Toxin

A toxin can be defined as a substance that is synthesised by a plant species, an animal, or by micro-organisms, that is harmful to another organism.

From: Analytica Chimica Acta , 2009

Chemical weapons of mass destruction and terrorism: a threat analysis

René Pita , ... Kamil Kuca , in Handbook of Toxicology of Chemical Warfare Agents (Third Edition), 2020

7.2.5 Toxins

Toxins are chemical substances of biological origin, although synthesis procedures for some nonprotein toxins that have been studied as weapons are widely available ( Jacobi et al., 1984; Tanino et al., 1977). Toxins are included in the CWC because it covers toxic chemicals "regardless of their origin or of their method of production." Actually, two toxins, ricin and saxitoxin, are explicitly included in Schedule 1 of the CWC. However, toxins are also included in the Biological and Toxin Weapons. For these reasons, toxins can be considered CWs, biological weapons, or mid-spectrum agents.

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Marine Venoms and Toxins

W.R. Kem , in Encyclopedia of Toxicology (Third Edition), 2014

Abstract

Toxins are naturally occurring molecules that are injurious to some living organism. The scientific study of toxins is sometimes referred to as toxinology, a branch of toxicology. Many animals and a few plants secrete venoms to either defend themselves or to paralyze their prey. Generally, venoms are complex mixtures of substances, including toxins, that together exert a greater effect than would a single substance. For instance, phospholipases, proteases, and hyaluronidases, commonly present in animal venoms, facilitate the distribution of ion channel and receptor modulating toxins by permeabilizing lipid membranes (lysolecithin), digesting proteins, and breaking down connective tissues, respectively, that are barriers to the distribution of toxins throughout the body. Marine organisms contain a wide variety of potent venoms and toxins that cause medical problems for those that come in contact with them. In addition, some of the purified toxins are becoming useful chemical tools for biomedical research.

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Bio Warfare and Terrorism: Toxins and Other Mid-Spectrum Agents

James M. Madsen , in Encyclopedia of Toxicology (Second Edition), 2005

Introduction and Classification

Toxins are toxic chemicals that can be elaborated by a biological organism. The word 'toxin' is often loosely used to mean poison but should be reserved for its more restricted definition; toxicant is a better synonym for poison. Several of the less complex toxins can now be synthesized in the laboratory or produced by other organisms following gene insertion, but synthetic toxins identical to their naturally occurring counterparts are still by definition toxins. Related terms include phycotoxins (toxins from algae), mycotoxins (fungal toxins), phytotoxins (plant toxins), and venoms (toxins from animals, especially vertebrates). Endotoxins are lipopolysaccharide toxins in the cell walls of certain gram-negative bacteria, and enterotoxins are toxins, such as cholera toxin, that damage intestinal mucosal cells. An exotoxin is a toxin that an organism releases into the environment. The actual toxin secreted by cells has in some cases been altered from the protoxin initially formed within the cells. Toxins usually do not perform crucial metabolic functions within their organisms of origin but act as offensive or defensive reactions to other organisms.

More than 400 toxins are known. They may be grouped according to size: low-molecular weight (LMW) toxins, which may be either peptides or nonpeptide organic compounds such as domoic acid, weigh less than 1   kDa and, if peptides, have no more than ∼10 amino acids; heavier (larger) toxins are called protein toxins. Classification by organism of origin leads to the division of toxins into bacterial, algal, fungal, plant, marine dinoflagellate, marine soft coral, arthropod, molluscan, and vertebrate toxins. Toxins of similar chemical structure can be grouped together. Pathophysiologically, toxins comprise at least three major groups depending upon their toxicodynamics, or mechanisms of action. Neurotoxins, which affect neurotransmission, include botulinum toxin (which blocks the release of acetylcholine from cholinergic neurons), anatoxin, saxitoxin, and many animal venoms, some of which act presynaptically and others of which act postsynaptically. Membrane-damaging toxins include ricin, microcystin (which is also a hepatotoxin), certain venoms (such as the hemolytic snake venoms), and the trichothecene mycotoxins. Superantigen toxins such as staphylococcal enterotoxin B, toxic shock syndrome toxin-1, and streptococcal pyrogenic exotoxins exert pronounced systemic effects by activating the immune system in a nonspecific way.

Bioregulators are potent low-molecular peptides and proteins that modulate a wide variety of physiological processes such as inflammation, blood clotting, and neurotransmission. Unlike most toxins, they have definite roles in the normal physiology of their hosts. Bioregulators are not normally considered poisons but at toxicological doses may produce dramatic effects on blood pressure, body temperature, and other physiological parameters.

As chemicals produced by biological organisms, toxins and bioregulators occupy a zone that lies between chemical and biological agents and overlaps them to some extent. Saxitoxin and ricin are listed as chemical agents in the Chemical Weapons Convention, and toxins are listed separately from biological agents in the Biological and Toxin Weapons Convention (BTWC). The usual practice is to group toxins with biological agents. This is natural and appropriate from the perspectives of production, storage, and treaty issues, since toxins are generally produced by and often stored near their biological agents of origin. However, from a clinical standpoint, both toxins and bioregulators resemble other chemicals in that they do not replicate inside their hosts, are not transmissible, and are amenable to a chemical-based approach to clinical management. The term mid-spectrum agents (or mid-spectrum chemical warfare agents) has been proposed to refer to toxins and bioregulators along with synthetic viruses and genocidal agents produced by recent advances in biotechnology. Table 1 displays one classification scheme for these compounds; the agents that are underlined will receive particular attention in this entry. Agents discussed as separate entries in this encyclopedia are also so indicated.

Table 1. Toxins and other mid-spectrum agents relevant to warfare and terrorism: a classification scheme

TOXINS
Bacterial toxins
Phycotoxins (algal toxins)
Botulinum toxin (CDC Category A)
Epsilon toxin from Clostridium perfringens (CDC Category B)
Staphylococcal enterotoxin B (SEB) (CDC Category B)
Diphtheria toxin
Tetanus toxin
Shigatoxin (veratoxin)
Mycotoxins (fungal toxins)
Aflatoxins
Ergot alkaloids (historical)
Trichothecene mycotoxins
  Stachybotrotoxins, including satratoxin H
T-2 mycotoxins
Marine toxins
Phycotoxins (algal toxins)
  Algal toxins (blue-green algal) toxins
    Anatoxin-A (AnTx-a)
    Microcystins and nodularins
  Saxitoxins(STX), causing paralytic shellfish poisoning (PSP)
  Diatom toxin
  Domoic acid, causing amnesic shellfish poisoning (ASP)
  Dinoflagellate toxins
    Brevetoxins (PbTx), causing neurotoxic shellfish poisoning (NSP)
    Ciguatoxins (CTX) and maitotoxins (MTX), causing ciguateric fish poisoning (CFP)
    Diarrheic shellfish toxins (DST), causing diarrheic shellfish poisoning (DSP)
      Okadaic acid
    Palytoxin (concentrated by corals)
Conotoxins (from cone snails)
Scombrotoxins (mainly histamine)
Tetrodotoxin (TTX)
Phytotoxins (plant toxins)
(numerous alkaloids, including curare)
Type 2 ribosomal-inhibitory-protein (RIP) toxins
Ricin (CDC Category B)
Abrin
Eranthis hyemalis lectin (EHL) from winter aconite
  Modeccin
  Viscumin
  Volkensin
Venoms from land animals
Invertebrate toxins, mostly from arthropods
Vertebrate toxins
  Amphibian toxins, including batrachotoxin
  Snake and lizard venoms
  Bird toxins (mainly batrachotoxin)
BIOREGULATORS
Cytokines
Early-phase proinflammatory cytokines (endogenous pyrogens)
  Interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α)
  IL-6
  IL-18
  Interferon gamma (IFN-γ)
Chemokines
  IL-8
Eicosanoids (prostanoids and leukotrienes)
Prostaglandin D2 (PGD2), leukotrienes C4 (LTC4), LTD4, LTE4
LTB4
Neurotransmitters and hormones
Catecholamines (e.g., epinephrine, norepinephrine, serotonin, dopamine)
Amino acid neurotransmitters (e.g., glutamate, aspartate, glycine, and γ-aminobutyric acid, or GABA)
Neuropeptides
  Neuropeptide Y
  Opioids (endorphins and enkephalins)
  Tachykinins
    Neurokinins A and B
    Substance P
Insulin
Vasopressin
Cholecystokinin
Somatostatin
Neurotensin
Bombesin
Vasoactive plasma proteases
Kallikreins and bradykinins
Tissue factor and thrombin
SYNTHETIC VIRUSES
Poliovirus
Other viruses identical to their natural counterparts
Genetically modified or combined synthetic viruses
GENOCIDAL AGENTS
Toxins, bioregulators, synthetic viruses, or traditional agents modified to enhance virulence
Toxins, bioregulators, synthetic viruses, or traditional agents modified to target specific genotypes

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Agricultural and Related Biotechnologies

C.G. Trick , in Comprehensive Biotechnology (Third Edition), 2011

4.26.6 Toxin Studies Using Chemostats

Toxins are elements of cells with a wide breadth of interest. Biotechnologists seek a means to culture cells such that the level of harvestable toxins is maximized. Ecologists seek an understanding of the environmental factors that enhance or reduce the public heath risk of algal toxins. In both types of studies, chemostats contribute significantly to our understanding of toxin production. Most algal toxins are not constantly produced, but are produced under specific conditions or at a specific time during the growth phase. Many of the toxins can be recognized in properly designed batch-culture experiments; however, the constantly altering conditions do not usually result in maximal toxin production. Chemostat studies can differentiate the three key factors that regulate the biochemistry of toxin production: the level of nutrient supply, the composition of the limiting nutrient, and the growth rate of the community. 1 In traditional batch-type growth cultures, at least two of the three factors are being modified over time. As the cells make the transition from nutrient-replete to nutrient-limited condition, growth rates are reduced. As toxin levels in many algal systems are regulated by these two factors, the period when toxin production is maximum is limited. Chemostats allow for the simultaneous control of both the limiting factor and the growth rate – factors critical to the production of a wide number of secondary metabolites, including toxins.

Recent key research has illustrated the complex nature of toxin regulation and the value of chemostats. 14 As a secondary metabolite, toxin production is often not due to specific induction but rather a consequence of the cellular housekeeping of metabolites and elements. Cells with an abundance of one element, nitrogen for example, may require that the excess element be stored as a biochemical component that serves as the precursor of the cellular toxin. The completion of the toxin structure may require additional elements that are obtained from the environment or similarly stored. Thus, the chemical composition of the medium or environment is critical for completing toxin production. Thus, the level of nonlimiting nutrients in the medium equally influences toxin levels of algal cells, grown under specific limitations. While the permutations of the ecological stoichiometry are complex, the study can best be performed through chemostat experiments where the levels of nonlimiting nutrients and/or light can be maintained in conjunction with the limiting nutrient and the established growth rate.

Chemostats provide a unique opportunity to study extracellular toxins. Accepting that the release of toxic compounds into the medium is a dynamic process that has some level of feedback regulation, external toxins will accumulate in a batch-culture experiment. The flow-through chemostat culture system parallels allow for the harvesting of the flow-through cell and extracellular production. Thus, cells in culture do not achieve the benefit of the extracellular product and will continually produce the toxin external to the cell.

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Botulinum Toxin

Y.L. Leung , S.A. Burr , in Encyclopedia of Toxicology (Third Edition), 2014

Chronic Toxicity (and Exposure)

Human

Toxin type A is used for medical purposes (e.g., in the treatment of dystonia, hyperhidrosis, strabismus, and hypertonia due to neuromuscular disorders such as cerebral palsies). In the cosmetic industry, this toxin is used for the temporary removal of deep glabellar lines (wrinkles). The temporary action of botulinum type A toxin is due to the regeneration of motor end plates.

In Vitro Toxicity

Botulinum type B toxin entry into PC12 cells has been found to be mediated by synaptotagmins I and II, which act as receptor agonists for the toxin. For types A and E, this has not been found.

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Animal Venoms in Medicine

Z. Takacs , S. Nathan , in Encyclopedia of Toxicology (Third Edition), 2014

Diagnostics

Toxins are used in approximately 15 diagnostic assays in clinical hemostasis laboratories and as a test for myasthenia gravis. All toxins are originated from snake venoms ( Table 1).

Table 1. Clinical diagnostics derived from animal venom toxins

Test/Reagent name Species origin Mechanism of action Test for
anti-Cav2 antibodies assay Geography cone snail (Conus geographus) or Magician's cone snail (Conus magus) radioiodinated (Cg) ω-conotoxin GVIA or (Cm) ω-conotoxin MVIIC binding to Cav2.2, 2.1 respectively Lambert-Eaton myasthenic syndrome
Anti-nAChR antibodies assay Many-banded krait (Bungarus multicinctus) or 'Cobras' (Naja spp.) Radioiodinated (Bm) α-bungarotoxin or (N) cobratoxin binding to nAChR Myasthenia gravis
Anti-nAChR antibodies assay Monocellate cobra (Naja kaouthia) Eu3+-α-cobratoxin binding to nAChR Myasthenia gravis
BOTROCETIN® Neuwied's lancehead (Bothrops neuwiedi) or Jararaca (Bothrops jararaca) Induces von Willebrand factor (vWF) dependent platelet aggregation von Willebrand factor (vWF) level
Factor V activator (RVV-V) Russell's viper (Daboia russelii) Activates factor V Factor V determination
PEFAKIT® PiCT® Russell's viper (Daboia russelii) Activates factor V Anticoagulant activity based on factor Xa and/or factor IIa inhibition
PEFAKIT® APC-R Factor V Leiden Russell's viper (Daboia russelii); and Tiger snake (Notechis scutatus) (Dr) activates factor V; and (Ns) activates prothrombin Factor V Leiden mutation (FV:Q506)
PROTAC® Copperhead (Agkistrodon contortrix) Activates protein C Protein C and protein S levels
PROC® GLOBAL Copperhead (Agkistrodon contortrix) Activates protein C Protein C and protein S pathway abnormalities
CRYOCHECK™ CLOT C™ Copperhead (Agkistrodon contortrix); and Russell's viper (Daboia russelii) (Ac) activates protein C; and (Dr) activates factor X Protein C activity
CRYOCHECK™ CLOT S™ Copperhead (Agkistrodon contortrix); and Russell's viper (Daboia russelii) (Ac) activates protein C; and (Dr) activates factor X Protein S activity
REPTILASE® Time Common lancehead (Bothrops atrox) or Brazilian lancehead (Bothrops moojeni) Cleaves Aα-chain of fibrinogen Fibrinogen level and function; heparin contamination
Textarin time Eastern brown snake (Pseudonaja textilis) PL dependent prothrombin activator Activated protein C resistance; lupus anticoagulants
Textarin/ecarin ratio Eastern brown snake (Pseudonaja textilis); and Saw-scaled viper (Echis carinatus) (Pt) PL dependent prothrombin activator; and (Ec) activates prothrombin to meizothrombin in the absence of PL Confirmation of lupus anticoagulants
Ecarin clotting time Saw-scaled viper (Echis carinatus) Activates prothrombin to meizothrombin in the absence of PL Direct thrombin inhibitors; prothrombin quantification; lupus anticoagulants
Factor X activator (RVV-X) Russell's viper (Daboia russelii) Activates factor X Lupus anticoagulants; distinguishing between factor VII and factor X deficiency
SPECTROZYME® FXa Russell's viper (Daboia russelii) Activates factor X Factor X activity
STACLOT® APC-R Western rattlesnake (Crotalus oreganus) Activates factor X Activated protein C resistance
Stypven time (Russell's viper venom time) Russell's viper (Daboia russelii) Activates factor X Factor VII or X deficiency
Dilute Russell's viper venom time (dRVVT) Russell's viper (Daboia russelii) Activates factor X Lupus anticoagulants
Dilute Russell's viper venom confirm DVVCONFIRM® Russell's viper (Daboia russelii) Activates factor X; extra PL corrects dRVVT Confirmation of lupus anticoagulants
Taipan snake venom time Taipan (Oxyuranus scutellatus) Prothrombin activator, stimulated by PL Lupus anticoagulants

Note: Order is based on the molecular weight of the principal (or first) toxin molecule responsible for activity. The extent of utilization, test name, and classification varies. Per classification, some tests may overlap. Test variations exist (e.g., Taipan snake venom time/ecarin time). Only one brand name (in parentheses) is provided as an example. PL, phospholipid.

The vertebrate hemostatic system, a delicate interaction among thrombocytes (known also as platelets in mammalian vertebrates), endothelial cells, subendothelial structures, and plasma proteins is easily vulnerable to disruptive biochemical or biophysical factors. This very system is a major and multipoint target for toxins that can lead to lethal thromboembolic events or hemorrhage (Figure 2). The mechanism of action of toxins is often extremely similar to the corresponding physiological clotting factor, and they can activate or inactivate numerous phases of blood coagulation. Importantly, however, because of acting independently from cofactors, or by being resistant to inhibitors, or to proteolytic degradation, the target organism's own control mechanisms are ineffective against the action of toxins. As a result, toxins with defined mechanisms of action, restricted substrate specificity, and unaffected by the inhibitory pathways are valuable sources of diagnostic tools.

Figure 2. Viper venom targets blood coagulation. 20 min whole blood clotting test. Left: Healthy control. Right: Adult patient in Nepal, bitten by a suspected Mountain pit viper (Ovophis monticola) and displays signs of consumption coagulopathy (Photo: Dr Zoltan Takacs).

Current diagnostics are mostly enzymatic toxins; nonenzymatic examples are BOTROCETIN® or α-bungarotoxin. They are typically purified directly from the crude venom, thus subject to taxonomic, geographic variability, and possibly misidentification. For example, geographical variability in Russell's viper venom (D. russelii) has been attributed to variability in the test results. Additionally, presence of toxin isoforms in a single venom could complicate test reproducibility.

While some tests have limited use, venoms are used, for example, to identify factor V Leiden mutation, one of the most common hereditary procoagulant states. Dilute Russell's viper venom time is widely used to detect lupus anticoagulants, a major risk factor for arterial and venous thrombosis, accounting for ∼15% of patients with thromboembolic events. The availability of direct diagnosis (e.g., by sequencing) is expected to overtake the utilization of some toxin-based tests.

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Introduction to Clinical Neurotoxicology

Michael R. Dobbs , in Clinical Neurotoxicology, 2009

INTRODUCTION

Toxins are causes of neurological diseases from antiquity to contemporary times. Pliny described "palsy" from exposure to lead dust in the 1st century AD, one of the earliest known medical neurotoxic descriptions. 1 Although carbon monoxide has long been known to cause acute central nervous system (CNS) damage, it is only recently that we are finding delayed CNS injury in people poisoned by this molecule. 2

Toxins and environmental conditions are important and underrecognized causes of neurological disease. In addition to chemical toxins, extremes of cold, heat, and altitude all can have adverse effects on our bodies and nervous systems. As medical developments occur and scientific knowledge advances, new toxic and environmental causes of diseases are discovered.

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Harmful Algal Blooms

J.M. Burkholder , in Encyclopedia of Inland Waters, 2009

Complex mix of toxins

The toxins of Prymnesium parvum have been reported to include lipopolysaccharides (hemolysins), a galactoglycerolipid, polyene polyethers, cyclo amines (fast-acting ichthyotoxins), reactive oxygen species (H2O2, O 2 − , OH−), dimethylsulfoniopropionate (DMSP), and toxic fatty acids with assorted fish-killing, cytotoxic, hemolytic, hepatotoxic, neurotoxic, and/or antimicrobial (allelopathic) activity. Some of the toxins are only partially characterized; moreover, such a complex mixture makes it difficult to assess the influence of each toxic component, and there are conflicting accounts of required conditions (temperature and salinity, role of fish) for toxin production. Detection of toxins other than hemolysins also has been difficult, and some components are highly instable (e.g., the ichthyotoxins and hemolysins are light-sensitive). The toxins remain difficult to quantify as well, despite several decades of research, and routine methodologies have not been established to isolate and quantify the various toxic fractions. Two glycosidic toxins from P. parvum recently were chemically characterized as prymnesin-1 (C107H154Cl3NO44) and prymnesin-2 (C96H136Cl3NO35), and they have similar hemolytic activity. When released from P. parvum cells, the toxins form micelles and apparently require activation by cofactors, that can include dissolved potassium, calcium, magnesium, sodium, streptomycin, neomycin, spermine, or other polyamines.

Given this complex situation, what is the 'nutrient stress connection?' The toxins, including a mix of phosphate-containing proteolipids, are thought to be precursors of P. parvum structural membrane components, or products of imbalanced cell membrane metabolism. The hemolytic toxins accumulate within cells during exponential growth phase, and are released into the surrounding medium during stationary phase when growth is limited or stressed. High toxin activity occurs under Pi limitation apparently because formation of phospholipids for membrane synthesis is disrupted, leading to leakage of cellular metabolites including toxins. Nutrient stress (Pi or Ni limitation) has been shown to significantly increase P. parvum toxin production/release.

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Microbes and Plants

Walter K. Dodds , Matt R. Whiles , in Freshwater Ecology (Third Edition), 2020

These toxins can be responsible for a variety of problems, including illness of humans who drink water containing the toxins, death of dialysis patients dialyzed with water containing the toxins, dermatitis from skin contact, potential long-term liver damage from contaminated water supplies, and animal deaths from drinking water containing cyanobacterial blooms ( Falconer, 1999; Codd, et al., 1999). Cyanobacterial toxins could facilitate cancer by enhancing melanoma invasion of other cells (Zhang et al., 2012), and toxin concentrations also correlated with rates of nonalcoholic liver disease (Zhang et al., 2015). Cyanobacterial toxins can accumulate in fish and contaminate some of the largest freshwater fisheries in the world (Poste et al., 2011). At least 25 genera containing 40 species of cyanobacteria have members that produce toxins (Codd, 1995; Carmichael, 1997).

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Food Toxicology

S.L. Taylor , J.L. Baumert , in Encyclopedia of Agriculture and Food Systems, 2014

Botulism

Botulinal toxins are potent neurotoxins produced in foods under anaerobic conditions during growth of Clostridium botulinum (Parkinson and Ito, 2002). Toxin formation occurs in underprocessed canned foods. The commercial canning process is predicated on the destruction of C. botulinum and its spores so that the spores will not germinate, grow, and produce toxin on storage of the canned product. Canned foods are especially susceptible because of the anaerobic conditions. Seven different toxin-producing strains of C. botulinum have been identified, but types A, B, and E are the strains most commonly associated with foodborne illness (Parkinson and Ito, 2002). The botulinal toxins are proteins with a molecular mass of approximately 150   kDa (Parkinson and Ito, 2002). The botulinal toxins exert their neurotoxic effect by inhibiting the release of acetylcholine at the nerve synapses. Thus, the peripheral nervous system is affected. Botulinal toxins are among the most potent toxins known to humans. In cases of botulism, clinical symptoms begin to develop 12–48   h after exposure to the toxin with weakness, dizziness, and mouth dryness occasionally accompanied by nausea and vomiting. Neurological symptoms follow, including blurred vision, inability to swallow, aphasia, and weakness of the skeletal muscles. Symptoms can ultimately progress to respiratory paralysis and death. The vegetative cell of C. botulinum and the botulinal toxins are easily destroyed by heat, but the spores are heat resistant. When thermal processing (canning) is not properly performed, spores will survive, germinate, and grow if suitable anaerobic conditions exist (Parkinson and Ito, 2002).

Infant botulism is a different but related illness where the spores enter the gastrointestinal system early in life before competitive intestinal microflora are in place to resist their germination and growth (Parkinson and Ito, 2002). The growth of C. botulinum ensues in the intestinal tract. Toxin production then occurs in the intestinal tract of the infant and causes severe illness. Infant botulism is avoided by limiting the intake of spores by infants. Honey is a frequent source of the spores in the infant diet (Parkinson and Ito, 2002).

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