Toxins and Venoms: Ernest Hodgson

CHAPTER FOURTEEN
Toxins and Venoms

Ernest Hodgson
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh,
North Carolina, USA
Contents
1. Introduction 374
2. Toxins 374
2.1 Introduction 374
2.2 Microbial toxins 375
2.3 Mycotoxins 378
2.4 Algal Toxicoses 383
2.5 Plant Toxins 386
2.6 Animal toxins 404
3. Venoms 407
3.1 Coelenterates 407
3.2 Arachnids 407
3.3 Insecta 408
3.4 Fish 409
4. Summary and Conclusions 412
References 413
Abstract
Toxins are produced by numerous microorganisms and invertebrates as well as by
higher plants and animals. Venoms are produced by many groups of animals, from coe-
lenterates to vertebrates. While toxins and venoms are the primary toxicological con-
cern in natural ecosystems, they are frequently of importance in agroecosystems and
in military deployments. They belong to a very large number of chemical classes and
consequently are usually classified according to the groups of organisms producing
them, for example, mycotoxins, algal toxins, and insect venoms. Plant toxins are repre-
sentative of a larger group of phytochemicals known as secondary plant chemicals or
plant allelochemicals. They may be acutely toxic, have chronic toxicity, or may be toxic
at one dose but therapeutic at a lower dose. Some drugs of abuse are plant toxins abuse.
A representative selection of the more important members of each category is
provided.
Progress in Molecular Biology and Translational Science, Volume 112 # 2012 Elsevier Inc. 373
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-415813-9.00014-3
374 Ernest Hodgson
1. INTRODUCTION
The framework for this chapter is derived from that of Chapter 4 of “A
Textbook of Modern Toxicology, 4th edition”1 and many of the examples
are reprinted, updated, and/or adapted, with permission, from the 2nd edi-
tion of “The Dictionary of Toxicology”.2 In natural ecosystems, toxic haz-
ards occur from exposure to toxicants introduced from outside the
ecosystem via either air or water transport or from plant and animal toxins
and animal venoms. The first are largely dealt with in other chapters, while
some information on plant toxins and animal venoms is provided in the cur-
rent chapter. These toxicants (toxins and venoms) are not only found in nat-
ural ecosystems, but they may also be found in agroecosystems, in military
deployments, and, to a lesser extent, in urban environments. Which of them
are found in any particular ecosystem (natural, agroecosystem, military de-
ployment, or urban) will depend on climate, geographic location, and de-
gree of urbanization.
Since the number of plant and animal toxins that has been described and,
in many cases characterized, is very large, they cannot all be given separate
treatment. However, general information on classes of toxins and venoms is
provided with enough specific examples of importance to demonstrate not
only the numbers involved but also the toxicological and chemical complex-
ity involved within these classes of environmental toxicants.
Any discussion devoted primarily to toxins first necessitates the under-
standing and distinction between the toxicological terms toxicant and toxin.
A toxicant is any chemical, of natural or synthetic origin, capable of causing a
deleterious effect on a living organism. A toxin is a toxicant that is produced
by a living organism. Toxin should never be as a synonym for toxicant—all
toxins are toxicants, but not all toxicants are toxins.
2. TOXINS
2.1. Introduction
Toxins, whether produced by higher animals or plants or by insects, mi-
crobes, or other organisms, are generally metabolic products that appeared
to have evolved as defense mechanisms for the purpose of repelling or killing
predators or pathogens. The action of toxins has long been recognized and
understood throughout human history. For example, a number of ancient
civilizations are known to have used toxins for medicinal (therapeutic),
Toxins and Venoms 375
judicial, and/or criminal purposes.3 One continues to discover and under-

stand the biological activity of natural products, some with beneficial phar-
maceutical or therapeutic effects whose safety and efficacy are thoroughly
tested, and others for less laudable purposes such as biological or chemical
warfare or as drugs of abuse. Toxins may be classified in various ways
depending on interest and need, such as by chemical class, biological origin,
target organ toxicity, or mode of action, but are commonly classified
according to source.
2.2. Microbial toxins

The term “microbial toxin” is usually reserved by microbiologists for toxic
substances produced by microorganisms that are of high molecular weight
and have antigenic properties; toxic compounds produced by bacteria that
do not fit these criteria are usually referred to simply as poisons. Many of the
former are proteins or mucoproteins and may have a variety of enzymatic
properties. They include some of the most toxic substances known, such
as tetanus toxin, botulinum toxin, and diphtheria toxin.
The range of poisonous chemicals produced by bacteria is large. Such
compounds may also be used for beneficial purposes, for example, the
insecticidal properties of Bacillus thuringiensis, due to a toxin, are utilized
in agriculture in a number of different ways. In the case of B. thuringiensis,
the organism or the isolated toxin can be used as an insecticide or the insec-
ticidal properties can be conferred on crop plants by genetic engineering.4
However, bacterial toxins are not normally considered environmental
toxicants and, with only a small number of exceptions, are not considered
further.
2.2.1 Cyanobacterial (blue–green bacteria)

One of these exceptions of importance, particularly in some natural aquatic
environments, is the cyanobacterial toxins, although cyanobacteria have
many properties characteristic of plants and, in fact, are often called
blue–green algae. Cyanobacterial (blue–green bacteria) toxin poisoning
was first recognized in the late 1800s. Although human poisonings are
rare, kills of livestock, other mammals, birds, fish, and aquatic invertebrates
are common. It is caused by a variety of toxins, including anatoxin,
microcystin, and nodularin, produced by several species of cyanobacteria in-
cluding Anabaena, Aphanizomenon, Nodularia, Oscillatoria, and Microcystis.
The main contamination sites include all eutrophic freshwater rivers,
lakes, and streams.
376 Ernest Hodgson
2.2.2 Microcystis aeruginosa

Blooms of this toxic cyanobacterium (sometimes called blue–green algae)
were first reported in 1878 and are increasingly common in freshwaters re-
ceiving nutrients (phosphates and nitrates) from agricultural fertilizers or
treated domestic sewage and thus may be considered hazards of both the
agroecosystem and the domestic environment. Deaths of livestock and other
domestic animals are well known, and the hazard to humans is now receiv-
ing attention. An epidemiological study comparing hepatic enzymes in the
blood of people drinking from a water supply containing a bloom of Micro-
cystis with those of other consumers utilizing different water supplies showed
a significant rise in g-glutamyl transferase in the blood of people whose water
supply contained Microcystis. Microcystis aeruginosa is the most common of all
toxin-forming cyanobacteria. There are reports of toxic blooms of this spe-
cies from all continents except Antarctica.
Microcystis has been shown to be hepatotoxic, the hepatotoxicity
being due to a family of closely related heptapeptides, called microcystins
[structure: cyclo-D-Ala-L-X-erythro-beta-methyl-D-isoAsp-L-Y-Adda-D-
isoGlu-N-methyldehydroAla; where Adda is 3-amino-9-methoxy-2,6,
8-trimethyl-10-phenyldeca-4,6-dienoic acid, and the amino acids X and
Y are variable]. The microcystins are very stable, with little loss of toxicity
on boiling or from typical water treatment and the liver is the target organ.
Although the liver lesions caused by microcystin are well documented, the
mode of action of microcystin is not well known. Microcystins are toxic
orally, by i.p. or i.v. injection. Following a lethal dose of microcystin
(LD50 in mice i.p. <0.1 mg/kg) death can occur in as little as 1 h. Circula-
tory shock, brought on by a massive liver hemorrhage, is the cause of death.
However, no direct cardiovascular toxicity has been seen. Hepatocyte ne-
crosis and disruption of endothelial cells and of the space of Disse have been
shown to occur as early as 15 min following injection.2,5,6
2.2.3 Botulism
The poisoning caused by consumption of food in which there has been
growth of one or more strains of the anaerobic bacterium Clostridium botuli-
num. Such growth results in production of the proteinaceous botulinum exo-
toxin. While there are occasional commercial episodes, botulism often occurs
as a result of home canning where insufficient heat processing or inadequate
sealing is at fault, and thus may be considered a hazard of the domestic envi-
ronment. Botulinum toxins interfere with cholinergic neurotransmission
and ultimately cause death by peripheral mechanisms (respiratory failure
and cardiac arrest), although there are also profound CNS effects. Botulinum
antiserum may prevent further damage when poisoning is confirmed, but the
only alternate therapy is supportive. In survivors, there are often significant
permanent sequelae. Botulinum toxin is a generic term referring to at least
eight biological substances produced during anaerobic growth of C. botulinum.
These bacterial toxins comprise a family of structurally homologous proteins,
designed A–G, indicating that they have evolved from a common ancestor
protein. Botulinum toxin is highly potent, with an LD50 in mice of 2 ng/kg,
i.p. Botulinum toxin acts to block release of acetylcholine from cholinergic
nerve endings. Interaction between the toxin and cholinergic nerve endings
involves binding of the toxin to a receptor. Binding is essential to paralysis but
is not itself toxic. After binding, translocation of the receptor–toxin complex
or some portion thereof occurs. The internalized toxin evokes a lytic effect,
resulting in the blockade of transmitter release. It appears that the heavy chain
of the toxin provides the mechanism of intracellular delivery, and the light
chain is the actual inhibitor of neurotransmitter release.
Symptoms of botulism in humans include nausea, vomiting, diarrhea,
abdominal distress, double vision, and muscular paralysis 8 h to 8 days after
ingestion. Marked muscle fatigue, ptosis, and dysarthria lead to death due to
respiratory paralysis.2,7
2.2.4 Tetanus
Tetanus is an acute disease caused by the toxin produced by Clostridium
tetani, growing anaerobically at the site of an injury. The spores of C. tetani
are found in soil, and thus, tetanus is a particular threat to human health in
the agroecosystem, although it may occur in other environments. Fre-
quently fatal, it is characterized by persistent tonic spasm of certain voluntary
muscles.
The term tetanus also refers to a normal, sustained contraction and is used
to describe experimentally induced sustained muscle contractions or
toxicant-induced sustained muscle contractions caused, for example, by
strychnine.
Tetanus toxin (tetanospasmin) is a 150,000-Da neurotoxic protein com-
posed of one heavy and one light peptide chain linked by a disulfide bond. It is
heat labile and easily oxidized. The toxin blocks the release of amino acid neu-
rotransmitters from inhibitory interneurons in the ventral horn of the spinal
cord. The toxin binds to presynaptic endings of motor neurons and is inter-
nalized, thereby gaining entry to the CNS. It is transported by retrograde
intra-axonal transport to the cell bodies in the spinal cord. Trans-synaptic
378 Ernest Hodgson
transport of the toxin accounts for the presence and primary action of the
toxin on interneurons of the spinal cord. C. tetani infection occurs in deep
wounds under anaerobic conditions. Symptoms of tetanus include muscle
stiffness progressing to rigidity and convulsive spasms. Profuse sweating
and tachycardia are common. Congestive heart failure may arise from hyp-
oxia or by a direct action of the toxin on autonomic neurons and myocardial
cells. The fatality rate is 50–60%. Intensive life support measures must be un-
dertaken to ensure adequate hydration and ventilation. Antiserum will bind
free toxin but is effective only when used early in treatment.2,8
Microbial toxins may also be used for beneficial purposes. Avermectin9
has generated considerable interest both as an insecticide and for the control
of nematode parasites of domestic animals. Avermectins are microbially de-
rived insecticides and miticides of complex chemical structure that interact
as agonists at the GABA receptor/chloride ionophore leading to sedation,
anesthesia, coma, and depression of vital centers. They may also act as ago-
nists at the glycine receptor leading to paralysis. The avermectins display low
acute mammalian toxicity.10
2.3. Mycotoxins
The range of chemical structures and biological activity among the broad class of
fungal metabolites is very large and cannot be summarized briefly. Mycotoxins
do not constitute a separate chemical category, and as a group, they lack common
molecular features. Mycotoxins of most environmental interest are those found
in human food (domestic environment) or in the feed of domestic animals
(agroecosystem). They include the ergot alkaloids produced by Claviceps sp., af-
latoxins and related compounds produced by Aspergillus sp., and the trichothe-
cenes produced by several genera of fungi imperfecti, primarily Fusarium sp.
2.3.1 Ergot alkaloids

Ergot alkaloids are known to affect the nervous system and to be vasocon-
strictors. Historically, ingestion of contaminated grain, particularly rye, has
been implicated in epidemics of both gangrenous and convulsive ergotism
(St. Anthony’s fire), although such epidemics no longer occur in humans
due to increased knowledge of the cause and to more varied modern diets.
Outbreaks of ergotism in livestock do still occur, however. These com-
pounds have also been used as abortifacients.
The ergot alkaloids are derivatives of ergotine, the most active being am-
ides of lysergic acid. Ergot alkaloids are compounds derived from the para-
sitic fungus Claviceps purpurea, which grows on rye as well as other grains.
Ergot alkaloids are often divided into (1) amine alkaloids (e.g., lysergic acid9
OH
H3C O
N
O N H
H N
O
O
N
CH3
H
HN
Ergotamine
O
O
O
O
O OCH3
Aflatoxin B1
H H OH
H3C O
O
(CH3)2CHCH2COO
OOCCH3
CH3
CH2OOCCH3
T-2 toxin
COOH
H2N C H
CH2CH2CONH
HO
coprine
Figure 14.1 Mycotoxins: some representative examples.
ergonovine and methylergonovine, methysergide, lergotrile) and (2) amino

acid alkaloids (e.g., ergotamine9 bromocriptine) (Fig. 14.1) and have a wide
range of physiological effects. These effects are largely due to their agonist,
partial agonist, and/or antagonistic effects at biogenic amine receptor sites.
380 Ernest Hodgson
H H
N N
CH3 CH3
HO O CH2CH2N
CH2CH2N
CH3 P O CH3
OH
HO
Psilocin
Psilocybin
OCH3 O OCH3
O
H3CO O
Cl H3C
Griseofluvin
O
CCH2CH2CH3
OH
O
Ipomeanol
Figure 14.1—cont’d
Ergot alkaloids increase uterine motility, have complex effects on cardiovas-

cular function, and suppress prolactin secretion. The ergot alkaloids are
highly toxic and can result in nausea, vomiting, decreased circulation, rapid
and weak pulse, and coma.2
2.3.2 Aflatoxins
Aflatoxins are produced by species of the genus Aspergillus, particularly
A. flavus, a common fungus found as a contaminant of grain, maize, peanuts,
and so on. First implicated in poultry diseases such as Turkey-X disease, they
were subsequently shown to cause cancer in experimental animals and, from
epidemiological studies, in humans.
Aflatoxin B1 (Fig. 14.1),9 the most toxic of the aflatoxins, must be acti-
vated enzymatically by cytochrome P450 to exert its toxic effects. Aflatoxins
are a family of mycotoxins produced by Aspergillus that includes both carcin-
ogens and hepatotoxicants. Aflatoxins affect male reproductive capacity and
growth rate in birds. Aflatoxin B1 is hepatotoxic and is one of the most po-
tent carcinogens known, being active at dietary doses in the parts per billion
range. Aflatoxins are found as contaminants in both human foodstuffs and
animal feed, particularly in corn and peanuts. The extent of aflatoxin con-
tamination is a function of environmental conditions at the time of harvest as
well as storage conditions.
Although generally a liver carcinogen, there are species differences,
mice being relatively insensitive and showing lung tumors on treatment.
Aflatoxin B1 is oxidized by the cytochrome P450-dependent mono-
oxygenase system to form a highly reactive epoxide. Carcinogenesis is be-
lieved to be initiated when this potent electrophile reacts with DNA, and
hepatotoxicity when it reacts with proteins to cause either fatty liver or liver
necrosis. Epidemiological studies in Africa and Asia indicated that it is a
human liver carcinogen, although similar studies in North America where
aflatoxin contamination is common were generally negative. Studies on the
occurrence of hepatitis B virus indicate that the presence of this virus,
endemic in many African and Asian populations, may potentiate aflatoxin
carcinogenicity.2,11–13
2.3.3 Trichothecenes
Trichothecenes (Merck Index) are a large class of sesquiterpenoid fungal
metabolites produced particularly by members of the genera Fusarium and
Trichoderma. They are frequently acutely toxic, displaying bacteriocidal,
fungicidal, and insecticidal activity, as well as causing a variety of clinical
symptoms in mammals, including diarrhea, anorexia, and ataxia. They have
been implicated in natural intoxications in both humans and animals, such as
Abakabi disease in Japan and stachybotryotoxicosis in the USSR. The
structure of T-2 toxin is shown in Fig. 14.1.2,13
2.3.4 Amanitin
Amanitin9 is derived from the highly poisonous fungus Amanita phalloides
(death cap). Alpha-amanitin, a cyclic octapeptide, is toxic because of its af-
finity for RNA polymerase II in eukaryotic cells. Since this enzyme is re-
sponsible for mRNA synthesis in the cell, the compound is a potent and
selective inhibitor of mRNA synthesis. It is effective at concentrations
below 1 mg/ml, and its specific action has made it useful in experimental
biology. It is often used with actinomycin D to block RNA synthesis.
The genes encoding this and similar toxins have been elucidated.2,14
382 Ernest Hodgson
2.3.5 Coprine
Coprine (1-cyclopropanol-1-N5-glutamine) is a compound produced by
edible mushrooms of the genus Coprinopsis (e.g., C. atramentaria, the death
cap, the ink cap) that on ingestion causes a marked ethanol sensitivity. The
mechanism appears to be inhibition of the low Km form of liver acetalde-
hyde dehydrogenase by the active metabolite cyclopropanone hydrate.
Although the overall effect resembles that of disulfiram, coprine
(Fig. 14.1) does not affect dopamine-b-decarboxylase and is a more potent
ethanol-sensitizing agent.2,15
2.3.6 Psilocybin
Psilocybin (3[2-(dimethylamino)ethyl]indol-4-ol dihydrogen phosphate es-
ter; O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine)9 is an hallucino-
genic (psychedelic) agent that occurs naturally in certain fungi of the
genera Psilocybe, Stropharia, and Conocybe. These so-called magic mushrooms
were known as Teonanacatl and were used in ancient Aztec religious rites.
Psilocybin (Fig. 14.1) may catalyze the onset of severe emotional problems
or psychosis in predisposed individuals. The mechanism of action is not
known, although an interaction with serotonin receptors is possible. Intox-
ication causes perceptual alterations and illusions, including changes in
touch, taste, and odor. Vividly colored closed-eye imagery is pronounced
with psilocybin, and the thinking process is substantially altered. At high
doses, it causes hallucinations and loss of contact with reality. Psilocin
(Fig. 14.1)9 is a minor hallucinogenic constituent of the same species of
mushroom.2
2.3.7 Griseofulvin
Griseofulvin (2S-trans-7-chloro-2,4,6-trimethoxy-6-methylspiro[benzo-
furan-2(3H), 10 [2]cyclohexene]-3,4-dione)9 is an antifungal agent produced
by Penicillium griseofulvum strains that has a low acute toxicity, the oral LD50
in rodents being greater than 10 g/kg. Griseofulvin binds to tubulin, affect-
ing microtubule function and inhibiting mitosis.16 Griseofulvin (Fig. 14.1) is
used as a fungistatic drug in humans and, in agriculture, is also used to control
fungal diseases.
2.3.8 Ipomeanol (1-(3-furyl)-4-hydroxypentanone)

The most important member of a group of furan derivatives responsible for
the lung edema found in cattle fed moldy sweet potatoes infected with the
fungus Fusarium solani and known collectively as the “LE factor.” Ipomeanol
is the best known example of a toxic compound activated in the lung. These
furans are produced by the fungus from a precursor produced by the plant in
response to fungal infection.
Pulmonary injury by 4-ipomeanol is caused by a highly reactive,
alkylating metabolite, probably an epoxide, produced by cytochrome
P450 isoforms, the two major lung cytochrome P450 isoforms both readily
metabolizing 4-ipomeanol. Consequently, activation in the lung is much
greater than that in the liver, which contains significantly lower levels of
these two isoforms. These isozymes are concentrated in the Clara cells,
which are the cells most affected by 4-ipomeanol toxicity.2,17
2.3.9 Ochratoxins
Ochratoxins are a group of toxins produced by Aspergillus ochraceus, and Pen-
icillium viridicatum, the three most important being named ochratoxins A, B,
and C. Of these, ochratoxin A ((R)-N-((5-chloro-3,4-dihydro-8-hydroxy-
3-methyl-1-oxo-1H-2-benzopyran-7-yl)carbonyl)-L-phenylalanine9 is the
major component. Ochratoxins are frequently found as natural contaminants
on peanuts, corn, and stored grains and are toxic to humans and livestock.2
2.3.10 Zearalenone
Zearalenone is a mycotoxin produced by Fusarium which is estrogenic and
causes hyperestrogenic effects. It is found on corn, barley, wheat, hay, oats,
and other agricultural commodities. It can cause adverse effects on repro-
duction in domestic animals, particularly swine.13
2.4. Algal Toxicoses

Algal toxins include a number of chemicals derived from species of dinofla-
gellates and diatoms. The toxins produced by these freshwater and marine
organisms often accumulate in fish and shellfish, causing both human and
animal poisonings, as well as fish kills. Unlike many of the microbial toxins,
algal toxins are generally heat stable and, therefore, not altered by cooking,
which increases the likelihood of human exposure and toxicity. The follow-
ing are some of the more common algal toxins and their toxic syndromes
responsible for human poisonings worldwide.
2.4.1 Amnesic shellfish poisoning

Amnesic shellfish poisoning was first identified in 1987 from Prince Edward
Island, Canada, after four people died from eating contaminated mussels. It is
caused by domoic acid (Fig. 14.2) produced by several species of
384 Ernest Hodgson
H
HOOC N
CH3
HOOC
COOH
H3C
Domoic acid
H OCONH2
+ N
H2N
N
HC
OH NH
N
H NH
+
Saxitoxin
Figure 14.2 Algal toxins: some representative examples.
Pseudonitzschia diatoms as well as Chondria armata. The main contamination

problems include mussels, clams, and crabs of the Pacific Northwest of the
United States and Canada. Domoic acid (2S-(2a,3b,4b(1Z,3E,5S*))-2-
carboxy-4-(5-carboxy-1-methyl-1,3-hexadienyl)-3-pyrrolidineacetic acid)9
is an excitatory amino acid and is a structural analog of kainic acid.2,13
2.4.2 Paralytic (paresthetic) shellfish poisoning

Paralytic (paresthetic) shellfish poisoning was first determined to be a problem in
1942 after three people and many seabirds died from eating shellfish on the
west coast of the United States, near the Columbia River. It is caused by the
saxitoxin family of toxins (saxitoxin þ 18 related compounds) (Fig. 14.2)9
produced by several species of Alexandrium dinoflagellates. The main con-
tamination problems include the mussels, clams, crabs, and fish of the Pacific
Northwest and Northeast Atlantic.
Poisoning results from ingestion of shellfish contaminated with marine di-
noflagellates of the genus Gonyaulax that produce saxitoxin. The toxin pro-
duces paresthesia, aberrations in sensory perception and proprioception,
ataxia, weakness, and respiratory failure. Saxitoxin is a small, water-soluble
molecule synthesized by G. catenalla and G. excavata. During seasons when
dinoflagellates “bloom,” filter-feeding shellfish become contaminated with
accumulated toxin and are toxic when eaten. Saxitoxin blocks nerve
membrane sodium channels in nanomolar concentrations when applied ex-

ternally. The mechanism of action on nerves is the same as that of tetrodo-
toxin, although recovery from saxitoxin block occurs slightly faster than
that after tetrodotoxin block. The i.p. LD50 in mice is 10 mg/kg. Symptoms
in humans within 30 min of ingestion include tingling and burning in face,
lips, tongue, and eventually the whole body, paresthesia followed by numb-
ness, ataxia, general motor incoordination, confusion, and headache. Death
due to respiratory paralysis occurs within 12 h.2,13
2.4.3 Neurotoxic shellfish poisoning

Neurotoxic shellfish poisoning is caused by a red-tide producer that was first
identified in 1880 from Florida, with earlier historical references. It causes
sickness in humans lasting several days. Although not fatal to humans, neu-
rotoxic shellfish poisoning is known to kill fish, invertebrates, seabirds, and
marine mammals (e.g., manatees). It is caused by the brevetoxin family of
toxins (brevetoxin þ 10 related compounds9 produced by the dinoflagellate
Karenia brevis (¼Gymnodinium breve). The main contamination problems in-
clude oysters, clams, and other filter feeders of the Gulf of Mexico and
southeast Atlantic, including North Carolina.2,13
2.4.4 Ciguatera fish poisoning

Ciguatera fish poisoning was first identified in 1511 and is a tropical–subtropical
seafood poisoning that affects up to 50,000 people each year and, in the
United States, it is the most often reported food-borne disease caused by
a chemical rather than a microorganism. Caused by consumption of reef
fishes (e.g., grouper, snapper), sickness in humans lasts several days to weeks,
but the human fatality rate is low. It is caused by the ciguatoxin family of
toxins (ciguatoxin þ 3 or more related compounds9 produced by several spe-
cies of dinoflagellates including Gambierdiscus, Prorocentrum, and Ostreopsis.
Ciguatera refers to intoxication resulting from these reefs and other fish
and is distinct from that associated with the pufferfish. Unlike other dino-
flagellate toxins, ciguatoxin is rarely concentrated by filter-feeding mollusks
(shellfish) because of the sessile existence of the ciguatoxigenic dinoflagellates
on macroalgae. The term “ciguatera” is derived from the Spanish word for
snail (cigua) based on the belief that a marine turban snail was responsible for
poisoning settlers in Cuba. The illness is characterized initially by gastroin-
testinal inflammation, leading to severe dehydration and weakness and even-
tually cardiovascular and neurological distress. The most distinctive features
of ciguatera are severe pruritus, hot/cold reversal, and tingling and numbness
386 Ernest Hodgson
of the extremities. The neurological symptoms are persistent and highly var-
iable among individuals and among regions. A large dinoflagellate
(Gambierdiscus toxicus) produces two toxins, ciguatoxin and maitotoxin, with
similar chemical and pharmacological properties. Similarly active com-
pounds have been extracted from the Gymodinium sanguineum, Gonyaulax
polyhedra, Coolia menotes, and Amphidinium elegans. Intoxication caused by
brevetoxins is similar to ciguatoxin, distinguished only by time of onset.
Ciguatoxin is insoluble in water or benzene, but readily partitions with
methanol, acetone, ethanol or isopropanol. Ciguatoxin is a white solid lipid
with the probable configuration of a highly oxygenated long-chain fatty
acid. Proton NMR suggests a molecular weight of 1111 Da and polymer
formula of C53H77NO24 or C54H78O24, and it may be structurally related
to okadaic acid and brevetoxin c. Two additional toxins have been extracted
from ciguatoxic fish: one (scaritoxin) is ether-soluble and the other
(maitotoxin) is more water-soluble. Scaritoxin may be a fish metabolite
of ciguatoxin, whereas maitotoxin has been produced in abundance in di-
noflagellate cultures; however, it is not well characterized.2,13
2.4.5 Ambush predator (Pfiesteria piscicida and toxic Pfiesteria

complex) toxins
Ambush predator (Pfiesteria piscicida and toxic Pfiesteria complex) toxins
come from members belonging to this group of organisms that were first
identified in 1991 from estuaries in North Carolina.18 They were believed
to produce a toxin that has been implicated in several large fish kills and is
suspect in causing adverse human health effects. However, the toxin or
toxins are not yet identified, and toxicity tests are not universally conclusive.
Produced by several dinoflagellate species including Pfiesteria piscicida,
P. shumwayae, and perhaps several other unidentified, unnamed dinoflagel-
lates belonging to the potentially toxic Pfiesteria complex. The main prob-
lems include major fish kills in North Carolina and Maryland and potential
human health effects. The range may extend from the Gulf of Mexico to the
Atlantic estuarine waters, including Florida, North Carolina, Maryland, and
Delaware, and possibly outward to Europe.19
2.5. Plant Toxins

Plant toxicants, also known as plant allelochemicals or secondary plant
chemicals, are chemicals that are believed to have evolved as defense mech-
anisms against herbivores, particularly insects and mammals. They may be
repellent, but not particularly toxic, or they may be acutely toxic to a wide
range of organisms. Plant toxicants include many types of chemicals, such as

sulfur compounds, lipids, phenols, alkaloids, and glycosides. A useful sum-
mary of the toxic effects of plants, written from the point of view of target
organ effects in humans, is that of Norton.20
Some of the drugs of abuse such as cocaine, caffeine, nicotine, morphine,
and the cannabinoids are plant toxins. Toxic constituents of plants may form
part of the human diet. The carcinogen safrole is found in black pepper, and
solanine and chaconine, which are cholinesterase inhibitors and possible terato-
gens, are found in potatoes. Quinones and phenols are widespread in food. Poi-
soning of domestic animals by plants is still important in veterinary toxicology.
Alkaloids are organic nitrogenous bases produced primarily by dicotyledon-
ous plants, the ergot alkaloids being an important exception. They occur as salts
with organic hydroxy acids such as hydroxybutanedioic, 2-hydroxy-1,2,3-
propanetricarboxylic, tannic, and quinic (1,3,4,5-tetrahydroxycyclohex
anecarboxylic) acids. They often have potent pharmacological activity and as a
result form the basis of many drugs. The majority are toxic both by inhalation
and ingestion. They vary considerably in their chemical properties and constitu-
tion depending on the parent base: aryl-substituted amines, indole, pyridine,
quinoline, or isoquinoline. Drug preparations are usually based on the salts
(e.g., hydrochloride, bromide, sulfate). There are a very large number of plant
alkaloids, and some of the more important ones are included below.
Lipid is a general term for a set of chemicals sharing a common physical
property, namely, solubility in organic solvents such as chloroform,
methanol, ether, etc. The lipid class is chemically diverse and includes such
chemical categories as neutral fats, phospholipids, and sterols.
Phenols are organic chemicals in which an hydroxyl group is attached
directly to a carbon atom of an aromatic ring, while glycosides are water-
soluble compounds resulting from the combination of a sugar with another
organic chemical having an appropriate substituent group, such as a
hydroxyl (OH) group.
From the point of view of relevance to human health and to humans in
the environment, plant toxins may be classified into five general groups:
First, acutely toxic plants that may be eaten but appear to have no positive
attributes. Livestock poisoning by such plants is still an important
veterinary problem in some agroecosystems.
2.5.1 Abrin (toxalbumin)

Abrin (toxalbumin) is a lectin composed of two polypeptide chains con-
nected by a disulfide bridge.9 It is nearly identical to the toxin produced
388 Ernest Hodgson
by the castor bean (Ricinus communis). Abrin is found in the seed of the rosary
pea (Abrus precatorius), a common vine of the tropics. The LD50 in mice is
0.02 mg/kg, i. p. Ingestion of one chewed or broken seed can be fatal. It
is a gastrointestinal toxin; one of the polypeptide chains binds to the
intestinal cell membrane, allowing the other chain to enter the cytoplasm.
Ribosomal protein synthesis is inhibited, resulting in cell death. Death
may occur from loss of intestinal function and consequent alterations in
plasma composition leading to secondary cerebral edema and cardiac
arrhythmia.2 Jequirity beans are black and scarlet beans of the plant
A. precatorius sometimes used in “folk-art” necklaces that contain toxic
lectins similar to those found in castor bean. Abrin-a, consisting of an
A chain of 250 amino acids and a B chain of 267 amino acids, is the most
effective protein synthesis inhibitor of several abrins found in this species.
LD50 to mouse is <0.1 mg/kg; thus, abrin is one of the most acutely toxic
compounds known.2
2.5.2 Ricin
Ricin9 is a toxic lectin and hemagglutinin from the castor plant, R. communis,
now known to be a mixture of several different proteins of which two ag-
glutinins and two toxins have been isolated. Ricin is extremely toxic, and
the i.p. LD50 in mice is approximately 1.0 mg ricin N/kg body wt. At lower
doses, it has antitumor activity. Although the seeds (castor beans) of
R. communis are toxic, the toxicity is not due entirely to ricin. Other toxic
products are present, and ricin, in any case, would be expected to be hydro-
lyzed by proteolytic enzymes.2,21
2.5.3 Ricinine (1,2-dihydro-4-methoxy-1-methyl-2-

oxo-3pyridinecarbonitrile)
Ricinine (1,2-dihydro-4-methoxy-1-methyl-2-oxo-3pyridinecarbonitrile)9
is a toxic compound produced by the castor plant R. communis. It causes
nausea, vomiting, gastroenteritis, liver and kidney damage and, in severe
cases, convulsions, coma, hypotension, respiratory depression, and death.
No specific therapy is available.2,22
2.5.4 Aconitum species

A genus of the family Ranunculaceae, A. napellus is the cultivated aconite,
A. columbianum is a native of moist woodlands in Western North America,
A reclinatum and A. uncinatum are native to the eastern United States, while
A. japonicum and A. carmichaelii are oriental species that are used in oriental
medicine. Aconitum species contain several C19 diterpenoid ester

alkaloids that are potent poisons, including aconitine, mesaconitine, and
jesaconitine. Historically, aconite root has been used for homicides, as an
arrow poison, and in medicine and includes Monkshood (also known as
Wolfsbane and Dogsbane).
2.5.5 Aconitine (16-ethyl-1,16,19-trimethoxy-4-(methoxymethyl)

aconitane-3,8,10,11,18-pentol 8-acetate 10-benzoate)
Aconitine (16-ethyl-1,16,19-trimethoxy-4-(methoxymethyl)aconitane-
3,8,10,11,18-pentol 8-acetate 10-benzoate)9 is a toxic alkaloid that causes
reflex bradycardia, induces arrhythmias and causes nausea, vomiting and
weakness. Aconitine acts on nerve axons by opening sodium channels, as
well as by inhibiting complete repolarization of the membrane of myocardial
tissue, causing repetitive firing. The oral LD50 in mice is about 1 mg/kg.2,23
2.5.6 Buckthorn toxins (coyotillo, tullidora)

Buckthorn toxins (Coyotillo, Tullidora) are found in the fruit of the spineless
shrub Karwinskia humboldtiana, a desert species found in northern Mexico and
southwest Texas, USA. The four principal K. humboldtiana toxins are 7-[30 ,
40 -dihydro-70 ,90 -dimethoxy-10 ,30 -dimethyl-100 -hydroxy-10 H-naphtho(20 ,30 -
c0 )pyran-50 -yl]-3,4-dihydro-3-methyl-3,8,9-trihydroxy-1(2H)-anthracenone
(T-544); 3,4-dihydro-3,di-30 -methyl-10 ,3,8,80 ,9-pentahydroxy(7,100 -bianth-
racene)-1, 90 (2H,100 H)-dione (T-496); 7-(20 -aceto-60 ,80 -dimethoxy-30 -
methyl-10 -hydroxynaphth-40 yl)-3,4-dihydro-3-methyl-3,8,9-trihydroxy-1
(2H)-anthracenone (T-516); and 3,30 -dimethyl-3,30 ,8,80 ,9,90 -hexahydroxy-
3,30 ,4,40 -tetrahydro-(7,100 bianthracene)-1,10 (2H,20 H)-dione (T-514). Buck-
thorn toxins produce segmental demyelination of peripheral nerves in man and
animals. Clinical manifestations of the demyelinatingneuropathyinhumans be-
gin 5–20 days after ingestion of the fruit and include malaise, quadriparesis, and
paralysis of bulbar and respiratory muscles, and recovery requires 3–12 months.
Therapy consists of general supportive care. It has been suggested that daily ad-
ministration of thiamine may be of therapeutic value.2,24
2.5.7 Urushiols
Urushiols are substitutes 1-(alkyl)- or 1-(alkenyl)-2,3-dihydroxybenzenes,
where the alkyl/alkenyl group is C15–C17 with one to three double bonds.9
Urushiol is a mixture of several catechol derivatives that are the main con-
stituents of the irritant oil of plants of the Toxicodendron species, such as poi-
son ivy, poison oak, and the Asiatic lacquer tree. It is responsible for the
390 Ernest Hodgson
dermatitis condition commonly known as poison ivy, and this is an impor-

tant environmental hazard in natural environments and the agroecosystem as
well as urban environments and military deployments. Urushiol causes
hypersensitivity in a large percentage of the population by dermal contact,
or more seriously, through inhalation of burning vegetation.2
2.5.8 Lathyrism
Lathyrism is a neurological disorder involving spastic paraplegia, pain, and
paresthesia that results from ingestion of Lathyrus plant seeds. Osteolathyrism
is a related skeletal disorder produced in animals by the sweet pea
Lathyrus odoratus or its active constituent, b-aminoproprionitrile9 or other
aminonitriles and is characterized by skeletal and connective tissue damage,
dissecting aneurysm, hemorrhaging, and growth retardation.2
2.5.9 Tubocurarine
Tubocurarine9 is the active principle of curare (Merck Index), an extract of
South American plants of the genus Chondrodendron. In addition to the use of
crude extracts as arrow poisons by certain South American natives, purified
tubocurarine was once widely used as a skeletal muscle relaxant during sur-
gery, but the natural agent has now largely been replaced by synthetic
curarimimetics. The mode of action is a highly selective blockade of acetyl-
choline nicotinic receptors. Because penetration of the blood–brain barrier is
negligible, peripheral application of tubocurarine results selectively in paralysis
of striated skeletal muscle. The i.p. LD50 in mice is 0.63 mg/kg.2
2.5.10 Picrotoxin (cocculin)

Picrotoxin (cocculin)9 is a product of the shrub Anamirta cocculus, a com-
pound made up of 1 mol of picrotoxinin plus 1 mol of picrotin, the latter
being inactive. Picrotoxin is highly toxic, particularly to fish, and has an
LD50 in mice of 7.2 mg/kg, i.p. Although not used clinically for this pur-
pose, picrotoxin has central and respiratory stimulant properties and can
be used as an antidote to barbiturate poisoning in animals. At larger doses, pic-
rotoxin induces convulsions, salivation, emesis, and hypertension. Its action is
due to the blockade, centrally, of g-amino butyric acid (GABA). Picrotoxinin
is (1aR-(1aa, 2ab,3b,6b,6ab,8aS*,8bb,9R*)]-hexahydro-2a-hydroxy-8b-
methyl-9-(1-methyl-ethenyl)-3,6-methano-8H-1,5,7-trioxacyclopenta[ij]
cycloprop[a]azulene-4,8(3H)-dione (Fig. 14.3).9 Findings indicate the exis-
tence of a picrotoxin-binding site on the ionophore that includes GABA
and benzodiazepine recognition sites, as well as a chloride channel. Picrotoxin
OH
OH
R
OCH3 R = (CH2)14CH3
CN = (CH2)7CH CH(CH2)5CH3
= (CH2)7CH CHCH2CH CH(CH2)2CH3
= (CH2)7CH CHCH2CH CHCH CHCH3
N O = (CH2)7CH CHCH2CH CHCH2CH CH2
Ricinine Urushiols
OH O CH3 CH3 OCH3

N O
CH3(CH2)5CHCH2CH CH(CH2)7COH +
H2C OH
Ricinoleic acid H
O
+
CH2 N
OH
OH H3C H
CH3O OCH3 CH3O
OCOC6H5 d-Tubocurarine
CH3CH2 N OH O
O H
HO OCOCH3
CH2
CH3
OCH3
OCH3 O
O
OH
Aconitine O C
H2C CH3
Picrotoxinin
O
R¢O CH2OCR
N
Pyrrolizidine alkaloids, general formula
H N
H
N H
O O
Strychnine
Figure 14.3 Acutely toxic plant toxins: some representative examples.
392 Ernest Hodgson
is absorbed relatively slowly with a short duration of action. It is highly toxic in

humans with doses as low as 20 mg, resulting in poisoning. The i.p LD50 in
mice is approximately 3 mg/kg.2,25
2.5.11 Pyrrolizidine alkaloids

Pyrrolizidine alkaloids (Fig. 14.3) are highly toxic alkaloids produced by
plants of the genera Crotolaria, Senecio, and Heliotropium. Monocrotaline
is a typical pyrrolizidine alkaloid. Pyrrolizidine alkaloids are potent
hepatotoxicants and carcinogens. These compounds may contribute to hu-
man liver cancer incidence in some parts of the world; in others, they are the
cause of acute poisoning episodes in food animals. Pyrrolizidine alkaloids are
activated to electrophilic intermediates by cytochrome P450.2
2.5.12 Strychnine (strychnidin-10-one)

Strychnine (strychnidin-10-one) (Fig. 14.3)9 is the extremely poisonous
principal alkaloid from the seeds of Strychnos nux vomica. A muscle relaxant
that is used to kill vermin and also used in homeopathic medicine, it inter-
feres with spinal cord glycine function. Strychnine poisoning results in hy-
persensitivity to sensory stimuli and convulsions, which impair respiration
and result in respiratory and metabolic acidosis. Death may occur after as
few as two to five such convulsions. Strychnine, although having a role
in research, has no therapeutic utility, its primary use being as a rodenticide.
Its actions occur primarily, but not exclusively, in the spinal cord. Strychnine
blocks inhibition in the CNS as opposed to enhancing excitation. Its potent
convulsant properties are due to the antagonism of the inhibitory effects of
glycine.2,26
Second, chemicals that are toxic, but not acutely toxic, and are constitu-
ents of plants that form part of the human diet. For example, the carcin-
ogen safrole and related compounds are found in black pepper. Solanine
and chaconine, which are cholinesterase inhibitors and possible terato-
gens, are found in potatoes, and quinines and phenols are widespread
in food.
2.5.13 Prunus species

Members of the genus Prunus contain amygdalin, a cyanogenic diglucoside,
9
D-mandelonitrile-beta-D-gentiobioside, usually in the kernels of the pits.
Prunasin is the hydrolysis product of D-mandelonitrile-beta-D-glucoside.
Prunus species include P. armeniaca (apricot), P. dulcis (bitter almond),
P. persica (peach), P. serotina (black or wild cherry), and P. virginiana
v. melanocarpa (choke cherry). Amygdalin becomes dangerous when

hydrolyzed by emulsin in the crushed seed or by some human gut micro-
organisms to yield cyanide. Laetrile, a purported cancer cure, is largely
amygdalin. Amygdalin [(6-O-b-D-glucopyranosyl-b-D-glucopyranosyl)
oxy]benzenacetonitrile (Fig. 14.4)9 is a cyanogenic glycoside occurring in
HO
HO
O
HO
O
OH
HO
O
HO
O CN
OH
Amygdalin R1 R2
H H
OH
HO O
H3C CH3
H3C OH
OO N N CH3 OR3 OH
OH
OH
R1 R2 R3
HO Grayantoxin I OH CH3 COCH3
OH Grayantoxin III OH CH3 H
Grayantoxin II CH2 CH2 H
Cycasin
OH
H
C OH
O
O HO C
HC OH
HO CH3
CH
HO CH3 3
H3C CH3
Gossypol
Figure 14.4 Less acutely toxic plant toxins: some representative examples.
394 Ernest Hodgson
seeds, principally in bitter almonds and peach and apricot pits. It has been
promoted as a treatment for cancer, but controlled clinical trials have repeat-
edly failed to confirm such claims. Its toxic actions are those that can be as-
cribed to cyanide as the cyanide released on hydrolysis inhibits cellular
respiration by binding to the trivalent iron of cytochrome oxidase in mito-
chondria, blocking oxygen utilization and resulting in cytotoxic hypoxia.2
2.5.14 Cycasin
Consumption of flour made from nuts of the cycad plant (e.g., on the
island of Guam) has been associated with hepatotoxicity, carcinogenicity,
teratogenesis, and neurotoxicity. The toxic component is cycasin, a
glucoside that is hydrolyzed in vivo to the toxic species methylazoxy-
methanol. Cycasin (methylazoxymethanol-b-D-glucoside) (Fig. 14.4),9 a
naturally occurring alkylating agent produced by the cycad, is found in
the flour made from the cycad nut and, when fed to rats, causes cancer
of the liver, kidney, and digestive tract. Ingestion of this plant by animals
or humans has been associated with hepatotoxicity, carcinogenicity, tera-
togenesis, and neurotoxicity that have been linked to its conversion to
methylazoxymethanol. If cycasin is injected i.p. rather than given
orally, or if it is fed to germ-free rats, it is not carcinogenic, because glu-
cosidases in the intestinal microflora are necessary for conversion to
methylazoxymethanol.2
2.5.15 Gossypol
Gossypol, 1,10 .6,60 .7,70 -hexahydroxy-3,30 -dimethyl-5,50 -bis(1-methylethyl)
[2,20 binaphthalene]-8,80 dicabroxaldehyde (Fig. 14.4),9 is a secondary plant
product produced by some varieties of cotton and found in cottonseed meal
and cottonseed oil from those varieties. It affects the male reproductive system
and has potential use as a male contraceptive agent. In animal studies, large
doses caused lung edema and paralysis.27
The plant family Solanaceae contains a number of poisonous species due
to the presence in them of alkaloids such as solanine. The Irish, or common,
potato (Solanum tuberosum) is among the solanaceous plants known to con-
tain solanine or other toxic alkaloids. In the normal potato tuber, the alka-
loids are present in nontoxic amounts; however, in green or stressed potato
tubers, the levels may be toxic. Another member of the family is the tomato,
Lycopersicon esculentum, which has alkaloids in the leaves and vines but not in
the fruit. Other well-known toxic plants in this family include S. dulcamara,
the deadly nightshade, as well as a variety of other nightshade species. Sweet

potato, Ipomoea batatas, is not a member of this family and, although it may
contain a toxic furanoterpenoid, ipomemarone, seldom is associated with ep-
isodes of acute poisoning. Nicotiana tabacum, tobacco, as well as other Nicotiana
species are also members of the solanaceae. Smoking N. tabacum has been
established as a cause of lung and other cancers and is also associated, possibly
due to high content of nicotine, with cardiovascular and other health deficits.
Nicotine is also classified as a drug of abuse.2
2.5.16 Grayanotoxins
Grayanotoxins (andromedotoxin; rhodotoxin; dodecahydro-1,1,4a,
8a-tetramethyl-7,9aa H-cyclopenta[b]heptalene-2,4,8,11,11-aa,12(1H)-
hexol-12-acetate (GTX-I); GTX-II; GTX-III) (Fig. 14.4)9 are found in
the leaves and flowers of plants of the Ericaceae family, such as rhododen-
dron (Rhododendron maximum) and mountain laurel (Kalmia latifolia). Three
toxic components exist: GTX-I, GTX-II, and GTX-III. GTX-I and GTX-
III are most potent with the LD50s in male mice of 1.28 and 0.91 mg/kg, i.
p., respectively. The complex actions arise from a reversible increase in
membrane permeability to Naþ, resulting in depolarization, which can be
blocked by tetrodotoxin. This mechanism is the basis of the membrane de-
polarization in squid axon, the positive inotropic effect in mammalian myo-
cardium and may involve the Naþ/Ca2 þ exchange system. Grayanotoxins
affect both cardiovascular and respiratory systems. Symptoms include a
burning sensation in the mouth and pharynx, anoxia, salivation, emesis,
muscular weakness, dimness of vision and bradycardia followed by severe
hypotension, respiratory paralysis, coma, and death.2,28
2.5.17 Pokeweed
Pokeweed, Phytolacca americana, also known as pokeberry, poke, inkberry,
etc. A native weed of the eastern United States used in folk medicine as a
purgative, salve, and bronchodilator. Young leaves are eaten in the rural
southern United States (“poke salad”). It contains a powerful gastrointestinal
irritant, phytolaccine, that can cause effects ranging from a burning sensation
of the alimentary tract to severe hemorrhagic gastritis.
Third, many plants or plant allelochemicals that are toxic at one dose may
be useful therapeutic agents at a lower dose. They may also serve as the
basis for the synthesis of other, more effective, therapeutic agents.
396 Ernest Hodgson
2.5.18 Belladonna
Belladonna (Atropa belladonna; deadly nightshade) is a toxic plant associated with
the production of the so-called belladonna alkaloids, most of which are quite
toxic and some of which have clinical utility at lower doses. Deadly nightshade
produces mostly atropine. Serious intoxication can result from ingestion of
berries of this or other solanaceous plants that produce these alkaloids.
Belladonna alkaloids (Fig. 14.5) are organic esters formed from tropic
acid and an organic base such as tropine or scopine. Atropine and scopol-
amine9 are the two most important belladonna alkaloids. These alkaloids
are associated not only with Atropa belladonna, which produces mostly at-
ropine,9 but also with other solanaceous plants such as Datura stramonium
(Jimsonweed), Hyoscyamus niger (henbane), and Scopolia carniolica. The latter
two plants produce scopolamine.9
Poisoning is not uncommon from ingestion of pharmacological prepara-
tions or, particularly in children, from ingestion of berries or plants. Typically,
the patient has a dry mouth, blurred vision, and increased temperature. Mem-
ory and orientation are disturbed, and hallucinations are common. In severe
cases, depression and circulatory collapse may occur, followed by death from
respiratory failure. Atropine and related belladonna alkaloids exert their toxic
action by binding to muscarinic cholinergic receptors in the nervous system.
Atropine (dl-hyoscyamine; tropine tropate; tropic acid ester with
tropine; dl-tropyl tropate; a-(hydroxymethyl)benzeneacetic acid 8-
methyl-8-azabicyclo[3.2.1]oct-3-yl ester; 1aH,5aH-tropan-3aol (þ)-
tropate) (Fig. 14.5)9 is one of the principal alkaloids from Atropa belladonna.
It is known to cross the blood–brain barrier. The oral LD50 in rats is 750 mg/
kg. Atropine exerts its pharmacodynamic effects by competitively blocking
muscarinic acetylcholine receptor sites. Atropine or atropinic drugs result in
pupil dilation, dry mouth, inhibition of activity of sweat glands and, at toxic
doses, tachycardia, palpitation, speech disturbance, blurred vision, restless-
ness, irritability, disorientation, hallucinations, or delirium.2
2.5.19 Cinchona alkaloids

Cinchona alkaloids are derived from the bark of Cinchona officinalis L. They
include the antimalarials quinine9 and cinchonine ((9s)-chinchonan-9-ol)
(Fig. 14.5) as well as the antiarrhythmic quinidine.
2.5.20 Digitoxin
Digitoxin (3-[(O-2,6-dideoxy-b-D-ribo-hexopyranosyl-(1,4)-O-2,6-
dideoxy-b-D-ribo-hexopyranosyl-(1,4)-2,6-dideoxy-b-D-ribo-hexopyran
osyl)oxy]-14-hydroxycard-20(22) enolide) is a secondary glycoside
CH2OH
CH3
HCCOOH N
O
OH O OH
CH3
Tropic acid Tropine CH3
H3C
O NH O CH3 H
Belladonna alkaloids
O
O
OH O O
CH3 OH
N CH3
O O
CH2OH
Taxol
OOCCH
C6H5 HO
Atropine
O
H
H2C N
CH3
HO
N
HO Morphine
H
OCH3
OCH3
N
Cinchonine
CH3O
CH3 N
CH3 CH3O
O
Papaverine
OH
O
HO
H
Digitoxigenin
Figure 14.5 Some examples of plant toxins therapeutic at low dose.
extracted from Digitalis purpurea.9 The aglycone is digitoxigenin (Fig. 14.5).

It is cardiotonic and is used to increase cardiac contractility in the treatment
of heart failure. The steroid nucleus and lactone ring are necessary for activ-
ity; other constituents influence pharmacokinetic variables. Its oral LD50 is
60 mg/kg in guinea pigs and 0.18 mg/kg in cats. It acts by inhibiting
398 Ernest Hodgson
Naþ/Kþ-ATPase associated with the membrane-bound “Na pump.” It

causes an alteration of cardiac electrical function, resulting in premature
atrial beats, atrial fibrillation, atrioventricular block, ventricular tachycardia,
and ventricular fibrillation. Symptoms include arrhythmia, anorexia, nausea,
vomiting, diarrhea, and disorientation. Digoxin is a secondary glycoside
extracted from D. purpurea similar to digitoxin.2
2.5.21 Yew
Yew, Taxus brevifolia, the Western yew, is a tree of the family Taxaceae
found in the western United States and T. canadensis in the eastern United
States. T. cuspidata, the Japanese yew, and T. baccata, a European yew, are
grown as ornamentals. The principal toxic constituents of yew are the alka-
loids taxine A and B Merck Index), both capable of causing digitalis-like poi-
soning (i.e., hypotension, bradycardia, and depressed myocardial
contractility and conduction delay). Various yew preparations have been
used in folk medicine, and an anticancer agent, Taxol, extracted from
yew, has been shown to be clinically effective. Taxol (Paclitaxel)
(Fig. 14.5)9 is an antineoplastic agent from the yew Taxus cuspidata and
T. brevifolia, with the highest concentrations occurring in the needles and
bark. Taxol prevents the dissociation of microtubules into tubulin.2
2.5.22 Opium (gum opium; crude opium)

Opium (gum opium; crude opium) is the air dried, milky exudation from
incised unripe capsules of Papaver somniferum. This resin contains two groups
of alkaloids: phenanthrenes (including morphine9 and codeine9) and ben-
zylisoquinolines (including papaverine9). Morphine is by far the most prev-
alent alkaloid (10–16%) in opium, and its pharmacological properties
account for both the licit and the illicit use of opium. Opium alkaloids
are extracted from exudate of unripe capsules of P. somniferum. Morphine
(7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,6a-diol; morphium;
morphia) (Fig. 14.5)9 is an alkaloid of the opium poppy that makes up be-
tween 9% and 14% of opium. Morphine is usually used clinically as an an-
algesic in the form of the sulfate or hydrochloride salt. The most important
acute toxic effect of large doses of morphine is depression of the respiratory
centers in the medulla and pons. Morphine and related drugs also cause som-
nolence, coma, cold clammy skin, bradycardia, and hypotension. Initial
doses of morphine seem to stimulate the chemoreceptor trigger zone to in-
duce emesis, with subsequent doses blocking the vomiting center, hence
blocking emesis. Morphine also has profound effects on the gastrointestinal
tract, increasing the tone of the intestinal tract, but decreasing the propulsive
or spasmodic reflexes, thus resulting in constipation. Morphine stimulates
the nucleus of the third cranial nerve to produce miosis, making pinpoint
pupil a diagnostic sign both in morphine overdose and morphine addiction.
Morphine causes a variety of effects on the CNS and is highly addictive.
Many behavioral changes are seen, ranging from euphoria to sedation, these
behavioral effects contributing to the problem of abuse. Morphine and re-
lated compounds act by binding to specific high-affinity receptors concen-
trated in the nervous system, but also located elsewhere in the body. In the
nervous system, the endogenous ligands for these morphine receptors are the
opioid peptides that include the enkephalins, endorphins, and dynorphins.
The multiple and complex actions of morphine are due, in part, to the fact
that it acts as an agonist at many of these classes of receptors.2,29
2.5.23 Papaverine
Papaverine (1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline;
6,7-dimethoxy-1-veratrylisoquinoline) (Fig. 14.5)9 is an alkaloid found in
crude opium, but chemically and pharmacologically quite different from
the opioids. Its major actions are smooth muscle relaxation and coronary
and cerebral vasodilation, although demonstrations of clinical efficacy are lac-
king. The vasodilatory action may be due to the inhibition of cyclic nucleo-
tide phosphodiesterase. Systemic administration of high doses can induce
arrhythmias, and the side effects of papaverine include drowsiness, gastroin-
testinal distress, tachycardia, facial flushing, and, potentially, liver toxicity.
The LD50 in rats is 750 mg/kg.2
Fourth, plant allelochemicals may be useful biocides or form the basis for
the synthesis of useful biocides.
2.5.24 Pyrethrum
The insecticidal extract of the pyrethrum flower Pyrethrum (Chrysanthemum
cinerariaefolium) is known as pyrethrins.9 Of the six insecticidal constituents of
the extract of the pyrethrum flowers Pyrethrum (Chrysanthemum) cinerariae
(folium), pyrethrins I (Fig. 14.6) and II are most prominent, existing in
the ratio 71:21:7 for pyrethrin (I and II), cinerin (I and II), and jasmolin
(I and II). Pyrethrins are potent, nonsystemic, contact insecticides, causing
rapid paralysis or knockdown and death at a later stage in a variety of insects.
They exhibit low vertebrate toxicity with an acute oral LD50 in rats of
1.2 g/kg. The mechanism of action involves modification of nerve mem-
brane Naþ channels. Opening and closing of the Naþ channel is slowed,
400 Ernest Hodgson
O
H3C CH3
CH2CH CHCH CH2
H COO
H3C CH3
H
C C
R H
Pyrethrin I
Figure 14.6 Pyrethrin I, a plant toxin useful as a biocide.
resulting in increased Naþ permeability and depolarization leading to hyper-

excitability. Symptoms in humans include gastrointestinal irritation, nausea,
vomiting, diarrhea, numbness of tongue and lips, syncope, hyperexcitability,
incoordination, convulsions, muscular paralysis, collapse, and death due to
respiratory paralysis. Treatment involves gastric lavage, emetics, cathartics,
demulcents, artificial respiration if necessary, and short-acting barbiturates
for convulsions. Pyrethroid insecticides are a relatively new class of synthetic
insecticides based on the pyrethrins. They are characterized by a high selec-
tivity index and a failure to accumulate either in vivo or in the environment.
Their mode of action is similar to that of the pyrethrins. This class includes
compounds such as fenvalerate, resmethrin, bioresmethrin, and permethrin.2
Fifth, many of the common drugs of abuse such as cocaine, caffeine, nic-
otine, morphine, and the cannabinoids are plant toxins.
2.5.25 Cannabiaceae (Cannabidaceae)

The Cannabiaceae (Cannabidaceae) is a family of dicotyledonous plants that
contains only two genera Humulus and Cannabis. Humulus lupulus (hop) is a
perennial climbing herb widely cultivated for its inflorescences, used to fla-
vor beer. Cannabis sativa (hemp) is cultivated in temperate and tropical re-
gions for its fiber, and for the drug (known variously as ganja, marijuana,
charas, bhang, pot, etc.) contained in its resin. Cannabinoids are a chemically
diverse class of chemicals that activate cannabinoid receptors. They include
endocannabinoids produced by the body and the group of C21 compounds
typical of and present in Cannabis sativa. It includes their carboxylic acids,
analogs, and transformation products. Currently, 61 different cannabinoids
have been identified in Cannabis, and, as yet, none have been isolated from
any other plant or animal species. Cannabis sativa is a plant that was named
and described by Linnaeus in 1753. The psychoactivity of Cannabis has been
known since antiquity. The plant has been used for its drug effects in India
for as long as 3500 years, and Moslems have used the drug for centuries.
Various preparations of this plant are smoked or ingested by 200–300 million

people throughout the world. Accordingly, these preparations undoubtedly
constitute the most widely used illicit drugs. Cannabis has been cultivated for
at least 5000 years, spreading originally from central Asia to all temperate and
tropical areas of the world. Cannabis has been a valued agricultural crop for
many reasons. The durable fibers of the woody trunk are known as hemp
and have been used to produce rope and twine, as well as fine or rough cloth.
The Cannabis plant is possibly the most efficient source of paper pulp, pro-
ducing up to five times as much cellulose per acre per year as trees. Cannabis
seeds are used as food by man, poultry, and other birds, as well as furnishing
hemp seed oil for paint and soap. The plant produces as many as 61 specific
C21 compounds known as cannabinoids, of which (-)-D-9-trans-
tetrahydrocannabinol (Fig. 14.7) (Merck Index) is the major source of
psychoactivity.2,30
CH3
N O
OCH3
O
Cocaine
H3C O
O
O H
O NCH3
H3C O
Heroin
N
N CH3
Nicotine
Figure 14.7 Plant toxins used as drugs of abuse.
402 Ernest Hodgson
2.5.26 Coca
Coca (Erythroxylon coca; hayo; ipado) is a plant originally found in
Bolivia, Brazil, and Peru (but now cultivated elsewhere) that contains the
alkaloid cocaine (3-(benzoyloxy)-8-methyl-8-azabicyclo[3.2.1] octane-2-
carboxylic acid methyl ester; ethylbenzoylecgonine) (Fig. 14.7)9 in its leaves.
The leaves were often chewed by South American Indians to eliminate
fatigue. Administration of cocaine causes feelings of well being, stimulation,
and euphoria, although at higher doses dysphoria may result. It may cause
elevation of blood pressure, palpitation, and tachycardia, as well as various
CNS effects, including psychotic effects at higher doses. Chronic use, espe-
cially at high doses as often occurs with drug abuse, can cause a condition often
indistinguishable from schizophrenia. Abrupt withdrawal may result in fa-
tigue, depression, and sleep changes. Several biochemical mechanisms may
be involved in the actions of cocaine in the CNS, principally inhibition of
monoamine uptake. This resulting increase in the synaptic availability of
dopamine, norepinephrine, and serotonin is responsible for its central actions,
whereas adrenergic effects cause most of its peripheral sympathomimetic
effects. The lethality of cocaine is probably due to the local anesthetic prop-
erties of cocaine and actions on various CNS neurons, possibly coupled with
its effects on monoamine uptake. Although both the free base and salts (prin-
cipally the hydrochloride) have been used clinically, in abuse of cocaine, the
free base may be used. Its i.v. LD50 in rats is 17.5 mg/kg. Many of its actions
can be blocked by adrenergic and dopamine antagonists.2,31
2.5.27 Heroin
Heroin (7,8-didehydro-4,5a-epoxy-17-methylmorphinan-3,6-diol dia-
cetate; diacetylmorphine) (Fig. 14.7)9 is a semisynthetic opium alkaloid de-
rived from extracts of the opium poppy, made by acetylation of morphine.
Heroin is much more potent than opium, and somewhat more potent than
its parent compound, morphine. Unlike morphine, heroin is not generally
employed clinically but is primarily a major drug of abuse. The pharmaco-
logical responses and the problems of tolerance to and dependence on heroin
are essentially identical to those of morphine. The primary toxicological
problem is one of overdose, marked by three cardinal signs: depressed res-
piration, coma, and pinpoint pupils.2
2.5.28 Jimsonweed
Jimsonweed, Datura spp. (including D. stramonium, D. sanguinea, D. aurea).
Jimsonweed is also known as thorn apple, datura, devil’s apple, locoweed,
etc. Its toxic, mind altering properties have been known for millennia, and
it is frequently abused for its hallucinogenic properties. Toxic properties are

due to tropane belladonna alkaloids such as atropine (Fig. 14.5), hyoscya-
mine, and scopolamine.9 Related plants include Atropa belladonna or deadly
nightshade, Hyoscyamus niger or henbane, and Mandragora officinarum or man-
drake, all containing hyoscyamine and scopolamine.
2.5.29 Morning glory

Plants of the family Convolvulaceae. The seeds of several, but by no means
all, species of this family contain psychomimetic compounds structurally re-
lated to LSD. Seeds of several species including Ipomoea violacea and Turbina
corymbosa have been used in religious rites in Mexico since the Aztec era.
Compounds found in the above species include elymoclavine, lysergol,
ergometrine, ergine, isoergine, and chanoclavine. Effects are similar to those
of LSD, including the effects of toxic overdose.
2.5.30 Solanaceae
The plant family Solanaceae contains a number of poisonous species due to
the presence in them of alkaloids such as solanine.9 The Irish, or common,
potato (Solanum tuberosum) is among the solanaceous plants known to con-
tain solanine or other toxic alkaloids. In the normal potato tuber, the alka-
loids are present in nontoxic amounts; however, in green or stressed potato
tubers, the levels may be toxic. Another member of the family is the tomato,
Lycopersicon esculentum, which has alkaloids in the leaves and vines but not in
the fruit. Other well-known toxic plants in this family include S. dulcamara,
the deadly nightshade, as well as a variety of other nightshade species. Sweet
potato, Ipomoea batatas, is not a member of this family and, although it may
contain a toxic furanoterpenoid, ipomearone, seldom is associated with ep-
isodes of acute poisoning. Nicotiana tabacum, tobacco, as well as other Nico-
tiana species are also members of the solanaceae. Smoking N. tabacum has
been established as a cause of lung and other cancers and is also associated,
possibly due to high content of nicotine, with cardiovascular and other
health deficits.2
Tobacco, Nicotiana tabacum, the cultured tobacco of commerce, is widely
used either by inhaling the smoke derived by burning the cured leaf in cig-
arettes, cigars or pipes, by chewing the cured leaf or by sniffing dried prep-
arations of the leaf. Although the native leaf contains 1–6% of the toxic
alkaloid, nicotine,9 blending of different varieties is used to maintain a con-
centration of 1–2% nicotine in tobacco products. Tobacco smoke contains
numerous toxic chemicals including organic carcinogens such as polycyclic
aromatic hydrocarbons and aromatic amines, inorganic carcinogens such as
404 Ernest Hodgson
polonium 210, and arsenic and toxic alkaloids such as nicotine. Nicotine
extracted from tobacco has also been used as an insecticide. Nicotine (S)-
3-(1-methyl-2-pyrrolidinyl) pyridine, a constituent of Nicotiana tabacum, is
a colorless liquid produced from tobacco extracts. Nicotine has been used
as a contact insecticide and greenhouse fumigant as well as a drug of abuse.
Used as either the technical alkaloid or as nicotine sulfate, it has now been
largely superceded by organophosphorus insecticides. Nicotine is a neu-
rotoxicant acting on ganglial synapses of insect CNS and stimulates nicotinic
receptors of mammalian autonomic ganglia and neuromuscular junctions.
Symptoms in humans include salivation, vomiting, muscular weakness, fibril-
lation, and, ultimately, chronic convulsions and cessation of respiration.
Chronic use of tobacco-containing products is now thought to have addictive
properties because of the indirect effects of nicotine on brain dopamine
neurotransmission. The acute oral LD50 in rats is 50–60 mg/kg, and the acute
dermal LD50 in rabbits is 50 mg/kg.2
2.6. Animal toxins

All phyla of animals include organisms that produce toxins. Some such animals
are passively venomous (i.e., from chance ingestion), whereas others are ac-
tively venomous, injecting poisons through specially adapted stings or mouth
parts. Many toxinologists consider it more appropriate to refer only to the lat-
ter group as venomous, the former being considered simply as poisonous.
The chemistry of animal toxins includes enzymes, neurotoxic and car-
diotoxic peptides, proteins, and small molecules such as biogenic amines, al-
kaloids, glycosides, and terpenes. The venoms may be complex mixtures
including both proteins and small molecules and depend upon the interac-
tion of the various components for the full expression of their toxic effect.
For example, bee venom contains a biogenic amine, histamine, three pep-
tides, and two enzymes. Snake venoms frequently contain toxins that are
peptides with 60–70 amino acids. The cardiotoxic or neurotoxic effects
of these toxins are enhanced by enzymes such as phospholipases, peptidases,
or proteases that are often present.
Some species from practically all phyla of animals produce toxins for ei-
ther offensive or defensive purposes. Some are passively venomous, often
following inadvertent ingestion, whereas others are actively venomous,
injecting poisons through specially adapted stings or mouthparts. It may
be more appropriate to refer to the latter group only as venomous and to
refer to the former simply as poisonous. The chemistry of animal toxins
extends from enzymes and neurotoxic and cardiotoxic peptides and proteins
to many small molecules such as biogenic amines, alkaloids, glycosides, ter-
penes, and others. In many cases, the venoms are complex mixtures that in-
clude both proteins and small molecules and depend on the interaction of
the components for the full expression of their toxic effect. For example,
bee venom contains a biogenic amine, histamine, three peptides, and two
enzymes. The venoms and defensive secretions of insects may also contain
many relatively simple toxicants or irritants such as formic acid, benzoqui-
none, and other quinines, or terpenes such as citronellal. Bites and stings
from the Hymenoptera (ants, bees, wasps, and hornets) result in 5–60 fatal
anaphylactic reactions each year in the United States. According to experts,
about 0.3–3.0% of the U.S. population experiences anaphylactic reactions
from insect stings and bites.
Many fish species, over 700 species worldwide, are either directly toxic
or, upon ingestion, are poisonous to humans. A classic example is the toxin
produced by the puffer fishes (Sphaeroides spp.) called tetrodotoxin (TTX).
Tetrodotoxin is concentrated in the gonads, liver, intestine, and skin and
poisonings occur most frequently in Japan and other Asian countries where
the flesh, considered a delicacy, is eaten as “fugu.” Death occurs within
5–30 min and the fatality rate is about 60%. TTX is an inhibitor of the
voltage-sensitive Na channel (like saxitoxin); it may also be found in some
salamanders and may be bacterial in origin.
2.6.1 Tetrodotoxin
Tetrodotoxin (Fig. 14.8)9 is a toxin contained in the ovary and liver of puffer
fish, in the eggs of the California newt, and in some other animals, although
it is, apparently, synthesized by symbiotic bacteria. It is used as a chemical
tool for the study of ion channels, and its mode of action, binding to
voltage-gated sodium in nerve cell membranes, was first elucidated by
Narahashi and Moore in 1964.32,33 The s.c. LD50 in mice is 10 mg/kg. It
is a toxicant of nerve and muscle by blocking sodium channels, this
action causing nerve and muscle paralysis. Symptoms include weakening
of voluntary muscles, respiratory failure from paralysis of the diaphragm
and hypotension. There is no antidote.2
2.6.2 Batrachotoxin
Batrachotoxin (30 ,90 -epoxy-14a,18a-(epoxyethano-N-methylimino)-5b-
pregna-7,16-diene-3b, 11a, 20a (2,4-dimethyl-1H-pyrrole-3-carboxylate)
(Fig. 14.8)9 is one of the most toxic (LD50 in mice is 2 mg/kg, i.v.) of the four
406 Ernest Hodgson
O-
H OH
O
+ H O
H2N
H OH
N
N H
H H
HO CH2OH
H
H OH
Tetrodotoxin
H3C
H3C O NH
HO O CH
CH3 3
CH3 N
O O
H
Batrachotoxin
Figure 14.8 Animal toxins: some representative examples.
steroidal alkaloids extracted from the skin of the Columbian arrow poison
frog Phyllobates aurotaenia. Three other steroidal alkaloids are present:
iso-BTX, pseudo-BTX, and BTX-A. BTX is one of the most potent and
specific activators of sodium channels. BTX modifies the activation and in-
activation of sodium channels, causing them to remain open at the resting
membrane potential, thereby increasing the resting sodium permeability.34
BTX binds to the same receptor site as several other lipid-soluble neuro-
toxins (i.e., veratridine, aconitine, and grayanotoxin), but the BTX site is
distinct from that of tetrodotoxin. The increase in membrane sodium
permeability is irreversible. BTX has no effect on intact skin, but causes
long-lasting pungent pain, not unlike a bee sting, when in contact with
broken skin. Consumption of material exposed to BTX is dangerous only
if in contact with an abrasion of the digestive tract. BTX blocks neuromus-
cular transmission and evokes muscular contracture. Death results from
respiratory paralysis. BTX also causes arrhythmias, ventricular tachycardia,
and fibrillation.2,35
3. VENOMS
A venom is a toxin produced by an animal specifically for the poison-
ing of other species via a mechanism designed to deliver the toxin to its prey.
Examples include the venom of bees and wasps, delivered by a sting, and the
venom of snakes, delivered by fangs. An antivenin (or antivenom) is a ther-
apeutic agent produced against a venom, such as from snakes or black widow
spiders, by animals, frequently horses, that have been immunized against the
venom. If delivered soon enough after envenomation, the antivenin can
prevent or attenuate signs of poisoning and/or death. Such therapy may
cause its own toxicological consequences from immune response to the
foreign protein that constitutes the antivenin.
3.1. Coelenterates
3.1.1 Palytoxin
A poisonous material derived from Palythoa toxica, a coral that grows in tidal
pools near the Hawaiian island of Maui. The toxin (C129H223N3O54)
contains 64 disymmetric carbon atoms,9 and formerly was used by natives
to poison their spears.
3.2. Arachnids
3.2.1 Scorpionidae
The scorpionidae is a subgroup of the Arachnida containing over 600
known species, all of which cause painful stings in humans. Fortunately, only
a small number of species are dangerous. The latter includes Centruroides
sculpturatus, found throughout the desert southwest of the Unites States
and in northern Mexico. In adults, the results of envenomation are similar
in severity to a bee or wasp sting and usually resolve in about 10 h without
long-term effects. In children, the effects are more extensive and may be se-
rious or even fatal. The most toxic scorpion venoms are produced by scor-
pions of the family Buthidae. The neurotoxin is a small basic protein
(Mr ¼ 7000) containing hyaluronidase components. Toxicity depends on
the presence of disulfide bonds and lysine residues. It potentiates the release
of acetylcholine by motor neurons and postganglionic autonomic neurons.
Axonal Naþ permeability is increased. Symptoms include local inflamma-
tion and pain, restlessness, malaise, sympathetic discharge, cardiac arrhyth-
mia, and respiratory compromise.28
408 Ernest Hodgson
3.2.2 Black widow spider

The black widow spider, Latrodectus mactans, is a member of a genus collec-
tively known as the widow spiders. The venom is extremely toxic and is
primarily neurotoxic, producing little local tissue reaction. Although the
complex venom contains many components, including hyaluronidase,
phosphodiesterase, GABA, and 5-hydroxytrypamine, the high molecular
weight neurotoxin (ca. 130,000 Da) appears to be responsible for the high
toxicity to mammals. Latrotoxin is the toxic fraction of the venom from spi-
ders of the genus Latrodectus, a protein with a molecular weight of 5000 con-
taining predominantly basic residues. Its LD50 in mice is 0.55 mg/kg. It is a
neurotoxin that appears to be preferentially accumulated in central and pe-
ripheral nervous systems. It causes explosive, nonspecific release of vesicle-
bound neurotransmitters, followed by destruction of prejunctional nerve
endings. Common symptoms include intense pain, restlessness, irritability,
tremors, superficial breathing, tachycardia, and hypertension. Black widow
spider bites are more serious and life-threatening to children than adults.2
3.2.3 Brown recluse spider

The brown recluse spider is technically Loxosceles reclusa. However, the ge-
nus Loxosceles contains many species (13 are native to the United States).
Probably the most dangerous species is L. laeta, a native of South America.
The most serious effect of brown recluse venom is the production of
necrotic lesions in the skin, lesions that may become extensive and take many
months to heal. The venom is primarily cytotoxic and is very complex, in-
cluding such enzymes as hyaluronidase, collagenase, esterases, proteases, phos-
pholipase, deoxyribonuclease, and ribonuclease, but the factor(s) responsible
for the skin lesions is not known with certainty.2,36
3.3. Insecta
3.3.1 Honey bee
Honey bee stings can cause IgE-mediated sensitivity. The bees that cause
these reactions are from European varieties (primarily Apis mellifera mellifera
and A. m. ligustica), although the so-called Africanized honey bees (A. m.
scutellata) present a particular threat because these bees are sensitive to slight
disturbance of their colony and frequently mount massive attacks, occasion-
ally delivering hundreds of stings in an individual attack. In nonsensitized
individuals, systemic toxic reactions from bee stings may require 50 simul-
taneous stings. The toxic reactions include vomiting, diarrhea, hemoglobin-
uria, acute renal failure with elevated serum levels of BUN, creatinine and
creatine phosphokinase, rhabdomyolysis, and thrombocytopenia. Stings in
airway regions tend to increase the risk of fatality. Whole venoms from Eu-
ropean and Africanized bees are biochemically similar, although some chro-
matographic differences have been found. Individual components of honey
bee venom are known to act synergistically. For example, melittin from bee
venom acts synergistically with bee venom phospholipase A2 on phospho-
lipid structures. Hyaluronidase is thought to facilitate distribution of other
venom components through tissues surrounding the sting site, and melittin
may facilitate entry of other more toxic components into the bloodstream.
Since anaphylactoid manifestations comprise only a part of the symptom
complex that results from massive envenomation, specific treatment for ana-
phylaxis may be inadequate in the management of these patients, and anti-
venom treatment may sometimes be appropriate.2,36,37
3.4. Fish
3.4.1 Stonefish
Stonefish, scorpaenids, or scorpionfish are members of the family
Scorpaenidae, a large family of venomous fish consisting of about 30 genera
and ca. 350 species, at least 80 of which have caused venomous injuries in
humans. The most dangerous is a scorpion fish belonging to the genus
Synanceia (Synanceja) and commonly called the stonefish. While scorpion fish
are widely distributed, the greatest number of species, including the two stone-
fish species S. horrida (trachnis) and S. verrucosa, are indigenous to the Indian and
Pacific oceans and the Red Sea. Stonefish contain a venom apparatus con-
sisting of 13 dorsal spines and pairs of venom glands located in the spines. Local
manifestations of poisoning include radiating pain, local paralysis, numbness of
the skin and an area of ischemia surrounded by erythema and ecchymosis about
the wound, extensive swelling, induration and edema of the limb, regional
lymphadenopathy, and tissue necrosis and sloughing of the wound site. Sys-
temic manifestations include respiratory distress, cardiac arrhythmias, hypo-
tension, generalized muscular weakness, convulsions, paralysis, and death.
Complications may include infection of the wound site, cutaneous granulo-
mas, and indolent ulcers and neuropathies. The stonefish venom causes a con-
duction block due to slow depolarization of the muscle membrane. In
addition, it may contain cytolytic toxins that play a role in toxicity.2
3.4.2 Snakes
Snake venoms have been studied extensively; their effects are due, in gen-
eral, to toxins that are peptides with 60–70 amino acids. These toxins are
cardiotoxic or neurotoxic, and their effects are usually accentuated by the
phospholipases, peptidases, proteases, and other enzymes present in venoms.
410 Ernest Hodgson
These enzymes may affect the blood-clotting mechanisms and damage

blood vessels. Snake bites are responsible for <10 deaths/year in the United
States, but many thousand worldwide. Many types of snakes, as well as other
reptiles, have highly developed secretory glands which can produce poisons
(venoms) that may be delivered to a victim during biting. Generally, this
mechanism is important in the ability of the snake to procure food. Venoms
often contain several active components that may work synergistically to in-
toxicate the target animal. A detailed study of the individual components
therefore may not provide full understanding of the actions of the intact
venom. Snake venoms are often classified according to the primary toxic
effect (e.g., neurotoxin, cardiotoxin, hemotoxin, myotoxin), but the toxic
effects of the venom may involve multiple tissues. The Elapidae are a family
of venomous snakes containing such snakes as coral snakes (Micrurus), cobras
(Naja), kraits (Bungarus), and mambas, whose venoms are primarily
neurotoxic.2,37–39
3.4.3 Cobra venom (cobratoxin)

Cobra venom (cobratoxin) is a small basic protein (Mr ¼ 7000). It contains
62 amino acids in a single chain, cross-linked by four disulfide bonds. The
toxin comprises 10% of the venom by weight. It is a neurotoxin that is se-
creted by glands of the cobra snake and injected into its prey via immobile,
grooved fangs. Cobratoxin may be radiolabeled and used as a specific
radioligand in binding studies performed on acetylcholine receptors.
Cobratoxin is absorbed from the subcutaneous tissues and is distributed
throughout the body. After intoxication, high concentrations are found at
the motor endplates of neuromuscular junctions, where it irreversibly binds
to acetylcholine receptors. The primary action is similar to that of curare, but
the binding process is slower. Symptoms include drooping of the eyelids,
accompanied by flaccid paralysis and neck flexor weakness. Respiratory fail-
ure may occur due to paralysis of the diaphragm or pharynx.2,37–40
3.4.4 a-Bungarotoxin
a-Bungarotoxin (Fig. 14.8)9 is a neurotoxin isolated from the venom of the
elapid snakes [Bungarus multicinctus and B. caeruleus (Indian krait)]. The LD50
of the venom in mice is 0.09 mg/kg. Electrophoresis of crude venom yields
at least three fractions, a-, b-, and g-bungarotoxin, with a-bungarotoxin
being the main fraction. The structure consists of a single polypeptide chain
containing 74 amino acids (molecular weight about 8000) cross-linked by
five disulfide bridges. a-Bungarotoxin is a highly specific blocker of the
junctional postsynaptic acetylcholine receptor. When labeled with 125I, it is

used to quantify acetylcholine receptors. a-Bungarotoxin suppresses the
sensitivity of the endplate membrane to acetylcholine. There is no effect
on resting or action potentials of muscle, and there is no presynaptic effect.
The neuromuscular block can be reversed by neostigmine and prevented by
pretreatment with d-tubocurarine. Symptoms in humans include headache,
dizziness, unconsciousness, visual and speech disorders, and sometimes
convulsions. Also abdominal pain and muscular paralysis that is particularly
severe occur within 10 h and may last for 4 days. Death is from respiratory
paralysis.33,37
3.4.5 b-Bungarotoxin
b-Bungarotoxin (Fig. 14.8)9 is a neurotoxin isolated from the venom of the
elapid snakes Bungarus multicinctus and B. caeruleus (Indian krait). The LD50 of
the venom in mice is 0.09 mg/kg. The toxin exists in the form of two poly-
peptide chains: the A chain of 71 amino acids and the B chain of 60 amino
acids. The A and B chains appear to differ with respect to enzymatic activity.
b-Bungarotoxin acts presynaptically to block neuromuscular transmission
through a specific increase in transmitter release. Spontaneous miniature
endplate potentials disappear completely after an initial period of increased
frequency. Endplate potentials evoked by nerve stimulation are also
blocked. It has no effect on endplate sensitivity to acetylcholine, and block-
ade is not prevented by pretreatment with d-tubocurarine. Synaptic vesicles
disappear after exposure to b-bungarotoxin, but not a-bungarotoxin, in
contrast to botulinum toxin which causes no ultrastructural changes despite
presynaptic action. Symptoms include headache, dizziness, visual and speech
disorders, unconsciousness, convulsions, abdominal pain, and muscular pa-
ralysis that may last 4 days, with death resulting from respiratory
paralysis.33,37
3.4.6 Mamba venom

The venom of the green mamba (Dendroaspis angusticeps) is the source of a-
dendrotoxin (a-DTX),9 a specific blocker of certain voltage-gated Kþ chan-
nels. In the brain, intracerebral injection of a-DTX causes convulsions by
precipitating neurotransmitter release, probably largely of glutamate.
Dendroaspis venom also contains fasciculin, a natural peptide inhibitor of
acetylcholinesterase. Finally, mamba venoms contain protein toxins that
are agonists for the muscarinic acetylcholine receptor.2,38
412 Ernest Hodgson
3.4.7 Rattlesnake venom

The product of the venom glands of snakes belonging to the family
Crotalidae; it is injected into the victim via two mobile, needle-sharp teeth.
The venom contains many noxious agents, rather than one specific toxin.
The lung appears to be the major target organ, where increased vascular per-
meability causes pulmonary congestion and hemorrhage, in addition to he-
molysis. Symptoms include local bleeding, severe pain, superficial edema of
rapid onset, hemorrhagic blister formation, and fang marks. Common field
emergency treatments such as incision and suction, tourniquets, and ice
packs are more damaging than useful. The spread of venom is limited by
avoidance of unnecessary motion. Antivenins should be started as soon as
possible.2,38
4. SUMMARY AND CONCLUSIONS

Adverse encounters with natural toxins such as mycotoxins, fish and
shellfish and plant toxins, as well as reptile and insect venoms result in harm
to humans and are a significant feature of natural environments. However,
toxins and other natural products also provide great benefit to society. For
example, some of the most widely used drugs and therapeutics such as strep-
tomycin, the aminoglycoside antibiotic from soil bacteria, and acetylsalicylic
acid (aspirin), the nonsteroidal anti-inflammatory from willow tree bark, are
used by millions of people every day to improve health and well-being.
A note on references
Although references are appropriate cited in the text and listed in the ref-
erence list following, three sources, used more extensively, deserve spe-
cial mention.
The Merck Index, 14th edition, 2006, is a valuable source of information
on chemical compounds with biological activity, including toxins and
venoms. The emphasis of the entries is chemical, and, as a consequence,
it is particularly valuable as a source of chemical names, alternate chem-
ical names and alternate common names.
Much of the text was developed from entries in the Dictionary of Tox-
icology, 2nd edition, 1998. Due to the submission (1998) date and the
differing requirements for dictionary entries, much of the material used
was updated or otherwise adapted. It might be noted that a revision of
this dictionary is in preparation and will, when complete, be available on
the web site of the Foundation for Toxicology and Agromedicine
(www.toxicologyagromed.org).
Casarett and Doull’s Toxicology, the Basic Science of Poisons, 7th edition
(2008), is a useful source of general information on many aspects of toxicol-
ogy that are relevant to this chapter, including metabolism of toxicants and
modes of toxic action. In addition, there are two chapters, 26—Properties
and Toxicities of Animal Venoms and 27—Toxic Effects of Plants.
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Toxins and Venoms: Ernest Hodgson

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CHAPTER FOURTEEN

Toxins and Venoms

judicial, and/or criminal purposes.3 One continues to discover and under-

2.2. Microbial toxins

2.2.1 Cyanobacterial (blue–green bacteria)

2.2.2 Microcystis aeruginosa

2.3.1 Ergot alkaloids

ergonovine and methylergonovine, methysergide, lergotrile) and (2) amino

Ergot alkaloids increase uterine motility, have complex effects on cardiovas-

2.3.8 Ipomeanol (1-(3-furyl)-4-hydroxypentanone)

2.4. Algal Toxicoses

2.4.1 Amnesic shellfish poisoning

Pseudonitzschia diatoms as well as Chondria armata. The main contamination

2.4.2 Paralytic (paresthetic) shellfish poisoning

membrane sodium channels in nanomolar concentrations when applied ex-

2.4.3 Neurotoxic shellfish poisoning

2.4.4 Ciguatera fish poisoning

2.4.5 Ambush predator (Pfiesteria piscicida and toxic Pfiesteria

2.5. Plant Toxins

range of organisms. Plant toxicants include many types of chemicals, such as

2.5.1 Abrin (toxalbumin)

2.5.3 Ricinine (1,2-dihydro-4-methoxy-1-methyl-2-

2.5.4 Aconitum species

medicine. Aconitum species contain several C19 diterpenoid ester

2.5.5 Aconitine (16-ethyl-1,16,19-trimethoxy-4-(methoxymethyl)

2.5.6 Buckthorn toxins (coyotillo, tullidora)

dermatitis condition commonly known as poison ivy, and this is an impor-

2.5.10 Picrotoxin (cocculin)

OH O CH3 CH3 OCH3

Pyrrolizidine alkaloids, general formula

is absorbed relatively slowly with a short duration of action. It is highly toxic in

2.5.11 Pyrrolizidine alkaloids

2.5.12 Strychnine (strychnidin-10-one)

2.5.13 Prunus species

v. melanocarpa (choke cherry). Amygdalin becomes dangerous when

the deadly nightshade, as well as a variety of other nightshade species. Sweet

2.5.19 Cinchona alkaloids

extracted from Digitalis purpurea.9 The aglycone is digitoxigenin (Fig. 14.5).

Naþ/Kþ-ATPase associated with the membrane-bound “Na pump.” It

2.5.22 Opium (gum opium; crude opium)

resulting in increased Naþ permeability and depolarization leading to hyper-

2.5.25 Cannabiaceae (Cannabidaceae)

Various preparations of this plant are smoked or ingested by 200–300 million

it is frequently abused for its hallucinogenic properties. Toxic properties are

2.5.29 Morning glory

2.6. Animal toxins

3.2.2 Black widow spider

3.2.3 Brown recluse spider

These enzymes may affect the blood-clotting mechanisms and damage

3.4.3 Cobra venom (cobratoxin)

junctional postsynaptic acetylcholine receptor. When labeled with 125I, it is

3.4.6 Mamba venom

3.4.7 Rattlesnake venom

4. SUMMARY AND CONCLUSIONS

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