerve agent vapor produces immediate ocular symptoms, rhinorrhea (filling ofthe nasal cavities with mucus fluid), and, in some patients, dyspnea (shortness ofbreath). These ocular effects are secondary to the localized uptake, for example, ofsarin (GB) vapor across the outermost layers of the eye, causing tears, pupillarysphincter contraction (miosis), and ocular pain. As the exposure increases, dyspneaand gastrointestinal symptoms ensue.
Exposure to high concentrations of nerve agent vapor causes immediate loss ofconsciousness, followed shortly by convulsions, flaccid paralysis, and respiratoryfailure. These generalized effects are caused by the rapid absorption of nerve agentvapor across the respiratory tract, producing maximal inhibition of acetylcholineesterase within seconds to minutes of exposure [7, 10].
The biomolecular mechanism of action of nerve agents is the disruption ofinformation between nerve cells (Figure 3.18, right column). It is caused byblocking the acetylcholine esterase, an enzyme that degrades the neurotransmitteracetylcholine, after being emitted by the synapses for information transfer between
Nerve agent startsdocking to the AChE
Native activity of AChE;acetylcholine cleavage
Transition stateTransition state
H3CH3C CH3
O
N CH2CH2· O
H3C
OH
+
+
+-
-
Anionic site
O
P
OOR2
R3
H
RL
-
Anionic site SerineEsteric site
SerineEsteric site
O
P
O
H
HHO
ORL
H-
Anionic site SerineEsteric site
OH-
Anionic site SerineEsteric site
Bond to breakPossible attractionif RL is appropriatelysized and charged
AcetylcholinesteraseAcetylcholinesterase
AcetylcholinesteraseAcetylcholinesterase
OR2
CH3
NH2C CH3
CH2CH2 OH
R3
or Acetic AcidCholine
O
CH3HO+
Docking process completed,AChE blocked
Irreversible interaction ofnerve agent with AChE
AChE ready to cleave anotheracetylcholine again
Regular action of AChE in thebody's nerve system
Figure 3.18 Natural effect of native acetylcholinesterase (AChE) (right-hand column) andblocking of AChE due to nerve agents (left-hand column).
3.4 Choking and Irritant Agents 97
cells. Clinical effects from nerve agent exposure are therefore caused by excessacetylcholine due to the blocked ability of the enzyme acetylcholine esterase tocleave acetylcholine at muscarinic, nicotinic, and central nervous system synapsesinto choline and acetic acid. Nerve agents act by first binding and then irreversiblyinactivating acetylcholine esterase (Figure 3.18, left column).
Excessive acetylcholine at these cholinergic receptors may account for the spec-trum of clinical effects observed in nerve agent exposure [17], namely, miosis andglandular hypersecretion, sweating and initial defasciculation followed by weaknessand flaccid paralysis. At central nerve system cholinergic receptors, nerve agentsproduce irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma,and respiratory depression.
3.4Choking and Irritant Agents
Choking agents inflict injury mainly on the respiratory tract, that is, the nose,throat, and especially the lungs. Attacked persons suffocate of suffer from reducedoxygen into their bloodstream. Victims typically inhale these agents, which causethe alveoli to secrete a fluid flow into the lungs, essentially ‘‘drowning’’ thesepersons internally. Table 3.18 gives examples and the nomenclature of chokingagents, as well as a summary of their physicochemical properties. As some ofthese substances are mass produced in the chemical industry their threat is mainlythrough asymmetric attacks. At present, they have less military significance thanblister and nerve agents. Thus they will be described only exemplarily.
Choking agents are gaseous or liquids with high volatility. They provide specificoptical recognition, and odors that are often reminiscent of suffocation. Their gasdensity is higher than air – they sink into and fill depressions, like trenches ordeeper bunker areas. They are more or less soluble in water. For instance 2.3 Lchlorine may be dissolved in 1 L water. Phosgene reacts in water, and thus rapidlyhydrolyzes, even at low temperatures; the hydrolysis of 1 g of phosgene even at 0 ◦Ctakes less than 20 seconds. This feature can be used to prevent exposure.
The effect on humans is mainly suffocation, choking, and poisonous impact. Thestrong irritation is mainly based on the on the high oxidation power of the relatedsubstances, mainly, on CL, with long lasting damage at the body. These substancesburn tissues in the eyes and respiratory tract and thus also lead to lachrymation,(e.g., DP). These attributes may serve for ‘‘personal detection’’ of choking agents.The poisoning effect of CG and related compounds, such as DP and PS, is based onthe decay of the molecule into CO (carbon monoxide). Such impacts of CO parallelto those seen with the blood blocking effect (see blood agents), namely, preventionof oxygen transport to, and removal of CO2 from, cells. All these chemicals actrapidly (burn of tissue), although poisoning may be delayed for more than 3 h afterexposure with minimal contact (especially for DP). PS is more toxic than chlorinebut less toxic than phosgene (CG) (Table 3.19).
98 3 Chemical Agents – Small Molecules with Deadly Properties
Tabl
e3.
18N
omen
clat
ure
and
phys
icoc
hem
ical
char
acte
riza
tion
ofch
okin
gag
ents
and
irri
tant
agen
ts.
Age
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3.6 Dissemination Systems of Chemical Warfare Agents 99
Table 3.19 Toxicity data of choking and irritant agents.
Variable Value (mg min m–3) Substance Application
LD50 500 ppm min−1 CG Inhalation (vapor/standard man)LC50 3200 ppm m–3 CG Vapor/standard man (75 kg)ICt50 1600 CG Vapor/standard man (75 kg)LCt50 3200 CG Vapor/standard man (75 kg)LD50 2900 mg m–3 CL Lethal after a short exposure timeICt50 1800 CL Vapor/standard man (75 kg)LCt50 19 000 CL Vapor/standard man (75 kg)LD50 Same data as CG DP Vapor/standard man (75 kg)ICt50 1600 DP Vapor/standard man (75 kg)LCt50 3000 DP Vapor/standard man (75 kg)LD 2300 mg m–3 PS Vapor/standard man (75 kg); 1 min
inhalationICt50 50–100 PS Vapor/standard man (75 kg)LCt50 2000–20 000 PS Vapor/standard man (75 kg)
3.5Incapacitating Agents
A wide range of possible nonlethal chemicals with a highly incapacitating impactwith psychological behavioral action has been developed. This class includesfentanyls, cannabioles (THC), phenothiazines, LSD, chemically related substances,and ketamine. As they are of lesser importance, only examples of such agents aredescribed here.
3-Quinuclidinyl benzilate, (BZ) is a crystalline, odorless substance, which isslightly soluble in water, soluble in diluted acids, and soluble stable in mostsolvents, for example, alcohol, acetone, trichloroethylene, and dimethylformamide.It is insoluble in aqueous alkaline solutions. It has a half-life of three to fourweeks in moist air and is extremely persistent in soil, water, and on mostsurfaces. BZ is an anticholinergic agent that affects both the peripheral and centralnervous systems. As a potent psychomimetic, only small doses are necessaryto produce incapacitation, but with delayed symptoms developing several hoursafter contact. BZ is a glycolate anticholinergic compound related to scopolamine,hyoscyamine, atropine, and other deliriants acting as a competitive inhibitor ofacetylcholine at postsynaptic receptors, and decreases the effective concentrationof acetylcholine seen by receptors at these sites. Impacts seen include panoramicillusions, hallucinations, and confusion [7, 10].
3.6Dissemination Systems of Chemical Warfare Agents
The application of chemical warfare agents requires a spreading system. Thus someaspects of this topic are discussed here, although the subject is of minor interest
100 3 Chemical Agents – Small Molecules with Deadly Properties
MissileWarheads
Aerial Bombs
Chemical Mines
PyrotechnicsAerodynamicForce
ArtilleryShells
Technologies forDissemination
Figure 3.19 Overview of the main technologies for dissemination of chemical warfareagents.
in terms of the main topic of this chapter. One of the most important factors inthe effectiveness of chemical weapons, and thus relating to the threat to soldiers,is the efficiency of dissemination. Various technologies have been developed andcan be used to disseminate chemical warfare agents. Here we address only someof the main technologies [18]. The possible arsenal of chemical warfare munitionsincludes various technologies (Figure 3.19).
For the different types of chemical warfare agents and according to environmentalconditions on the battlefield the different technologies are more or less applicable.In distributing the contaminant, losses of substances are considered to be to theadvantage of the attacked soldiers. Additional contaminated areas may be involved,which is not directly obvious. A high impact on the troops occurs when theintended particle size of the solid or liquid agents is realized by the explosion. Inaddition, contamination densities over the area should be homogeneous. Explosivedissemination produces an uncontrollable droplet size, usually having fine andcoarse particles. For example, the ‘‘central burster technology’’ in artillery shellsprovides contamination densities from a few milligrams per square meter toseveral hundred grams per square meter around the point of detonation. This hasto be considered for protection as well as for decontamination. Another aspect isagent loss by incineration in the initial blast, which is normal; additionally, agentmay be forced onto and in the ground by the blast, which has to be consideredfor decontamination later. Air burst munitions overcome these aspects and thusprovide a higher threat and impact on the attacked soldiers and civilians. Besidesdissemination by explosion, dispersal can be carried out by spraying from tanksor aircrafts via non-explosive dispersion. Additional factors, such as wind speedand direction, changes of the wind, the delivering vehicle, and so on, influence theoperation and the attacked troops significantly.
References 101
3.7Conclusions and Outlook
In this chapter we have brought out the special properties of chemical warfareagents. We have discussed the mechanisms of action of the main chemical warfareagents and gained an impression of the possible devastating effects of thesecompounds. Based on this information we should be able to follow the possiblechemical, biological, radiological, and nuclear (CBRN) countermeasures discussedlater.
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