Ch19_pg613-644.pdf

Toxins: Established and Emergent Threats

Chapter 19

Toxins: EsTablishEd and EmErgEnT

ThrEaTs

Patrick Williams, ms * ; scott Willens, DVm, P h D † ; Jaime anDerson, DVm, P h D ‡ ; michael aDler, P h D § ;

a n d corey J. hilmas, mD, P h D ¥

inTroduCTion

nature of the Threat

Established Threats

Emergent Threats

Toxins

Palytoxin

Tetrodotoxin and saxitoxin

brevetoxin

batrachotoxin

summary

* Research Biologist, Department of Neurobehavioral Toxicology, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road,

Aberdeen Proving Ground, Maryland 21010

† Major, Veterinary Corps, US Army; Chief of Department of Neurobehavioral Toxicology, Analytical Toxicology Division, US Army Medical Research

Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010

‡ Division Chief, Analytical Toxicology Division, Department of Neurobehavioral Toxicology, US Army Medical Research Institute of Chemical Defense,

3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010

§ Research Pharmacologist, Neurobehavioral Toxicology, Department of Neurobehavioral Toxicology, US Army Medical Research Institute of Chemical

Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010

¥ Research Physiologist and Pharmacologist, Analytical Toxicology Division, Department of Neurobehavioral Toxicology, US Army Medical Research

Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Maryland 21010

613

Medical Aspects of Chemical Warfare

inTroduCTion

in its definition of “toxin,” the 1993 chemical

Weapons convention includes “any chemical which

through its chemical action on life processes can cause

death, temporary incapacitation or permanent harm to

humans or animals,” regardless of its origin or method

of production. 1 Because there is no consensus on the

inclusion criterion for toxins, international law regards

a wide range of biological and chemical substances

as toxins.

an array of toxins exists among the species of all

kingdoms (table 19-1). many of these toxins have well-

characterized and therapeutic effects and have been

employed as medical treatments and scientific tools.

however, many can have nefarious applications, espe-

cially when used outside of their therapeutic indices.

the wide spectrum of toxins includes the follow-

ing three categories: 1) bacterial toxins (eg, botulinum

neurotoxin and staphylococcal enterotoxin), which

are high-molecular–weight proteins produced in

large quantity by industrial microbiological methods;

2) snake poisons, insect venoms, plant proteins, and

marine algae, which are either naturally occurring

or chemically synthesized (eg, curare, batrachotoxin

[BtX], and ricin); and 3) small molecules, such as

potassium fluoroacetate, which are synthesized by

chemical processes and produced by living organisms.

this chapter focuses on the second toxin group.

(tons) to produce an effective weapon. similarly, toxins

that produce mild effects following intoxication, or ef-

fects for which there are readily available treatments or

antitoxins, are less likely threats. many toxins can be

discounted as potential candidates for weaponization

based on this criterion alone.

second, the requirement to stockpile toxin suggests

that terrorists must possess the storage capability to

maintain toxin potency and prevent toxin degrada-

tion. Unstable toxins with short half-lives or toxins

that require special handling or storage conditions are

typically undesirable. terrorists’ surroundings must be

considered when assessing the stability of a potential

toxin threat. For example, terrorists operating out of

caves in mountains or tent encampments in the desert

will not possess the necessary equipment to handle and

store some toxins, but a small cell of college students or

a state-sponsored group might have access to storage

containers, a variety of solvents and acids to properly

buffer a toxin for long-term storage, temperature- and

humidity-controlled environments, and other special

handling equipment.

third, for a toxin to create mass casualties, a source

of the toxin must be readily available. it is unlikely

that terrorist groups would tend large snake farms, for

example, to harvest snake toxin for weaponization. in

addition to other logistical challenges, such an under-

taking would be conspicuous and time consuming.

however, if a commercial source of a particular toxin

is available, the toxin becomes more attractive to a ter-

rorist organization, particularly if the organization has

the secure infrastructure available to acquire, purify,

concentrate, and properly store toxin stocks. many

toxins have been chemically synthesized and are com-

mercially available to researchers and scientists. com-

mercially available toxins are typically sold in small

quantities for research purposes and are not cost pro-

hibitive; however, some terrorist organizations are able

to purchase and store toxins for future weaponization,

and the chemical reactions for the synthesis of many

toxins have been published in scientific literature and

are therefore available to these organizations. chemi-

cal synthesis begins with readily available, simple,

and nontoxic compounds, which could be easily and

inexpensively obtained from many scientific supply

houses. in many cases, the requisite knowledge, skills,

and apparatus to perform such synthesis are not trivial;

however, for the well-equipped and skilled terrorist,

there are no impediments to the synthesis and storage

of very large quantities of toxin.

a suitable delivery method must also be designed in

advance of bioweapon deployment for toxins to cause

a significant threat. While some toxins are lipid soluble

nature of the Threat

an attack involving a mass-casualty–producing

weapon, whether biological or chemical, can no longer

be anticipated only from hostile states. some nonstate

and terrorist entities have limited moral or social reser-

vations about attacking civilian populations with the

intent of causing large numbers of casualties. agents

considered “classical” chemical or biological weap-

ons, such as mustard gas, organophosphorous nerve

agents, botulinum toxin, and anthrax, threaten the

health and safety of civilian and military populations.

throughout the 20th century, numerous countries have

developed and stockpiled chemical and biological

agents. changes in the geopolitical climate over the

last 30 years have made it possible for these weapons

to fall into terrorists’ hands.

any toxin is a putative, mass-casualty–producing

weapon, and to objectively estimate the threats they

might pose, toxins must be evaluated against several

criteria. First, the potential weapon agent must be

suitably toxic. Groups who intend to injure or kill will

not waste time or limited resources on agents that are

harmless irritants to humans. marginally toxic com-

pounds must be stockpiled in very large quantities

614

Toxins: Established and Emergent Threats

TablE 19-1

lisT oF KnoWn Toxins and ThEir sourCEs

Toxin

source

α-aminitin Death cap mushroom , Amanita phalloides

α-latrotoxin Black widow spider venom, Latrodectus mactans

abrin, crystalline Jequirity beans, the seeds of Abrus precatorius

aconitine roots of monkshood, Aconitum napellus

aerolysin Aeromonas hydrophila

aflatoxin molds Aspergillus flavus and A parasiticus

anatoxin cyanobacteria, Anabaena flosaquae

atelopidtoxin Atelopus zeteki

Batrachotoxin Frogs, Phyllobates terribilis and P aurotaenia

Bee venom (apamin) honey bees, Apis mellifera

Botulinum toxin type a-G Clostridium botulinum bacteria

Brevetoxin Dinoflagellate algae, Ptychodiscus brevis or Gymnodinium breve

Brown recluse spider venom Loxosceles reclusa

c2 toxin, c3 toxin Clostridium botulinum

c-alkaloid e calabash-curare arrow poison

cholera toxin Vibrio cholerae

ciguatoxin Dinoflagellate Gambierdiscus toxicus

clostridium difficile toxin a and B Clostridium difficile

cobra neurotoxin indian cobra venom, Naja naja

conotoxins Pacific cone snails

Dendrotoxin Green mamba snake, Dendroaspis anguisticeps

Dermonecrotic toxin, pertussis toxin Bordetella pertussis

Diphtheria toxin Corynebacterium diphtheriae

d-tubocurarine tube-curare arrow poison

edema factor Bacillus anthracis

enterotoxins, exfoliative toxins, toxic-shock toxin Staphylococcus aureus

epsilon toxin

Clostridium perfringens

escherichia coli toxins (cytotoxic necrotizing

Escherichia coli

factors, heat-labile toxin, heat-stable toxin,

cytolethal distending toxin, heat-stable

enterotoxin-1)

exotoxin a

Pseudomonas aeruginosa

Fasciculin

Venom of the green mamba snake

Grayanotoxin

rhododendron and other ericaceae

hemolysin

Escherichia coli

histrionicotoxin

colombian frog, Dendrobates histrionicus

israeli scorpion venom (charybdotoxin)

Leiurus quinquestriatus hebraues

kokór arrow poison

colombian frog, Phyllobates aurotaenia

lethal factor

Bacillus anthracis

listeriolysin o

Listeria monocytogenes

maitotoxin

marine dinoflagellate, Gambierdiscus toxicus

microcystin

cyanobacteria, Microcystis aeruginosa

nicotine

Nicotiana tobacco plants

north american scorpion venom

Centruroides sculpturatus

ouabain

Strophanthus gratus seeds

Palytoxin

soft coral , Palythoa toxica

Perfringolysin o

Clostridium perfringens

Picrotoxin (cocculin)

Cocculus indicus, Anamirta cocculus

Pneumolysin

Streptococcus pneumoniae

Pumiliotoxin

Formicine ants of genera Brachymyrmex and Paratrechina and frog Den-

drobates pumilio

Pyrogenic exotoxins

Streptococcus pyogenes

( Table 19-1 continues )

615

Medical Aspects of Chemical Warfare

Table 19-1 continued

ricin, amorphous and crystalline

castor beans, the seeds of Ricinis communis

russell’s viper venom

Vipera russelli

salmonella toxin, cytotoxin, enterotoxin

Salmonella Typhimurium and S Enteritidis

saxitoxin

Dinoflagellate marine algae, Gonyaulax catenella and G tamarensis

shiga toxin

Escherichia coli/Shigella dysenteriae

staphylococcus aureus α - toxin

Staphyloccocus aureus

streptolysin o

Streptococcus pyogenes

strychnine

Stryhnos nuxvomica bark or seeds

taipoxin

australian taipan snake, Oxyuranus scutellatus

tetanus toxin

Clostridium tetani bacteria

tetrodotoxin

Puffer fishes and certain salamanders

textilotoxin

australian common brown snake, Pseudonaja textilis

tityustoxin

Brazilian scorpion, Tityus serrulatus

trichothecene mycotoxin (t-2)

Fusarial species of fungus

Veratridine

liliaceae

Western diamondback rattlesnake venom

Crotalus atrox

and readily absorbed through dermal layers (posing

contact hazards), most are water soluble. Water-soluble

toxins can be aerosolized for delivery to target popula-

tions, which allows toxin access to the more vulnerable

inner surfaces of the lung. aerosol particles between

0.5 and 5 µm in diameter are typically retained within

the lung, but smaller particles are not retained in the

airway and most are exhaled. Particles between 5 to 15

µm are generally sequestered in nasal mucosa or in the

trachea. a large percentage of aerosol particles larger

than 15 µm drop to the ground or onto flat surfaces in

the environment. Water-soluble toxins are generally

not volatile, and those particles falling onto the ground

no longer pose a respiratory threat. 2

many cases of accidental exposure to toxins in hu-

mans, especially from marine toxins, occur by inges-

tion. intoxication by agents such as tetrodotoxin (ttX;

isolated from the Japanese puffer fish) or brevetoxin

(Pbtx), implicated in neurotoxic shellfish poisoning

(nsP), suggest that water or food supplies could be

targeted for large-scale delivery of weaponized toxins

to civilian populations. several recent publications

have presented mathematical models of toxin weapons

delivered into food or water supplies. 3 these data sug-

gest that this means of toxin delivery would impose a

significant financial burden to diagnose and treat the

affected population, a compromise to key infrastruc-

ture, and a reallocation of resources to deliver clean

supplies to the effected population.

features with chemical warfare agents. toxins and

chemical warfare agents interfere with important

biological processes (eg, synaptic transmission, Dna

replication, and protein synthesis) and produce inca-

pacitation and death following acute exposure. 4 toxins

that are generally considered to be battlefield or bioter-

rorist threats include anthrax, botulinum neurotoxin,

staphylococcal enterotoxin B, t-2 mycotoxin, and ricin.

these five biotoxins are thought to be most likely used

in the event of warfare or bioterrorism, although they

represent a small subset of all lethal toxins known. 5

Potency, ease of production, stability, and prior his-

tory of weaponization are all factors hostile forces

must consider before deploying bioweapons. 4–6 the

centers for Disease control and Prevention (cDc)

have designated anthrax and botulinum neurotoxin

as category a threat agents, and staphylococcal en-

terotoxin B and ricin as category B agents (table 19-

2). 7 category a agents are defined as those that “can

be easily disseminated or transmitted from person

to person; result in high mortality rates and have the

potential for major public health impact; might cause

public panic and social disruption and require special

action for public health preparedness.” 7 category B

agents are defined as those that “are moderately easy

to disseminate; result in moderate morbidity rates and

low mortality rates; and require specific enhancements

of cDc’s diagnostic capacity and enhanced disease

surveillance.” 7 For example, t-2 mycotoxin, a category

B agent, is specifically addressed by the cDc as a select

agent and toxin and additionally regarded as a threat

because of its documented use in laos, Vietnam, and

cambodia during 1975–1978. 8 category c agents, the

third highest priority, “include emerging pathogens

that could be engineered for mass dissemination in

Established Threats

toxins of concern to the Us military and the De-

partment of homeland security comprise a group

of structurally diverse substances that share many

616

Toxins: Established and Emergent Threats

TablE 19-2

CEnTEr For disEasE ConTrol and PrEvEnTion ClassiFiCaTion oF bioTErrorism

agEnTs/disEasEs

Category a

Category b

Category C

anthrax

Brucellosis

emerging future toxin threats

Botulism epilson toxin of Clostridium perfringens

Plague Food safety threats ( Escherichia coli, Salmonella species, o157:h7,

smallpox Shigella )

tularemia Glanders

Viral hemmoragic Fevers meloidosis

Psittacosis

Q Fever

ricin toxin from Ricinus communis

staphylococcal enterotoxin B

typhus

Viral encephalitis

Water safety threats (eg, Vibrio cholerae , Cryptosporidium parvum )

Data source: Bioterrorism agents/diseases: emergency preparedness & response Web site. available at: http://www.bt.cdc.gov/agent/

agentlist-category.asp. accessed February 10, 2007.

the future because of availability; ease of production

and dissemination; and potential for high morbidity

and mortality rates and major health impact.” 7 these

emerging toxin threats are the focus of this chapter,

toxins that possess the properties of the more well-

known category a and B agents but that have not been

considered likely threats to date (see table 19-2).

death is potentially very large and includes the so-

dium channel toxins BtX, 9 Pbtx, 10 saxitoxin (stX), 11

ttX, 12 and pumiliotoxin. 13 others include palytoxin

(PtX), which alters the sodium-potassium exchanger

(sodium-potassium atPase), 14 and the nicotinic re-

ceptor agonist, anatoxin-a. 15 Because these toxins are

employed as pharmacological tools for studying ion

channel properties, active efforts to optimize their

synthesis are being developed. 16 if these efforts are

successful in generating large quantities of toxin,

members of this group will need to be reevaluated for

their potential as threat agents.

Emergent Threats

the group of biotoxins not considered immediate

threats with the potential to cause human illness and

Toxins

Palytoxin

the primary source is most likely a bacterium associ-

ated with soft corals that inhabit the digestive tract of

filefish (Figure 19-1). PtX is a large (molecular weight

2,678.5), water-soluble, nonproteinaceous polyether,

with molecular formula c 129 h 223 n 3 o 54 . PtX has an

exquisitely complex structure (see Figure 19-1). it was

first elucidated and synthesized in 1982 28 and is cur-

rently available from several commercial sources.

Synthesis

PtX is an extremely potent marine neurotoxin that

acts on sodium-potassium ion pumps. First isolated

from the zoanthid coral (genus Palythoa ) by moore

and scheuer, 17 PtX has long been categorized as a

marine animal toxin. it has been identified in several

species living in close contact with zoanthid anemo-

nes (eg, some dinoflagellates, Ostreopsis species); 18

Polychaete worms; 19 several species of xanthid crab

( Lophozozymus pictor and Demaina toxica ), 20 and several

species of fish. 21–23 PtX is found in the red alga Chondria

aramata . 24,25 PtX has also been associated with the blue

humphead parrotfish, 26 filefish, and serranid fish. 27

Mechanism of Action and Toxicity

PtX affects all excitable cells by inducing the ac-

tivity of a small conductance (9–25 ps), nonselective,

cationic channel, which triggers secondary activations

of voltage-dependent calcium channels and of sodium-

calcium exchange. in addition to electrically excitable

617

Plik z chomika:

Inne pliki z tego folderu:

Inne foldery tego chomika: