Nodularin R

Firefighting Protective Equipment: Wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes.

Extinguishing Media: Suitable: Water spray. Carbon dioxide, dry chemical powder, or appropriate foam.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a POTW is acceptable only after review by the governing authority. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must meet Hazardous Material Criteria for disposal.

Procedure to be followed in case of leak or spill: Evacuate area.

Procedure(s) of personal precaution(s): Wear self-contained breathing apparatus, rubber boots, and heavy rubber gloves.

Methods for cleaning up: Sweep up, place in a bag and hold for waste disposal. Avoid raising dust. Ventilate area and wash spill site after material pickup is complete.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Observe all federal, state, and local environmental regulations.

User exposure: Do not breathe dust. Do not get in eyes, on skin, on clothing. Avoid prolonged or repeated exposure.

Procedure(s) for personal precaution(s): Wear self-contained breathing apparatus, rubber boots, and heavy rubber gloves.

General hygiene measures: Wash contaminated clothing before reuse. Wash thoroughly after handling.

Dermal exposure: In case of skin contact, flush with copious amounts of water for at least 15 minutes. Remove contaminated clothing and shoes. Call a physician.

For more Preventive Measures (Complete) data for Nodularin (7 total), please visit the HSDB record page.

Personal Protective Equipment: Respiratory: Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Hand: Compatible chemical-resistant gloves. Eye: Chemical safety goggles.

Personal Protective Equipment: Hand: Compatible chemical-resistant gloves.

Personal Protective Equipment: Eye: Chemical safety goggles.

Nodularin and microcystin-LR are cyanobacterial toxins and environmental hazards. Nodularin inhibits protein phosphatases 1 and 2A with the same potency as does microcystin-LR, which has recently been identified as a potent tumor promoter in rat liver. ... A two-stage carcinogenesis experiment in /male F344/ rat liver initiated with diethylnitrosamine and without partial hepatectomy revealed that nodularin stimulated glutathione S-transferase placental form-positive foci in rat liver more effectively than did microcystin-LR, and that nodularin alone induced glutathione S-transferase placental form-positive foci as well as did diethylnitrosamine alone. Thus, nodularin itself is a new liver carcinogen, and microcystin-LR is a tumor promoter rather than a carcinogen. Nodularin induced hyperphosphorylation of cytokeratin peptides 8 and 18 in primary cultured rat hepatocytes 20% more effectively than did microcystin-LR, suggesting that nodularin penetrates more easily into the hepatocytes than does microcystin-LR. Nodularin up-regulated induction of c-jun, jun-B,jun-D,c-fos,fos-B, and fra-1 mRNA transcripts in rat liver after i.p. administration, and the accumulation of the mRNA transcripts was sustained for over 9 hr after treatment. The environmental hazards of cyanobacterial toxins are discussed in relation to human primary liver cancer in Qidong county in the People's Republic of China...

... The effect of nodularin (1, 5, and 10 ug/kg bw) and melatonin (5, 10, and 15 mg/kg bw) administration on the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) /were examined/ in mouse liver. Intraperitoneal treatment of mice with nodularin per 7 days decreased the activities of all estimated enzymes in a dose-dependent manner. Intraperitoneal treatment of animals with melatonin per 7 days increased the activities of SOD, CAT, and GSH-Px and this effect was concentration-dependent. Co-treatment (nodularin 5 ug/kg bw + melatonin 5, 10, and 15 mg/kg bw per 7 days) and post-treatment with melatonin (nodularin 5 ug/kg body weight per 7 days + melatonin 5, 10, and 15 mg/kg bw per next 7 days) increased the activities of SOD, CAT, and GSH-Px in comparison to the nodularin group. No significant differences from the nodularin group were noted in the group after pre-treatment with melatonin. In conclusion, these findings suggest that oxidative damage may be involved in the toxicity of nodularin. Moreover, co-treatment and post-treatment with 10 and 15 mg/kg bw of melatonin may protect against nodularin-induced oxidative stress. There was no protective effect of pre-treatment with melatonin.

The site of action of microcystins is the hepatocyte, the commonest cell type in the liver. They act by disrupting the cytoskeleton, the adaptable protein framework that constantly shapes and reshapes the cell as it responds to the environment. The cells die and this destroys the finer blood vessels of the liver leading to massive hepatic bleeding. The molecular target are a group of enzymes called protein phosphatases that play a role in regulating protein interactions and activities. Very well-defined types of protein phosphatase (type 1 and type 2A) are inhibited very specifically by very low concentrations of microcystins. This enzyme removes phosphate from a protein, a common step in many biochemical pathways. This inhibition, with subsequent build up of phosphorylated proteins, is believed to be a mechanism by which microcystins destroy livers. Microcystins also activate the enzyme phosphorylase b, which plays a very important role in the affairs of the hepatocyte. The combination of inhibition and activation is rapidly lethal to the cell. The specificity of some of these toxins makes them valuable research tools.

/BIRDS and MAMMALS/ Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea during the summer season. Nodularia blooms have caused several animal kills in the Baltic Sea area, and NODLN has been found in mussels and fish caught from the northern Baltic Sea in 1996 to 2002. We analyzed liver samples of common eider (Somateria mollissima) for NODLN by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography/mass spectrometry (LC-MS). Eiders feed extensively on mussel and can be exposed to NODLN by contaminated mussels. Fifteen eiders were shot and collected from three different sites in the western Gulf of Finland (northern Baltic Sea) in August and September 2002. Analyses by ELISA and LC-MS showed that eider liver samples contained 3 to 180 ug NODLN/kg dry weight and 0.1 to 5.8 ug NODLN/liver (dry wt). This is the first documentation of NODLN in seabirds and additional evidence for the transfer of NODLN in different parts of the Baltic Sea food web.

/AQUATIC SPECIES/ ... Baltic sea trout (Salmo trutta m. trutta L.) were exposed orally to a single dose of food containing nodularin (NODLN) (125 mg/kg ww) from N. spumigena (strain AV1, from the Baltic Sea). The level of exposure was 210-620 (average 440) ug NODLN per kg bw. Based on an 8-day survey under laboratory conditions, NODLN-like compounds accumulated in trout liver, with increasing liver concentrations (from 19 ug/kg on day 1 up to 1200 ug/kg on day 8 as measured with the EnviroLogix ELISA kit) during the experiment. Thus, accumulation of NODLN-like compounds in liver increased from 0.05% of the total NODLN dose administered on day 1 to 0.53% on day 8. However, the ELISA test kit is also sensitive to metabolites of algal hepatotoxins. In the HPLC chromatograms, no NODLN peak was detected after 24 hr that also suggested NODLN absorbed in trout was metabolized or bound rapidly. According to ELISA, NODLN-like compounds also accumulated in trout muscle in lower quantities (from 125 to 34 ug/kg dw). Histopathology revealed complete loss of liver architecture after 1-2 days of the single oral dose. From day 4 to 8, there was partial recovery of liver cells. NODLN did not affect thiamine levels or water content of trout liver. The results showed that NODLN rapidly induces severe but reversible liver damage...

/AQUATIC SPECIES/ The toxicity and metabolism of the cyanobacterial toxins microcystin-LR (MCLR), Dhb-microcystin-HtyR and nodularin were investigated in the cysts, nauplii and adults of the brine shrimp Artemia salina. The presence of the phase II detoxication system glutathione S-transferase (sGST) in these stages was shown using different substrates. Exposure of adult A. salina to the toxins led to an elevation of GST activity in vivo. All three toxins were conjugated to glutathione via GST, which has been shown as an initial step of microcystin and nodularin detoxication.

/AQUATIC SPECIES/ In this laboratory study the effects of the cyanobacterium Nodularia spumigena (strain AV1) that produces hepatotoxic nodularin (NODLN), non-toxic Nodularia sphaerocarpa (strain UP16f) and purified NODLN on the infaunal clam Macoma balthica from the Baltic Sea were examined. N. sphaerocarpa (2.4 and 12.5 mg dw l(-1)), N. spumigena (4 and 20 mg dw/L, intracellular NODLN content ca. 4 and 20 ug/L and purified NODLN (10 and 50 ug/L) were applied in experimental tanks at 24 hr intervals for 96 hr. Water samples were taken during the experiment for the measurement of soluble NODLN concentrations. The concentrations of total hepatotoxins in the soft tissues were analyzed with enzyme-linked immunosorbent assay (ELISA) and NODLN with high-performance liquid chromatography/diode array detection (HPLC/DAD). Acetylcholinesterase (AChE) activity was measured from the foot tissue samples taken at 0, 24 and 96 hr. In the water phase, 60-100% of NODLN in the pure-toxin treatments and all the NODLN in N. spumigena treatments appeared as a yet unidentified form with NODLN-like spectral characteristics. The compound was present in similar quantities also in the non-toxic N. sphaerocarpa treatments. In the toxic N. spumigena treatments the tissue concentration of hepatotoxic NODLN-like compounds (measured with ELISA) increased from the control levels of 0.16 to 16.6 ug/g dw (24 hr), reaching 30.3 ug/g dw at 96 hr. However, < 5% of the toxin detected by ELISA could be shown to be NODLN in HPLC/DAD analysis. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS) analyses revealed no NODLN-glutathione (GSH) conjugates in the tissues of M. balthica. Combining the responses in the AChE activity recorded after 24 and 96 hr exposure, increases by 46% (N. spumigena) and 36% (soluble NODLN) compared with the control activity were observed in the low-level toxic exposures. Oppositely, decreases by 19% (N. spumigena) and 27% (soluble NODLN) of control activity were observed in the high-level exposures. Only the differences between the increased and decreased AChE activities were statistically significant, with individuals exposed to high levels expressing approximately 55% of the activity of those exposed to low concentrations. The results show that M. balthica readily ingests toxic N. spumigena and that accumulation of peptides takes place rapidly, which has potential food chain effects through toxin enrichment. However, it appears that M. balthica is at least partly able to metabolize NODLN. In addition to hepatotoxicity, NODLN seems to induce concentration-dependent neurotoxic effects; this must be taken into consideration when applying AChE activity as a biomarker of specific anthropogenic contamination (e.g. organophosphate and carbamate pesticides).

Analysis of liver samples of 15 common eider (Somateria mollissima) from the western Gulf of Finland (northern Baltic Sea) collected in August-September, 2002, showed that eider liver samples contained 3 to 180 ug NODLN/kg dry weight and 0.1 to 5.8 ug nodularin/liver (dry wt)(1).

Thirty eiders (Somateria mollissima) were caught from the western Gulf of Finland between September 2002 and October 2004. Eiders from April to June 2003 were found dead. Nodularin was detected in 27 eiders; liver samples contained nodularin up to approximately 200 ug/kg dry weight and muscle samples at approximately 20 ug/kg dry weight(1).

Nodularin is a potent heptatoxin and tumor promoter. It is classified as a cyclic pentapeptide produced in large quantities by the cyanobacterium Nodularia spumigena and found living in mussels in several locations including the Baltic Sea, Australia, and brackish water lakes of New Zealand(1,2). Nodularin is produced by field and laboratory-cultured N. spumigena(3).

Nodularins are cyclic peptide toxins that have a ring structure of seven and five amino acids, respectively, which comprise one unique phenyl deca-dienoic acid, four invariable D-amino acids ... There are ... several variants of nodularin. These peptides are produced naturally by cyanobacteria, an evolutionarily very ancient group of photosynthetic prokaryotic organisms. The bacteria occur in filamentous and coccoid forms in free suspension in water or form layers (scums) on surfaces; they are distributed worldwide in water and soils, and on rock and plant surfaces ... Nodularin occurs in brackish waters. The concentration of toxin in water depends on the cell content of ... nodularins and the concentration of cells in the water. The peptide toxins are contained primarily within the cyanobacterial cells and are rarely released before the cells die or are destroyed (for instance, following water treatment or in the stomach, after ingestion). Due to widespread eutrophication in many settings, these toxins may occur more frequently and at unnaturally high concentration. In natural water bodies and in water storage reservoirs, the concentrations of toxin vary widely from undetectable to several milligrams per liter in cyanobacterial scums.

Nodularin is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea during the summer season. Nodularia blooms have caused several animal kills in the Baltic Sea area, and nodularin has been found in mussels and fish caught from the northern Baltic Sea in 1996 to 2002(1).

/SIGNS AND SYMPTOMS/ Most documented cases of human injury through cyanotoxins involved exposure through drinking-water, and they demonstrate that humans have become ill-in some cases seriously- through ingestion or aspiration of toxic cyanobacteria. Symptoms reported include abdominal pain, nausea, vomiting, diarrhea, sore throat, dry cough, headache, blistering of the mouth, atypical pneumonia and elevated liver enzymes in the serum, as well as hay fever symptoms, dizziness, fatigue, and skin and eye irritations. /Cyanotoxins/

/OTHER TOXICITY INFORMATION/ Nodularia spumigena was the first cyanobacterium recognized to cause animal death. The toxin produced by N. spumigena, called nodularin, acts as a hepatotoxin, in that it induces massive haemorrhages in the liver of mammals and causes disruption of the liver structure. To date, there have been no reports of human poisoning by N. spumigena, but humans may be as susceptible to the toxins as other mammals. Therefore, it is possible that small children may accidentally ingest toxic material in an amount that may have serious consequences.

Seasonally variable concentrations of nodularin toxin have been detected in the field depending on the size and location of cynaobacterial and algae blooms. Nodularin was detected in three-spined sticklebacks (35-170 ng/g), salmon/herring (2-6 ng/g), cod/flounder (25-400 ng/g. Mysid shrimp where also shown to accumulate nodularin in the laboratory(1). Aquatic biota exposed through natural routes have also shown concentrations of nodularin. Nodularin concentrations in flounder were 0.82-6.37 ug/g dried liver, in mussels 2.15 ug/g, and clams 0.1-0.13 ug/g(2).

Nodularin concentrations in Northern Baltic sea flounder livers collected on July 11, August 15, August 22, September 5, September 19, and September 27, 2002 were 250, 50, 15, 20 100, and 75 ug/kg dry weight, respectively. Sampling was conducted in response to intense cyanobacterial blooms in the Gulf of Finland in July-August 2002, consisting of Nodularia spumigena, Aphanizomenon sp., and Anabaena sp. Nodularin has been found to bioaccumulate in the Northern Baltic sea flounder due to their consumption of blue mussels(1).

Eleven roach and 15 flounders were caught from the western Gulf of Finland (northern Baltic Sea) between September 2002 and October 2004. Nodularin was detected in nine roach and eight flounders. Roach liver samples 20 to 900 ug nodularin/kg dry weight and muscle samples 2 to 200 ug nodularin/kg dry weight; flounder liver samples approximately 5 to 1,100 ug nodularin/kg dry weight and muscle samples up to 100 ug nodularin/kg dry weight(1).

AEROBIC: Nodularin, incubated of in the presence of the bacterial isolates did not reveal any degradation. However, natural microbial communities from sediment removed the toxin within 5-7 days(1).

AEROBIC: Nodularin was completely biodegraded in 18 days when incubated in water from Loch Roscobie, UK (frequently supports microcystin-containing blooms). When incubated in water from Forfar Loch, UK (eutrophic, no past history of algal bloom), the compound was 80% degraded in 24 days; biodegradation was preceded by a lag time of 15 days, after which degradation proceeded rapidly. No biodegradation was observed using water from River Carron, UK (no past blooms). Water samples were collected in March 2005 and August 2005. Proposed pathways for biodegradation of nodularin were via demethylation, decarboxylation, and/or hydrolysis(1).

Nodularin is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea during the summer season. Nodularia blooms have caused several animal kills in the Baltic Sea area, and nodularin has been found in mussels and fish caught from the northern Baltic Sea in 1996 to 2002.

Nodularin is produced by field and laboratory-cultured Nodularia spumigena

Potent inhibitor of protein phosphatases types 1 and 2A. Tumor promoter in experimental animal model.

Drinking water disinfection by chlorine is known to reduce concentration of microcystin, but compounds formed (dihydroxy-microcystin, monochloro-hydroxy-microcystin, monochloro-microcystin, monochloro-dihydroxy-microcystin, dichloro-dihydroxy-microcystin and trichloro-hydroxy-microcystin) are rarely considered. In this work the chlorination of microcystin-LR has been studied by monitoring reactants consumption and reaction products using the linear trap quad-Orbitrap (LTQ-Orbitrap) technology. Microcystin-LR was totally transformed within 2 min, meanwhile chlorine was consumed until 30 min with a rate of 12 M/M of toxin. Four new by-products of microcystin-LR were identified as well as their isomers: monochloro-microcystin, monochloro-dihydroxy-microcystin, dichloro-dihydroxy-microcystin and trichloro-hydroxy-microcystin. In addition, four new isomers were also observed, corresponding to the dihydroxy-microcystin already known. Besides, another compound previously observed was identified as monochloro-hydroxy-microcystin.

The hepatotoxins are produced by various species within the genera Microcystis, Anabaena, Oscillatoria, Nodularia, Nostoc, Cylindrospermopsis, and Umezakia, although not all strains do so. Most hepatotoxins (all cyclic heptapeptides) are microcystins. At least 50 congeners of microcystins are known, and several of these may be produced during a bloom. The chemical structure of microcystins includes two variable amino acids and an unusual aromatic amino acid, ADDA (3-amino-9- methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid), containing a substituted phenyldecadienoic acid. Different microcystins have different lipophilicities and polarities, which could affect their toxicity. ... Microcystis and Anabaena blooms occur widely in the temperate regions of the world. In general, 50-75% of bloom isolates can produce toxins, often with more than one toxin being present. Toxic and non-toxic blooms of the same species can be found together.