Background information
Cyanotoxins
Some cyanobacteria produce potent toxins and are thus a threat to human health either through contaminated drinking water or bathing in infested water bodies.
Cyanotoxins can be grouped according to their mode of action into:
- Hepatotoxins (microcystins, nodularins)
- Cytotoxins (cylindrospermopsins)
- Neurotoxins (anatoxins, saxitoxins)
- Dermatoxins (aplysiatoxin, lyngbyatoxin)
- Inflammatory substances (lipopolysaccharides)
In addition, cyanotoxins can be grouped according to their chemistry such as peptides (e.g. microcystins), alkaloids (e.g. anatoxins) and lipopolysaccharides.
Below you will find short fact sheets about the different types of toxins.
Microcystins
Chemistry. Microcystins are cyclic heptapeptides with the characteristic amino acid ADDA (3-Amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadiensäure) unique to microcystins and nodularins. To date more than 90 microcystin congeners (substances with the same basic structure) which differ primarily due to exchange of amino acids (especially at positions 2 and 4) and (de)methylation at several positions in the molecule have been described. Their nomenclature is based on the amino acids in positions 2 and 4, e.g. one of the most abundant microcystins, MC-LR, contains leucine (L) at position 2 and arginine (R.) at position 4.
Microcystins are largely cell-bound and released from the producer-cells only during cell die-off. Chemically, microcystins are very stable and cannot be destroyed by boiling of the water. Biologically, microcystins are degraded with half-lives of ~ 1- 4 days, often after a lag phase of a few days up to two weeks.
Producing cyanobacteria. Microcystins are primarily produced by members of the genera Microcystis, Planktothrix, Dolichospermum, Anabaena, and Nostoc.
Cyanobacteria having the microcystin-synthetase gene always produce microcystins independent of environmental factors.
Toxicity. Animal studies on the acute toxicity of microcystins has mainly shown severe damage of the liver, but the small intestine and the kidneys are also affected. The uptake of microcystins is through the bile-acid carrier which is largely found in the liver and to a smaller extent also in the small intestine epithelia. In the liver, microcystins damage the liver cells and capillaries leading to liver haemorrhages and finally to heart failure and death.
The basic mechanism of microcystin toxicity is the specific and irreversible inhibition of the protein phosphatases PP1 und PP2A. LD50 (intraperitoneal, i.p.,route, 24h exposure, 1) values range according to congener between 50 (MC-LR) and 600 (MC-RR) µg/kg body weight. Oral LD50-values are much higher (e.g. MC-LR 5000 µg/kg). Furthermore, microcystins promote the growth of tumours in the liver and intestine of animals and have been classified as possibly carcinogenic to humans (Group 2b) by the IARC (2006).
Guideline values. WHO recommends provisional guideline values (GV) which have been derived from toxicological data for Microcystin-LR, but due to the lack of toxicological data for other congeners the GV can be (as a conservative approach) applied to all congeners in a sample:
• for drinking water 1 µg/l for a daily lifetime exposure and 12 µg/l for a short-term exposure (daily over a two-week period, but only once in a season)
• for recreational water 24 µg/l
More information on the derivation of the guideline values can be found here.
Microcystin-LR
Nodularins
Chemistry. Nodularins are cyclic pentapeptides containing the characteristic ß-amino acid ADDA (3-Amino-9-methoxy-2,6,8-trimethyl-10-phenyl-4,6-decadiensäure) like microcystins. In contrast to microcystins only a few nodularin-congeners have been found to date, among which nodularin-R seems to be the most abundant.
Producing cyanobacteria. Nodularins have been found in the cyanobacterium Nodularia spumigena which occurs in brackish waters worldwide.
Toxicity. Nodularins are hepatotoxic and inhibit protein phosphatases PP1 und PP2A. In addition, nodularins are tumor promoting as well as carcinogenic. Though the acute toxicity of nodularin-R is similar to microcystins, no guideline value for nodularin in drinking water can be derived due to a lack in oral toxicological data.
Guideline value. Sufficient toxicological data are lacking for the derivation of a guideline value (GV) for nodularins.Tentatively, the microcystin GV can be applied due to the structural and toxicological similarity between microcystins and nodularins. New Zealand recommends 1 µg/l nodularin as a GV for drinking water.
Nodularin
Cylindrospermopsins
Chemistry. Cylindrospermopsin (CYN) is an alkaloid consisting of a tricyclic guanidine moiety combined with hydroxymethyluracil. Four more congeners are known 7-epi-CYN, 7-deoxy-CYN, 7-deoxy-desulfo-CYN and 7-deoxy-desulfo-12-acetyl-CYN. CYN is relatively stable at high temperatures and pH. Due to its zwitterionic nature, CYN is highly water soluble and is often found largely dissolved in the water. Biodegradation has been demonstrated for CYN, but in some water bodies the toxin has been found to be very persistent. Biodegradation seems to depend on temperature and pH.
Producing cyanobacteria. Cylindrospermopsin can be produced by (mostly nostocalean) cyanobacteria including Raphidiopsis (form. Cylindrospermopsis) raciborskii, Raphidiopsis sp., Aphanizomenon gracile, Chrysosporum (form. Aphanizomenon) ovalisporum, Aphanizomenon flos-aquae and_Umezakia natans.
Toxicology. Acute intoxication with cylindrospermopsin leads to severe liver damage, but other organs including the kidneys, lung, heart and thymus are also affected. The basic mechanism of cylindrospermopsin toxicity is a specific and irreversible inhibition of protein biosynthesis. CYN is also genotoxic and evidence exists for its carcinogenicity.
The LD50(i.p.) of CYN is around 2100 µg/kg from a single dose within 24h and decreases to 200 µg/kg after seven days with daily dosage. The oral LD50 is much higher (5000 µg/kg). 7-epi-CYN and 7-deoxy-CYN seem to have a similar toxicity.
Guideline values. WHO recommends the following provisional guideline values (GV) for cylindrospermopsin:
• for drinking water 0.7 µg/l for a daily lifetime exposure and 3 µg/l for a short-term exposure (daily over a two-week period, but only once in a season)
• for recreational water 6 µg/l
Also for cylindrospermopsin WHO recommends to apply the GV (derived for cylindrospermopsin) to the other congeners (or sum of). More information on the derivation of the guideline values can be found here.
Cylindrospermopsin
Anatoxins
Chemistry. Anatoxin-a (ATX-a) and homoanatoxin-a (HATX-a) as well as their dihydro derivatives are bicyclic amines. Anatoxin-a(s) is a natural organophosphate.
Producing cyanobacteria. ATX-a and HATX-a as well as their dihydro derivatives are produced by different cyanobacteria belonging to the genera Dolichospermum, Anabaena, Oscillatoria, Phormidium, Microcoleus, Tychonema, Aphanizomenon and Cylindrospermum, ATX-a(s) has been detected so far only in Anabaena.
Toxicology. All anatoxins are potent neurotoxins. Anatoxin-a and homoanatoxin-a as well as their dihydro derivatives act as analogues of acetylcholine. Intoxications result in a very rapid (minutes to a few hours) onset of convulsions, and death by respiratory paralysis. The LD50 for ATX-a and HATX-a are around 300-650 µg/kg (i.p.), the oral LD50 is higher (~ 3000-6000 µg/kg). First studies point to a similar toxicity of the dihydro-variants of ATX-a and HATX-a.
Anatoxin-a(s) inhibits acetylcholinesterases irreversibly leading to salivation, tremors, ataxia, convulsions and finally to death by respiratory paralysis within minutes to hours. The LD50 (i.p.) for ATX-a(s) 20 µg/kg.
No other major effects than neurotoxicity have been observed for anatoxin-a in acute, short-term or sub-chronic exposure studies.
Guideline values. Due to the lack of comprehensive toxicological data no guideline value (GV) can be derived for anatoxins. However, WHO provides a provisional health-based reference value for ATX-a:
• for drinking water 30 µg/l for acute and short-term exposure (no definition of “short-term”, but with the annotation that this concentration did not cause adverse health effects in a 28-days animal study). For the preparation of baby food 6 µg/l are recommended.
• for recreational water 60 µg/l
Canada and New Zealand recommend 3.7 µg/l and 6 µg/l for ATX-a, resp. New Zealand recommends 2 µg/l for HATX-a and 1 µg/l for ATX-a(s) in drinking water.
More information on the derivation of the guideline values can be found here.
Anatoxins
Paralytic shellfish poisons
Chemistry. Paralytic Shellfish Poisons (PSP) are a group of neurotoxic alkaloids with more than 20 congeners. They were originally isolated from marine dinoflagellates and are also named after the first congener isolated: saxitoxins.
Producing cyanobacteria. Production of PSP has been found in Aphanizomenon, Dolichospermum, Lyngbya, Raphidiopsis and Cylindrospermopsis.
Toxicology. PSPs act on the sodium channels of nerve cells preventing signal transmission, finally leading to death by respiratory paralysis. In humans, the toxins are excreted relatively quickly so that chronic effects due to PSP are unlikely. The LD50 (i.p.) of saxitoxin is 10 µg/kg, the oral LD50 is ~230 µg/kg.
So far, there are no reports of human intoxications due to water containing PSP-producing cyanobacteria. However, risks due to these toxins may be expected in situations of bathing accidents (“near-drowning”) during blooms of PSP-producing cyanobacteria.
Guideline values. WHO uses for the derivation of guideline values for saxitoxins primarily human data from seafood intoxications and are thus related to acute toxicity:
• for drinking water 3 µg/l – short-term value for acute exposure and bottle-fed infants;
• for recreational water 30 µg/l
Some countries (Brazil, New Zealand) recommend 3 µg/L (as STX-equivalents) for drinking water.
More information on the derivation of the guideline values can be found here.
Saxitoxin
Lynbyatoxin and Aplysiatoxin
Chemistry. Aplysiatoxin, debromoaplysiatoxin and lyngbyatoxin are all alkaloids. The name “Aplysiatoxin” relates to the marine snail Aplysia californica, which incorporates cyanobacteria and uses the toxin as a defence against enemies.
Producing cyanobacteria. Aplysiatoxin and debromoaplysiatoxin have been detected in different members of the genera Lyngbya, Schizothrix and Oscillatoria. Lynbyatoxin-a is produced by Lyngbya majuscula. All of these cyanobacteria can colonise the bottom or other surfaces of marine environments, in which bathers can easily come into contact with these mat-forming cyanobacteria.
Toxicology. Aplysiatoxins and lyngbyatoxin-a cause more or less severe dermatitis (e.g. “seeweed dermatitis” caused by lyngbyatoxin), and both activate proteinkinase C and are suspected tumour promoters.
Guideline value. No official GVs exist.
Lyngbyatoxin and Aplysiatoxin
Lipopolysaccharides
Chemistry. Lipopolysaccharides (LPS) or endotoxins are large molecules consisting of a lipid and a polysaccharide moiety. They are the major compounds of the outer membrane of Gram-negative bacteria and therefore also of cyanobacteria.
Producing cyanobacteria. All cyanobacteria.
Toxicology. Lipopolysaccharides of Gram-negative bacteria (e.g. Salmonella typhii) can cause severe physiopathological effects including fever, septic shock or multiple organ failure. Studies of the toxicity of LPS from Microcystis, Anabaena, Cylindrospermopsis and Phormidium, however, indicate that the cyanobacterial LPS are substantially less toxic than that of the other Gram-negative bacteria. No confincing evidence exist for cyanobacterial LPS being responsible for the more unspecific symptoms associated with cyanobacteria (gastrointestinal, dermatological or allergic reactions).
Guideline value. No official GVs exist.
Beta-methylamino-L-alanine (BMAA)
Beta-methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid produced by some cyanobacteria. Several toxicological studies indicate BMAA to be neurotoxic, however, other studies have found no indication of neurotoxicity. Also the relationship between the exposure to BMAA and the development of neurodegenerative diseases includinglike the amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS-PDC) is discussed controversially. Finally, while earlier studies report cyanobacteria to contain high amounts of BMAA, recent studies found no or lesser amounts of BMAA or its derivatives.
In conclusion, for a comprehensive risk assessment of BMAA in drinking and bathing water toxicological standard tests with subchronic oral dosing in combination with a comprehensive knowledge about the occurrence of BMAA in cyanobacteria and water bodies, as well as its behaviour during drinking water treatment are needed.
Beta-Methylamino-L-Alanine
[1] LD50
The median lethal dose of a substance, or the amount required to kill 50% of a given test population.